Section I.

Cancer Basics

Chapter 1. Genomics of Cancer

Chapter 2. Cancer Risk and Prevention
Chapter 3. Cancer Screening and Detection
Chapter 4. Cancer Diagnosis and Staging
Chapter 5. Pharmacogenomics
CHAPTER

Genomics of
1 Cancer
Julia A. Eggert, PhD, RN, AGN-BC, GNP, AOCN ®, FAAN (SC)

Introduction unique rates of growth, an assortment of undiffer-

entiated or differentiated cells in the same tumor,
Today, nurses in the oncology clinical setting a mixture of the cells’ sensitivities to detection, dif-
recognize they need more than a generalized ferent capacities to spread or metastasize, use of a
medical–surgical knowledge of cancer to provide variety of treatments or treatment types, therapy
personalized care for a patient being treated for responses, and finally multiple prognoses over time
a malignancy. The plan of care for a patient with due to transition of cancer cells, such as estrogen
cancer is based on a nurse’s specialized knowledge receptor–positive biomarkers in breast cancer to
and ability to anticipate signs and symptoms of the triple-negative biomarkers (Hassanpour & Deh-
emerging and changing biology of a cancer diag- ghani, 2017; MedicineNet, 2021).
nosis. This includes the provision of rationale for This chapter will describe the malignant changes
transformations occurring in the patient. Other of a cell and the resultant new biology of cancer
knowledge is comprised of an understanding of compared to a healthy cell. This information will
the initiation and progression of cancer, inflam- provide nurses new to oncology with a foundation
mation and its role in carcinogenesis, the multiple for understanding the development and growth of
types of cancer, the implications of that specific dis- cancer and its treatment and the basis to provide
ease diagnosis for the patient’s assessment, diagno- education to patients and families.
sis of a problem to be addressed by a nurse, how to
develop a specialized plan of care, identification of
appropriate interventions with personalized goals Background
for effectiveness, and how to evaluate the outcomes.
To emphasize, this long list of information needs Even though the same labels can describe the
to be anticipated and implemented by the knowl- characteristics and function of both healthy and
edgeable nurse in oncology. abnormal cells with cancer (malignancy), wide
A cancer diagnosis was once believed to be a variation exists in how they appear and function
single disorder. Today, it is known to be a complex (see Table 1-1).
diagnosis, with the potential to include multiple Knowledge of cancer as a disease has evolved
different diseases (some authors quote as few as from a characterization of six hallmarks identified
100 and as many as 277), many interactive causes, from studies in mouse models and cultured cells.
and occurrence at different ages throughout the life These are self-sufficiency in growth signals, insensitivity
span. The different types of cancer may also have to antigrowth signals, evasion of apoptosis with limit-

3
4 | SECTION I. CANCER BASICS

TABLE 1-1
COMPARISON OF HEALTHY CELLS AND CANCER CELLS
Characteristics Healthy Cell Cancer Cell

Shape Regular Irregular

Nucleus Proportionate size Larger, darker

Growth In control, systematic Out of control

Death Apoptosis or cell suicide –

Maturation Mature (cell differentiation) Immature, does not mature

Communication Communicates Does not communicate

Visibility Invisible to immune cells, cell Invisible to immune cells

surface identification

Blood supply Angiogenesis during repair Tumor angiogenesis

Oxygen Requires oxygen Does not like or require oxygen

(anaerobic)

Glucose Requires some glucose Craves glucose

Energy efficiency Very high (95%) Very low (5%)

Amount of adenosine triphosphate 38 units 2 units

Cell environment Alkaline Acidic

Nutrient preference Fat, ketone, glucose Glucose

less replicative potential, sustained angiogenesis, tis- trolled proliferation, spread, or metastasis (Sapi-
sue invasion, and metastasis (Fouad & Aanei, 2017). enza & Issa, 2016).
In 2011, more hallmarks were added to make a Carcinogens are chemical substances, or a mix-
total of 11. These included reprogramming energy ture of chemical substances, which can induce can-
metabolism and evasion of the immune response. Two cer after inhalation, ingestion, dermal application,
enabling traits of genome instability and mutation or injection. These substances can increase cancer
plus tumor-promoting inflammation were also added incidence or shorten time to tumor occurrence by
(Zhong et al., 2020). any dosage level, by any route, in any species of
Genetic alterations of cancer could be caused animals, compared to controls (Bordonaro, 2019;
by nurture. This concept includes obesity, lack of Calabrese et al., 2021). Environmental and chemi-
exercise, poor diet, and social habits, such as smok- cal human carcinogens include aflatoxins, asbes-
ing. All of these changes found in the microenvi- tos, nitrosamines, alcohol, and tobacco (Fishbein
ronment of cancer led to the decision that malig- et al., 2021).
nant growth results from changes in DNA, gene Studies on anti-inflammation have identified a
transcription, or gene translation. The resultant new superfamily of endogenous and specialized
defective protein or proteins transform healthy cells, known as pro–resolving lipid mediators or
cell components, with the cell developing uncon- resolvins. They have a strong novel inflammation
 Chapter 1. Genomics of Cancer | 5

clearing activity without being immunosuppres- depict the transformation of cells. Theories and
sive (Fishbein et al., 2021). This is unlike most models that describe carcinogenesis as a genetic
anti-inflammatory agents, including nonsteroidal disease include somatic mutation theory, multi-
anti-inflammatory drugs ibuprofen and celecoxib, stage models, two-hit theory, and evolutionary
that directly suppress cyclooxygenase enzyme activ- models.
ity. The pro-resolving lipid mediators serve as brake Theories describe the development of cancer
signals to turn off inflammation and act by clearing or unregulated cell division. A theory is “a plau-
up cellular debris supervised by immune cells (e.g., sible or scientifically acceptable general principle
macrophage) (Fishbein et al., 2021). Resolvins have or body of principles offered to explain phenom-
reduced localized proinflammatory cytokine levels ena” (Merriam-Webster, n.d.-b). Multiple theories
during resolution. Failure of resolution via these related to malignant transformation have developed
cells is important in pathogenesis and a unifying over the past 250 years, as morphological traits of
component of many underlying chronic inflam- tumors for pathologic diagnosis have been identi-
matory diseases, obesity, infection, asthma, wound fied and classified. In addition, acknowledgment
healing, Alzheimer disease, sepsis, aging, cardiovas- of the ability of cells to live forever with autonomy
cular diseases, and various ocular disorders (Serhan has been established as a necessary condition (Dou
& Levy, 2018). et al., 2020).

Somatic Mutation Theory

Terms and Concepts Somatic mutation theory considers cancer to
be a genetic disease. Multistate models view vari-
Pathology Reports ant phenotypes and healthy cellular populations
as able to coexist. This theory has been the pre-
Tumors typically grow and progress stepwise dominant cancer model for more than 50 years.
from healthy to very abnormal or undifferenti- Its principals include the following (Brücher &
ated (see Table 1-2). If cells divide too much but Jamall, 2016):
appear healthy, they are labeled hyperplasia. Dys- • Cancer is a disease of genetic variants.
plasia describes tumor cells and tissue that appear • Cancer is derived from a single somatic cell.
abnormal. If a tumor contains primarily altered • Initiation and carcinogenesis are irreversible.
cells, grows larger, and has not left the site of ori-
gin, it is labeled as a carcinoma in situ. A malig- Multistep Theory of Carcinogenesis
nant tissue has begun to invade nearby or distant Another popular theory of carcinogenesis
tissues. If tissue becomes malignant, it is named includes its three development stages: initiation,
based on the location and type of original tissue promotion, and progression. Metastasis is the
(see Chapter 6). fourth stage (see Figure 1-1).
Benign tissue does not spread from its initial During initiation, a permanent and irreversible
locations and may have abnormal features. This change, a variant, occurs to the cell’s genetic mate-
tissue may enlarge, causing pressure on adjacent rial, where the cell is primed to become malig-
tissue. Benign tissue can transform to malignant nant. Future generations of daughter cells will
tissue, such as with colon polyps. also carry the variant. Many initiators are specific
to particular tissue types and must be metabo-
Theories and Models Describing Cancer lized before they can cause a permanent change
to the gene. The greater the dosage of the ini-
A model visualizes the “pattern or figure of tiator, the higher the risk for the development
something to be made” (Merriam-Webster, n.d.-a). of tumors. In addition, cancer initiators need to
Models of carcinogenesis theories are included to be applied as a linear relationship in the right
6 | SECTION I. CANCER BASICS

TABLE 1-2
BIOMARKERS
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

ALK gene rearrange- Non-small cell lung cancer, Tumor To help determine treatment
ments and overexpres- anaplastic lung cancer, histio- and prognosis
sion cyte

Alpha-fetoprotein (AFP) Liver cancer and germ cell Blood To help diagnose liver cancer
tumors and follow response to treat-
ment; to assess stage, prog-
nosis, and response to treat-
ment of germ cell tumors

B-cell immunoglobulin B-cell lymphoma Blood, bone mar- To help in diagnosis, to eval-
gene rearrangement row, or tumor tis- uate effectiveness of treat-
sue ment, and to check for recur-
rence

BCL2 gene rearrange- Lymphomas and leukemias Blood, bone mar- For diagnosis and planning
ment row, or tumor tis- treatment, and to check for
sue recurrence

Beta-2-microimmuno- Multiple myeloma, chronic lym- Blood, urine, or To determine prognosis and
globulin (B2M) phoblastic leukemia, and some cerebrospinal fluid follow response to treatment
lymphomas

Bladder tumor antigen Bladder cancer and cancer of Urine As surveillance with cytology
(BTA) the kidney or ureter and cystoscopy of patients
already known to have blad-
der cancer

BRCA1 and BRCA2 gene Ovarian and breast cancers Blood and/or To help determine treatment
mutations tumor

BCR-ABL fusion gene Chronic myeloid leukemia, Blood or bone To confirm diagnosis, predict
(Philadelphia chromo- acute lymphoblastic leukemia, marrow response to targeted therapy,
some) and acute myelogenous leu- help determine treatment, and
kemia monitor disease status

BRAF V600 mutations Cutaneous melanoma, Tumor To help determine treatment

Erdheim-Chester disease,
Langerhans cell histiocyto-
sis, colorectal cancer, and
non-small cell lung cancer

C-kit/CD117 Gastrointestinal stromal tumor, Tumor, blood, or To help in diagnosis and to

mucosal melanoma, acute bone marrow help determine treatment
myeloid leukemia, and mast
cell disease

(Continued on next page)

 Chapter 1. Genomics of Cancer | 7

TABLE 1-2
BIOMARKERS (CONTINUED)
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

CA15-3/CA 27.29 Breast cancer Blood To assess whether treatment

is working or if the cancer has
recurred

CA19-9 Pancreatic, gallbladder, bile Blood To assess whether treatment

duct, and gastric cancers is working

CA-125 Ovarian cancer Blood To help in diagnosis, assess-

ment of response to treat-
ment, and evaluation of recur-
rence

CA 27.29 Breast cancer Blood To detect metastasis or recur-

rence

Calcitonin Medullary thyroid cancer Blood To aid in diagnosis, check

whether treatment is working,
and assess recurrence

Carcinoembryonic Colorectal cancer and some Blood To keep track of how well can-
antigen (CEA) other cancers cer treatments are working
and check if cancer has come
back or spread

Cluster of differentiation B-cell lymphomas and Blood and bone To help in diagnosis and to
19 (CD19) leukemias marrow help determine treatment

CD20 Non-Hodgkin lymphoma Blood To help determine treatment

CD22 B-cell lymphomas and Blood and bone To help in diagnosis and to
leukemias marrow help determine treatment

CD25 Non-Hodgkin (T-cell) Blood To help determine treatment

lymphoma

CD30 Classic Hodgkin lymphoma, Tumor To help determine treatment

B-cell and T-cell lymphomas

CD33 Acute myeloid leukemia Blood To help determine treatment

Chromogranin A (CgA) Neuroendocrine tumors Blood To help in diagnosis, assess-

ment of treatment response,
and evaluation of recurrence

Chromosome 17p Chronic lymphoblastic Blood To help determine treatment

deletion leukemia

(Continued on next page)

8 | SECTION I. CANCER BASICS

TABLE 1-2
BIOMARKERS (CONTINUED)
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

Chromosomes 3, 7, 17, Bladder cancer Urine To help in monitoring for

and 9p21 tumor recurrence

Circulating tumor cells Metastatic breast, prostate, Blood To inform clinical decision-
of epithelial origin and colorectal cancers making and assess prognosis
(CELLSEARCH)

Cytokeratin fragment Lung cancer Blood To help in monitoring for

21-1 recurrence

Cyclin D1 (CCND1) Lymphoma, myeloma Tumor To help in diagnosis

gene rearrangement or
expression

Des-gamma-carboxy Hepatocellular carcinoma Blood To monitor the effectiveness

prothrombin (DCP) of treatment and to detect
recurrence

DPD gene mutation Breast, colorectal, gastric, and Blood To predict the risk of a toxic
pancreatic cancers reaction to 5-fluorouracil
therapy

EGFR gene mutation Non-small cell lung cancer Tumor To help determine treatment
and prognosis

Estrogen receptor (ER)/ Breast cancer Tumor To help determine treatment

progesterone recep-
tor (PR)

FGFR2 and FGFR3 gene Bladder Tumor To help determine treatment

mutations

Fibrin/fibrinogen Bladder Urine To monitor progression and

response to treatment

FLT3 gene mutations Acute myeloid leukemia Blood To help determine treatment

Gastrin Gastrin-producing tumor (gas- Blood To help in diagnosis, to moni-

trinoma) tor the effectiveness of treat-
ment, and to detect recur-
rence

HE4 Ovarian cancer Blood To plan cancer treatment,

assess disease progression,
and monitor for recurrence

HER2/neu gene amplifi- Breast, ovarian, bladder, pan- Tumor To help determine treatment
cation or protein overex- creatic, and stomach cancers
pression

(Continued on next page)

 Chapter 1. Genomics of Cancer | 9

TABLE 1-2
BIOMARKERS (CONTINUED)
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

5-HIAA Carcinoid tumors Urine To help in diagnosis and to

monitor disease

IDH1 and IDH2 gene Acute myeloid leukemia Bone marrow and To help determine treatment
mutations blood

Immunoglobulins Multiple myeloma and Walden- Blood and urine To help diagnose disease,
ström macroglobulinemia assess response to treatment,
and look for recurrence

IRF4 gene rearrange- Lymphoma Tumor To help in diagnosis

ment

JAK2 gene mutation Certain types of leukemia Blood and bone To help in diagnosis
marrow

KRAS gene mutation Colorectal cancer and Tumor To help determine treatment
non-small cell lung cancer

Lactate dehydrogenase Germ cell tumors, lymphoma, Blood To assess stage, prognosis,
leukemia, melanoma, and neu- and response to treatment
roblastoma

Microsatellite instability Colorectal cancer and other Tumor To guide treatment and to
(MSI) and/or mismatch solid tumors identify those at high risk of
repair deficient (dMMR) certain cancer-predisposing
syndromes

MYC gene expression Lymphomas, leukemias Tumor To help in diagnosis and to

help determine treatment

MYD88 gene mutation Lymphoma, Waldenström Tumor To help in diagnosis and to

macroglobulinemia help determine treatment

Myeloperoxidase (MPO) Leukemia Blood To help in diagnosis

Neuron-specific Small cell lung cancer and neu- Blood To help in diagnosis and to
enolase (NSE) roblastoma assess response to treatment

NTRK gene fusion Any solid tumor Tumor To help determine treatment

Nuclear matrix Bladder cancer Urine To monitor response to treat-

protein 22 ment

PCA3 mRNA Prostate cancer Urine (collected To determine need for repeat
after digital rectal biopsy after negative biopsy
exam)

(Continued on next page)

10 | SECTION I. CANCER BASICS

TABLE 1-2
BIOMARKERS (CONTINUED)
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

PML/RARα fusion gene Acute promyelocytic leuke- Blood and bone To diagnose APL, to predict
mia (APL) marrow response to all-trans-retinoic
acid or arsenic trioxide ther-
apy, to assess effectiveness
of therapy, to monitor minimal
residual disease, and to pre-
dict early relapse

Prostatic acid phospha- Metastatic prostate cancer Blood To help in diagnosing poorly
tase (PAP) differentiated carcinomas

Programmed death Non-small cell lung cancer, Tumor To help determine treatment
ligand 1 (PD-L1) breast cancer, liver cancer,
stomach cancer, gastroesoph-
ageal junction cancer, classical
Hodgkin lymphoma, and other
aggressive lymphoma subtypes

Prostate-specific anti- Prostate cancer Blood To help in diagnosis, to assess

gen (PSA) response to treatment, and to
look for recurrence

ROS1 gene rearrange- Non-small cell lung cancer Tumor To help determine treatment
ment

Soluble Mesothelioma Blood To monitor progression or

mesothelin-related recurrence
peptides (SMRP)

Somatostatin receptor Neuroendocrine tumors affect- Tumor (by diag- To help determine treatment
ing the pancreas or gastroin- nostic imaging)
testinal tract (GEP-NETs)

T-cell receptor gene T-cell lymphoma Bone marrow, tis- To help in diagnosis; some-
rearrangement sue, body fluid, times to detect and evaluate
blood residual disease

Terminal transferase Leukemia, lymphoma Tumor, blood To help in diagnosis

(TdT)

Thiopurine Acute lymphoblastic leukemia Blood and buccal To predict the risk of severe
S-methyltransferase (cheek) swab bone marrow toxicity (myelo-
(TPMT) enzyme activity suppression) with thiopurine
or TPMT genetic test treatment

Thyroglobulin Thyroid cancer Blood To evaluate response to treat-

ment and to look for recur-
rence

(Continued on next page)

 Chapter 1. Genomics of Cancer | 11

TABLE 1-2
BIOMARKERS (CONTINUED)
Cancer Type or Substance
Biomarker Cancer-Like Conditions Analyzed How Used

UGT1A1*28 variant Colorectal cancer Blood and buccal To predict toxicity from irino-
homozygosity (cheek) swab tecan therapy

Urine catecholamines: Neuroblastoma Urine To help in diagnosis

VMA and HVA

Urokinase plasminogen Breast cancer Tumor To determine aggressiveness

activator (uPA) and plas- of cancer and guide treatment
minogen activator inhib-
itor (PAI-1)

FoundationOne CDx Any solid tumor Tumor, blood As a companion diagnostic

(F1CDx) genomic test test to determine treatment

Guardant360 CDx Any solid tumor Blood As a companion diagnos-

genomic test tic test to determine treat-
ment and for general tumor
mutation profiling

5-Protein signature Ovarian cancer Blood To pre-operatively assess pel-

(OVA1) vic mass for suspected ovar-
ian cancer

17-Gene signature Prostate cancer Tumor To predict the aggressiveness

(Oncotype DX GPS test) of prostate cancer and to help
manage treatment

21-Gene signature Breast cancer Tumor To evaluate risk of distant

(Oncotype DX) recurrence and to help plan
treatment

46-Gene signature Prostate cancer Tumor To predict the aggressiveness

(Prolaris) of prostate cancer and to help
manage treatment

70-Gene signature Breast cancer Tumor To evaluate risk of recurrence

(Mammaprint)

Note. From Tumor Markers in Common Use, by National Cancer Institute, 2021 (https://www.cancer.gov/about-cancer/diagnosis-
staging/diagnosis/tumor-markers-list). In the public domain.

amounts, in the right order, and at the right time. When a nonreactive compound stimulates tumor
Examples of initiators include tobacco smoke, development, it is called a promoter and is involved
radon, ultraviolet light, asbestos, medical radia- in the second stage of malignancy development. Pro-
tion, certain viruses, and air pollution. Some may moters are not typically mutagenic in this stage but
require high, low, or multiple doses over time accelerate to becoming cancer. Examples include
or doses in the right order at the right time with nitrites, alcohol, high estrogen levels, dietary fat,
other initiators. ultraviolet light, and saccharin (Libre Texts, 2020).
12 | SECTION I. CANCER BASICS

FIGURE 1-1
MULTISTEP CARCINOGENESIS

Note. From “Carcinogenesis,” by LibreTexts, 2020 (https://med.libretexts.org/Courses/American_Public_University/APUS%3A_An_

Introduction_to_Nutrition_(Byerley)/Text/07%3A_Nutrition_and_Cancer/7.02%3A_Carcinogenesis), licensed under CC BY-SA 3.0
(https://creativecommons.org/licenses/by-sa/3.0/deed.en).

The third stage is progression of the malignancy, cells can multiply, but only the cancer stem cell can
with movement into surrounding tissue and dis- become a new tumor (Werbowetski-Ogilivie, 2021).
semination throughout the organs and skeletal sys- The heterogeneous cells proliferate once the new
tem. This can include large pieces of tumor break- tumor is established, allowing the tumor to enlarge.
ing off from the main tumor or one cell hiding The cancer stem cell then moves into the resting
in the resting phase (G0). The cell remains in this phase (G0) (see Figure 1-4). Cells in this phase are
phase until a stimulus causes it to move into the resistant to treatment and remain as one surviv-
active cell cycle, with maturation leading to gener- ing cancer cell while treatment destroys the other
alized metastasis (see Figure 1-2).

Stochastic Modeling FIGURE 1-2

Two additional models represent how a theory CELL CYCLE WITH RESTING PHASE
might work and how cancer might develop in the
real world. The first is stochastic modeling, which
includes the two-hit theory (see Figure 1-3). This
model suggests that each cancer cell can multiply and
form new tumors. The malignant cells have a selective
advantage over healthy neighbors and proliferate rap-
idly, accumulating genetic damage with each genera-
tion. As the damage accumulates, the most aggressive
characteristics promote immortalized growth and the
formation of a tumor (Oduola & Li, 2018).
The individual cancer stem cell is the focus of
the second model and is supported by most can-
cer researchers. According to the Cancer Stem Cell
Model, many different types of cancer cells exist in
addition to endothelial, hematopoietic, stromal,
Note. From “Cell cycle,” by OpenStax, 2016 (https://commons
and other types of healthy cells to meet the func-
.wikimedia.org/wiki/File:0329_Cell_Cycle.jpg), licensed under
tioning needs of the tumor and demonstrate hetero- CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/deed
geneity. With proliferation, cell division occurs. All .en).
 Chapter 1. Genomics of Cancer | 13

FIGURE 1-3
KNUDSON’S “TWO HIT” THEORY OF CANCER DEVELOPMENT

Tumor

Heterogeneous
Cancer Cells

Normal Cell
Tumor

1st and 2nd “hits”

to the gene

Tumor
Tumor

Tumor

Theory: Two genes within a cell, one on each of a pair of chromosomes, each receive damage-causing hits prior
to the development of cancer. The malignant cells are heterogeneous and all have the capability of developing a
tumor.

Note. Based on information from Hanahan & Weinberg, 2011; Knudson, 1971; Reya et al., 2001; Wicha et al., 2006.

rapidly dividing stem cells (Werbowetski-Ogilivie, ability to come out of remission and become meta-
2021). Thus, months or years later, the resting can- static. Noncancer stem cells have meager potential
cer stem cell could move into the active phases of to become tumorigenic, develop more tumors, and
the cell cycle, proliferate, and cause exacerbation metastasize (Walcher et al., 2020).
of once-dormant cancer believed to be destroyed
(Werbowetski-Ogilivie, 2021).
An update of the Cancer Stem Cell Model is Structure and Function of DNA
known as the Plasticity Model of Cancer Stem Cells. and Chromosomes
This newer model suggests that plasticity (the abil-
ity to change throughout the cell’s life) allows can- Within the nucleus of each healthy human cell,
cer stem cells to become heterogeneous with the 23 pairs of chromosomes are present. These con-
14 | SECTION I. CANCER BASICS

FIGURE 1-4
CANCER STEM CELL THEORY OF CANCER DEVELOPMENT

Tumor

Heterogeneous
Cancer Cells

Tumor
Cancer Stem Cell

Tumor

Tumor
Theory: Cancer stem cells are the only type of heterogeneous cancer cells to develop into tumors.

Note. Based on information from Reya et al., 2001; Wicha et al., 2006.

sist of 22 pairs of nonsex chromosomes (auto- gene (BRCA1) is found on chromosome 17, with
somes) and one pair of sex chromosomes (XX for a band position of q21 on the long arm (see Fig-
female, XY for male). A person inherits one sex ure 1-5). If the position of a gene is uncertain, a
chromosome from the father and the other from range might be noted, such as 17q21–24 (Genetics
the mother. A chromosome has a short arm (p for Home Reference, 2021a, 2021b). BRCA2 is located
petite) and a long arm (q to follow p in the alpha- on chromosome 13 at band position 13.2 on the
bet), with a unique banding pattern to identify spe- q arm (see Figure 1-6).
cific regions. These regions are numbered from the Each chromosome is a single double-helix DNA
centromere to the end of each arm (Genetics Home molecule with millions of base pairs connected in a
Reference, 2021c). For example, the breast cancer long, unbroken string that intricately coils back on
 Chapter 1. Genomics of Cancer | 15

itself and is scattered with proteins called histones

FIGURE 1-5
BRCA1 GENE LOCATION (see Figure 1-7).
The central dogma of molecular biology states
that DNA (adenine [A], cytosine [C], guanine [G],
17p13 and thymine [T]) is transcribed to RNA (A, C, G,
and uracil [U]) and then translated into proteins
17p12 (Saw et al., 2021; Yi et al., 2020; see Figure 1-8).
For example, a string of DNA (ACTGTC) would
17p11.2 be transcribed as RNA (ACUGUC) and then to
17p11.1 messenger RNA (mRNA), where it is divided into
17q11.1 codons (three nucleotides used to specify an amino
17q11.2 acid) (UGA CAG) for translation from amino acid
17q12 to protein. This is important because any changes in
the codon spelling (mRNA triplet) could change the
protein outcome. Some amino acids have multiple
17q21
codon spellings. One example is leucine, which has
six spellings, allowing several mistakes without cre-
17q22 ating a problem protein. However, tryptophan has
one spelling (Algorithmic Arts, 2006). Any error in
17q23
this codon spelling would cause a dysfunctional or
17q24 nonfunctional protein (Ding et al., 2019).
Changes in DNA nucleotides can be a variant or
a polymorphism, depending on the frequency in
17q25 the general population. The change is called a poly-
morphism if it occurs in at least 1% of the popula-
tion and a variant if it occurs in less than 1%. To fur-
Note. From “Ideogram: Breast Cancer 1 (BRCA1),” by NCBI Map ther explain, a normal length of DNA is similar to a
Viewer, n.d. http://www.ncbi.nlm.nih.gov/projects/mapview/maps.
recipe for an ordinary chocolate cake. Although this
cgi?TAXID=9606&CHR=17&MAPS=genes-r%2Cpheno%2Cmo
rbid%2Cgenec&QUERY=BRCA1&BEG=17q21.1&END=17q21.1 is the most common, other cakes exist, including
&thmb=on. strawberry, white, spice, pineapple upside-down,

FIGURE 1-6
BRCA2 GENE LOCATION

Note. From “Ideogram: Breast Cancer 2 (BRCA2),” by NCBI Map Viewer, n.d. https://ghr.nlm.nih.gov/gene/BRCA2#location.
16 | SECTION I. CANCER BASICS

or late signal to end the compilation of amino acids

FIGURE 1-7
into a protein (National Cancer Institute [NCI],
DNA PACKAGING
2021b; Palma & Lejeune 2021).
Variants that occur within cells are somatic.
They accumulate over a lifetime and cause spo-
radic cancers, typically after an individual has
reached age 50 years. Variants in the ova or sperm
are germline and associated with inherited cancers,
typically in people aged younger than 50 years (see
Figure 1-10). The results of this genomic insta-
bility affect all future generations, depending on
the pattern of inheritance (NCI, 2021b; Palma &
Lejeune 2021).
Most patterns of inheritance follow the domi-
nant or recessive model developed by Gregor Men-
del (Saw et al., 2021). Each individual typically has
two sets of chromosomes. On each chromosome
is a gene, or allele, for a particular characteristic.
Although an allele may have a collection of many
different traits (such as blue, green, hazel, or brown
eyes), each chromosome can only exhibit one of
these. So, one chromosome may have the blue eyes
allele, and the second chromosome could have the
brown eyes allele. All other eye colors are still allelic
DNA is tightly wound around proteins called histones options but are not displayed by this set of chromo-
and packaged into cells’ nuclei in the form of chromo- somes. Each allele is either a dominant or recessive
somes. Genes are sections of DNA that, under the right type. For example, the brown eyes allele is domi-
circumstances, can be transcribed into proteins. Epi- nant over the recessive blue eyes allele. If the domi-
genetics determines which genes each cell transcribes
nant allele is inactivated or lost, the recessive allele
at any given moment.
will become active (Saw et al., 2021).
Note. From “Epigenetics—A New Frontier for Alcohol Research,” Sometimes an individual will have the dominant
by National Institute on Alcohol Abuse and Alcoholism, 2013,
allele without it being expressed. This is known as
Alcohol Alert, 86, p. 2. http://pubs.niaaa.nih.gov/publications/
aa86/aa86.htm. incomplete penetrance. The gene is there, but the
phenotype (the observable physical trait) is not
expressed. An example that illustrates this is a house
and lemon. These would be polymorphisms. They caught in a cloud of fog. The house is still standing
are good-tasting cakes but are not the most com- but is not visible because of the denseness of the
mon. Sometimes the recipe is misread, and the cake low-lying cloud cover. Age, modifier genes, carcino-
comes out of the oven as a pudding (see Figure gens, repair enzymes, and hormone or reproductive
1-9). This is a variant and not the desired outcome. factors affect penetrance (Saw et al., 2021).
Several types of variants exist. The most common
type is the point variant, in which only one nucleo-
tide base is altered. A nonsense variant occurs with DNA Changes and Cancer
premature termination of the protein. The stop
codon, which signals termination of the length of Descriptions of variants associated with cancer
amino acids, has been misspelled and gives an early include drivers and passengers. Driver variants, such
 Chapter 1. Genomics of Cancer | 17

FIGURE 1-8
MODIFIED CENTRAL DOGMA OF DNA MODEL
DNA Transcription →→→ Messenger RNA Translation →→ Protein

DNA Replication Protein regulation also occurs with small pieces of RNA, miRNA, and siRNA.

miRNA—microRNA; siRNA—small interfering RNA

Note. Based on information from Crick, 1970; Hayes et al., 2014.

as TP53, are commonly associated with the devel- within the cell to monitor and guarantee genomic
opment of cancer (oncogenesis) and offer a clonal stability and purity for the continued survival of the
advantage in the microenvironment of the evolv- human cell. These protective teams include DNA
ing cancer cell (Porta-Pardo et al., 2020). Within monitoring and repair enzymes. Checkpoint gate-
the same tumor, passenger variants are found but keepers function at significant points in the active
do not offer growth advantage and have no known phases of the cell cycle prior to DNA synthesis (S
contribution to the development of the cancer type. phase) and mitosis (M phase) to guarantee the
They seem to be along for the ride (Skvortsova et al., accuracy of the genome and cell cycle processes.
2019). Different cancers may have different driver If an error is present, the TP53 or retinoblastoma
and passenger variations but appear with similar protein tumor suppressor proteins cause cell cycle
phenotypes. The drivers in this group of variant arrest for repair or apoptosis (programmed cell
gene sets are targeted for treatment individually or
in a staggered approach (Skvortsova et al., 2019;
Stratton et al., 2020).
In healthy cells, driver and passenger variants FIGURE 1-9
can be restored to pre-damage level by healthy POLYMORPHISMS VERSUS VARIANTS
DNA repair mechanisms important for cancer-free
survival. These systems include (a) the nucleotide
excision repair groups with mutations associated
with xeroderma pigmentosum, (b) mismatch
repair genes accompanying inherited colorectal
cancer predisposition, (c) DNA crosslink repair
genes (Fanconi anemia), and (d) the well-known
DNA repair genes exemplified by the breast cancer
genes (BRCA1 and BRCA2). Approximately 130 ATG AGC AAG AGC GAG GAC
genes are linked to DNA repair (Skvortsova et al.,
The wild-type genotype is transcribed to a codon that
2019).
correctly spells a protein (e.g., recipe for a chocolate
Much of the scientific evidence about the devel- cake). When there is a polymorphism in the codon spell-
opment of cancer and its progression suggests that ing, it can still spell a correct amino acid (e.g., a cake, just
genomic instability is a precursor to changes asso- a different flavor). When the amino acid spelling is rare
ciated with the transformation of a cell into malig- and uncommon, it is a mutation and creates an unde-
sirable outcome (e.g., cookie, pie, or another undesired
nancy. Of question in this hypothesis is how the
result).
instability circumvents the careful security provided
18 | SECTION I. CANCER BASICS

occur above and over the DNA, so there is no effect

FIGURE 1-10
on the basic sequence, and the genotype is not
SOMATIC VERSUS GERMLINE VARIANTS
changed; however, the phenotypic outcome may
Somatic Cell Germline Cell (Egg or be altered. These phenotypic changes occur through
• Variant occurs in only Sperm) loosening or altering the tightly wound chromatin
one cell. • DNA in egg or sperm
• DNA damage may already has variant at con-
by binding the different chemicals in such a way
occur in one cell (not ception. that can determine when and where genes might
an egg or sperm) and • DNA damage is replicated be expressed or turned on (Strasser & Vaux, 2020).
accumulate over an in cell lineage, and a tumor Chromatin consists of proteins and DNA as part
extended period after develops in one organ or of the chromosomes (Skvortsova et al., 2019). The
conception. tissue type.
• Variant is not inherit- • As cells duplicate, DNA
major proteins of chromatin are histones, which
able. damage is incorporated are responsible for compacting the primary DNA
into every body cell and by twisting it tightly (like a jump rope) while wrap-
tissue type of the off- ping it tightly (like thread on a spool) so it fits within
spring. the nucleus of the cell. Similar to sewing bobbins,
• The potential for malig-
nancy exists in multiple
histones organize and control the long threads of
tissue types over time. DNA, wrapping them into a tight coil so that the
• Variant is passed to future DNA can fit neatly packaged inside the nucleus of a
generations. cell. The coiling is necessary because the strands of
Note. Based on information from National Cancer Institute, 2021b.
DNA in the body would stretch about five feet but
would be only 50 trillionths of an inch (2 nanome-
ters [nm]) wide. For comparison, the membrane of a
death) (Skvortsova et al., 2019; Strasser & Vaux, brightly colored soap bubble is between 100 and 400
2020). nm wide (UCSB ScienceLine, n.d.). This long but
Much research has confirmed that most human thin physical structure would be extremely fragile,
cancers lose function in the TP53 tumor suppres- hence the need for tight packaging to keep the DNA
sor pathway. Other genes involved in targeting and message intact. Once it is coiled around the histones,
repairing DNA damage have also been found to DNA continues twisting back upon itself (much like
lose function in multiple cancers (Skvortsova et al., the continued twisting of a jump rope) until it is
2019). Acquiring genomic damage permits evolving tightly wound, forming the chromatid seen in Figure
populations of precancerous cells to gain functional 1-7. These chromatids enable the chromosomes to
capabilities associated with malignant transforma- be visualized for karyotyping during the metaphase
tion. These include (a) self-sufficiency in growth of cell division (McCance & Huether, 2019).
signals, (b) insensitivity to antigrowth signals, (c) These continuous strands of DNA and histones
evasion of apoptosis, (d) sustained angiogenesis, appear like beads on a string (euchromatin). Mul-
(e) tissue invasion and metastasis, and (f) limit- tiple histones wrapped tightly together (heterochro-
less replicative potential (Strasser & Vaux, 2020). matin) prevent transcription and contain inactive
genes. The nucleosome comprises eight separate
histone molecules with two loops of DNA wrapped
Epigenetics around each group of eight histones (Skvortsova et
al., 2019; Strasser & Vaux, 2020).
Healthy Structure and Function
Epigenetic Modifications and Cancer
Changes that occur to DNA activity beyond
the actual sequence of the base pairs are termed The changes associated with epigenetics are
epigenetics (Strasser & Vaux, 2020). These changes caused when the DNA and the histone proteins
 Chapter 1. Genomics of Cancer | 19

become modified with the addition or removal of nontranscription, the genome tightly wraps genes
chemical groups (tags) (see Figure 1-11). Methyl to make them unreadable. During transcription, the
groups can be added to DNA at the cytosine and active genes are easily accessible when the genome
guanine nucleotides (CpG islands) and cause is relaxed.
silencing or stopping of transcription. Acetyl groups Collections of enzymes have been identified
loosen the interactions between histones and DNA, to have functioned as readers, writers, and erasers
allowing easier access to the DNA for transcription. in the epigenome. Epigenetic readers are enzymes
Because histones are proteins, they can be modi- that look for specific marks on post-translational
fied after translation by attaching acetyl, phosphate, histones or DNA where they can be modified with
or ubiquitin groups (Thakur & Fei, 2019; Uckel- chemical groups. Tightly packed histones do not
mann & Sixma, 2017; Zhang et al., 2020). During allow changes, so DNA translation is prevented.

FIGURE 1-11
EPIGENETICS

DNA and histones are covered with chemical tags. A variety of tags affect how histones interact with DNA. Some will
open a gap between for transcription and others will close a gap to prevent transcription.

Note. Image courtesy of Darryl Leja and National Human Genome Research Institute. https://www.genome.gov/dmd/img.
cfm?node=Photos/Graphics/Illustrations&id=97352.
20 | SECTION I. CANCER BASICS

Writers promote attachment of the chemical After replication, healthy cells contact the adja-
groups, like acetyl groups, to cause loose pack- cent cell membrane and inhibit growth. Malignant
ing of the histones for DNA expression (writing) cells lose this inhibition and continue to prolifer-
with active protein growth. These chemical groups ate, even though they have contact or are touch-
cause changes that alter the shape of the chroma- ing the cell next to them. This modification or loss
tin in specific places on the genome, making some of contact inhibition contributes to cell division,
areas more available for gene expression. Erasers persistent overgrowth of adjacent cells, and a lack
are collections of enzymes that remove (erase) his- of growth control by malignant cells. This is con-
tone modifiers (Skvortsova et al., 2019; Strasser & sidered a hallmark of cancer (McCance & Huether,
Vaux, 2020). 2019).
Malignant cell membranes have a lower level
Epigenetics and Cancer of electrical potential than healthy cells because of
the increased amounts of negatively charged phos-
Although increased DNA methylation is associ- pholipids in the cell membrane (Skvortsova et al.,
ated with certain genes, the methylation levels are 2019; Strasser & Vaux, 2020). Positively charged
overall lower in malignant cells than healthy cells. sodium and calcium channels contribute to apop-
Different types of cancer with similar characteristics tosis. Changes in the charge of the cell membrane
can have varied DNA methylation patterns (Thakur inhibit apoptosis and contribute to the longevity
& Fei, 2019; Zhang et al. 2020). of malignant cells.
Epigenetic-based tests have been developed and Alterations in lectin binding enable leukocytes
used with other diagnostic screening tests to iden- to adhere to and cover malignant cells. This change
tify colorectal cancers with increased methylation allows malignant cells to escape surveillance and
at the SEPT9 gene. For example, the Epi proColon travel to distant sites in the body as a bolus of
test is used to detect methylated Septin 9 DNA in healthy and abnormal cells (McCance & Huether,
EDTA plasma derived from the whole blood speci- 2019).
men of a patient. Patients with positive test results
should be referred for a diagnostic colonoscopy.
This test does not replace colorectal cancer screen- Self-Sufficiency in Growth Signals
ing tests recommended by appropriate guidelines
(Thakur & Fei, 2019; Zhang et al., 2020). Growth Factors
Cell behavior is controlled by circulating pro-
Healthy Versus Abnormal teins known as growth factors (ligands) that can
Cell Division act as chemical signals. They direct cell growth,
differentiation, and survival and determine tissue
Healthy cells cease to multiply once all available architecture and morphology. Growth factors must
intracellular space to grow has been overtaken by interact with their particular receptor to accomplish
tumor cells. Therapeutic agents that destroy cancer signaling (Erdogan & Webb, 2017).
cells can use cytoskeletal control to destroy. Growth factors associated with cancer develop-
Proteins, glycoproteins, and glycolipids are ment include epidermal growth factor, transform-
known to have altered mobility on the out- ing growth factor, and colony-stimulating factor.
side membrane of a malignant cell. This mobil- Other growth factors exist that are overproduced
ity enables cancer to change its surface to avoid and associated with different cancer types. For
immunosurveillance. Other outcomes could pro- example, platelet-derived growth factor is associ-
mote spread and metastasis (Skvortsova et al., 2019; ated with sarcomas and glioblastomas (Erdogan
Strasser & Vaux, 2020). & Webb, 2017).
 Chapter 1. Genomics of Cancer | 21

Growth Factor Receptors corresponds with more aggressive cancers, includ-

ing ovarian and breast cancers. When epidermal
As the first component in signaling pathways, growth factor receptor and transforming growth
growth factors bind to receptors to initiate sig- factor-beta are expressed, it is a prognostic marker
nal transduction across the cell membrane. Once for tumor relapse and decreased survival (Erdogan
a growth factor is bound to a receptor, a signal & Webb, 2017).
activates other markers in the cytoplasm, causing
the transmission of a message to the cell nucleus. Nonreceptor Tyrosine Kinases
The message causes a change in the expression of
specific genes that help usher the cell through its Some oncogenes do not require a receptor to ini-
growth cycle (Erdogan & Webb, 2017). Overproduc- tiate tyrosine kinase activity at the cell membrane.
tion of some growth factors causes altered cellu- One example is the SRC gene family. The protein
lar communication and is associated with cancers. from this gene initiates tyrosine kinase activity at
One of these, vascular endothelial growth factor, the C-terminus of the DNA, where biosynthesis
has an important role in tumor neoangiogenesis is supposed to end. The protein function persists
(new growth of vessels on a tumor). because no endpoint exists, allowing continued sig-
Lack of oxygen leads to the vascular endothelial naling to the cell nucleus and persistent cell growth.
growth factor-alpha protein transcription by bind- SRC-initiated activity increases in colon cancer and
ing to its designated cell surface receptors. The bind- other malignancies, such as neuroblastoma, small
ing trips a signal, indicating the need for increased cell lung cancer, breast adenocarcinomas, and rhab-
blood vessel permeability and resulting in angio- domyosarcoma (GeneCards, n.d.-b.).
genesis with even more proliferation of cells (Erdo-
gan & Webb, 2017). Vascular endothelial growth Intercellular Signaling Enzymes
factor is overexpressed in metastases of breast and
colorectal cancers. Oncoproteins with certain enzyme activity are
important for sending signals within cells and are
Tyrosine Kinase Activity called intracellular signaling enzymes. A common
example is enzymatic protein produced by the
Many cancer-related growth factor receptors RAF1 gene (GeneCards, n.d.-a). In the cytoplasm,
are stationed on the surface of the cell. Prolifera- tyrosine kinase activates the RAF1 enzyme. Once
tive signals are sent into the cytoplasm once they activated, the enzyme acts as a mediator between
are bound by a ligand that causes activation. Most the RAS (associated with the RAS oncogene) recep-
growth factor receptors possess tyrosine kinase tor on the cell membrane and the processes occur-
activity, which leads to reactions that stimulate ring in the cell nucleus by activating a series of
mitotic cell division, allowing rapid growth of the other kinases, including mitogen-activated protein
malignant cell (Erdogan & Webb, 2017). (referred to as MAP) kinases. These kinases are criti-
Examples of growth factor receptors that are cal for regulating the onset of cell division, apop-
cancer-causing (oncogenic) when overexpressed tosis, differentiation, and migration (Erdogan &
include HER2, epidermal growth factor receptor, Webb, 2017; GeneCards, n.d.-a).
and transforming growth factor-beta. A variety of
cancers express epidermal growth factor receptors, Membrane-Associated G Proteins
including non-small cell lung, breast, ovarian,
and colorectal cancer. Approximately 80%–100% The guanine nucleotide-binding proteins (G
of head and neck cancers overexpress epidermal proteins) are products of a family of genes, the RAS
growth factor receptors, which also is associated proto-oncogenes, which normally act as on–off
with lower survival. Increased HER2 expression switches for cell surface growth factor receptors.
22 | SECTION I. CANCER BASICS

Instead of being transmitted inside the cell mem- Cell growth is the accelerator. The tumor suppres-
brane, they transform adjacent G protein subunits sor genes are the brakes, which can prevent cellu-
below the membrane surface, beginning the sig- lar proliferation or suppress malignant transfor-
naling cascade inside the cell (Arang & Gutkind, mation. At the cellular level, variations in the cell
2020). cause tumor suppressor genes to lose function of
When the RAS gene mutates into the on posi- both alleles. In other words, the loss of function or
tion, it becomes a cancer-causing gene (onco- variant of both copies of the gene is required for
gene), and the changes interrupt a cascade of uncontrolled cell growth, leading to tumorigenesis
normally occurring signals in the cell cytoplasm. (National Center for Biotechnology Information
Normal RAS genes wait for prompting to send [NCBI], n.d.).
stimulatory signals from growth factor receptors
to other proteins. Variant RAS genes activate sig- Loss of Heterozygosity
naling pathways even when unprompted. Variant Homozygosity refers to the similarity between
RAS is found in virtually all types of human can- alleles. If there is an inherited variant of a tumor
cer and occurs in approximately two-thirds of all suppressor gene, it is considered heterozygous
malignant tumors. G proteins act at the cell mem- because the alleles are different. The gene’s func-
brane to cause malignant transformation (Arang tion and protein product are maintained because
& Gutkind, 2020). a healthy allele is present. Once the remaining
allele becomes a variant, the gene and its product
Transcription Factors will lose healthy functioning and heterozygosity.
Cells can experience loss of heterozygosity with
Proteins that bind to DNA and cause changes entire chromosome loss, translocation of a part
in gene expression are called transcription fac- of the chromosome, reduplication of a part of the
tors. These proteins have structures that can recog- chromosome that already has an abnormal gene,
nize specific DNA sequences (genes) involved in or the development of a point variation in the
growth and survival. Variant of the transcription second functioning allele. Loss of heterozygos-
factors that bind to genes involved in cell growth ity is associated with cancer susceptibility genes,
and survival allows for the malignant transforma- such as oncogenes and tumor suppressor genes
tion found in many tumors. Examples of cancers (e.g., TP53). Research is identifying an increas-
caused by this mechanism include Ewing sarcoma, ing number of tumor suppressor genes that, when
clear cell sarcoma, alveolar rhabdomyosarcoma, variants, are closely associated with the develop-
and many kinds of leukemia. Many transcription ment and progression of human cancers (NCI,
factor–induced cancers are characterized by translo- 2021a, 2021b).
cation of chromosomes (Donehower et al., 2019). TP53 (located on 17p13) commonly has dele-
One of the tumor suppressor genes, TP53, also acts tions and variations associated with a wide variety
as a transcription factor. In this role, TP53 senses of cancers, including lung, breast, esophageal, liver,
DNA damage and halts cell division by controlling bladder, and ovarian carcinomas; brain tumors; sar-
the expression of other genes that directly regulate comas; lymphomas; and leukemias. It is believed to
the cell cycle (Donehower et al., 2019). contribute to half of all sporadic human cancers,
making TP53 the most common genetic target for
Tumor Suppressor Genes variations leading to cancers (NCBI, n.d.). When
TP53 is inherited in the germ line as a variation,
Tumor suppressor genes (also called antion- it is transmitted in an autosomal dominant fash-
cogenes) normally suppress or negatively regu- ion, a hallmark of Li-Fraumeni syndrome. This rare
late cell proliferation by encoding proteins that disorder causes multiple cancers, including soft tis-
block the action of growth-promoting proteins. sue sarcomas, osteosarcomas, breast cancers, and
 Chapter 1. Genomics of Cancer | 23

different leukemias (Genetics Home Reference, long as the pathway is active, the cell functions cor-
2020a; NCBI, n.d.). rectly. If an interruption occurs because of a genetic
variant or protein dysfunction, the pathway is inter-
Functions of Tumor Suppressor Genes rupted, and the light is not turned on, causing a
Tumor suppressor gene products have specific poorly functioning or nonfunctioning pathway. As
functions in the cell nucleus and cytoplasm. If an option, another pathway could be available but
deregulation of the cell cycle occurs, which results lead to a different, potentially cancer-causing out-
in excess cell proliferation, the TP53 gene can halt come. Examples include nonproliferation of cells
cell division and induce apoptosis (NCBI, n.d.). versus continued proliferation of cells or apoptosis
Tumor suppressor genes also can encode pro- versus no cell death.
teins in the cytoplasm. The NF1 (neurofibromato- If the Hedgehog, Notch, or Wnt pathways overex-
sis) gene encodes a protein similar to those mod- press the wild-type signaling molecules or have acti-
ulating RAS oncogene function (Genetics Home vated variants, malignant conversion of adult stem
Reference, 2020b). Loss of NF1 may keep RAS acti- cells to cancer stem cells occurs (Strasser & Vaux,
vated and prolong the signal for cell proliferation 2020). Variation of BRCA1 can prevent DNA repair.
(Erdogan & Webb, 2017). Loss of other tumor sup- If PTEN is mutated or deleted, it can increase expres-
pressor genes, such as NF2 and APC (adenomatous sion of genes that promote continuous movement
polyposis coli), may cause cellular disorganization through the cell cycle (Strasser & Vaux, 2020). New
and lead to abnormal cell proliferation. therapies target some of these and other signaling
pathways, potentially initiating programmed cell
death.
Insensitivity to Antigrowth Signals
Antigrowth signals move the healthy cell from Limitless Potential for Replication
the cell cycle growth phases into the resting phase.
The transforming growth factor-beta pathway is the One factor allowing for limitless replicative
best example of a signaling mechanism that causes potential is expression of telomerase. Telomeres are
inhibition of cell growth and proliferation. This nucleoprotein structures found at the end of each
occurs in two ways in the healthy pathway. First, chromosome arm to maintain geonomic stability
transforming growth factor-beta prevents inactiva- (Turner et al., 2019).
tion of retinoblastoma protein, a tumor suppres- • Telomeres protect the end of chromosomes from
sor protein, and synthesis of the proteins from the damage with repetitive sequences of noncoding
tumor suppressor genes p15INK4α and p21. Second, DNA.
cells cannot move into and through the cell cycle • Telomerase added to the end of a telomere pre-
if cyclins are blocked. If the p15 protein is not syn- vents its destruction.
thesized, cyclins are not blocked, allowing cells to • Cells with increased telomerase are associated
continuously move into the active cell cycle with with longer telomeres and longevity of cell life.
growth and proliferation. Finally, retinoblastoma • Short telomeres are associated with a shorter life
protein tumor suppressor function is lost. These span.
interfering mechanisms, alone or in combination, • Each cell division causes telomeres to become
allow continued cell growth and proliferation shorter.
(Genetics Home Reference, 2020c). • Cancer stem cells have increased levels of telomer-
Much like lights on a Christmas tree, when the ase, leading to extended life enhanced by the pro-
circuit works well, all lights will come on and blink tected telomeres at the ends of the chromosome.
or not blink based on their function. The signal is • Increased telomerase also protects the cancer cell
turned on at the gene or protein level in a cell. As from apoptosis.
24 | SECTION I. CANCER BASICS

Nursing Implications Summary

Today, a nurse in the specialized oncology clini- The curricula in undergraduate nursing pro-
cal setting needs to have more than just a general grams do not typically include molecular biology.
knowledge of caring for patients with a cancer diag- With the completion of human genome sequenc-
nosis. Nurses need to understand the initiation and ing in 2003, many diagnostics and treatments have
progression of cancer, inflammation and its role in been developed that require an understanding of
carcinogenesis, the types of cancer, and implications certain characteristics of cells, the central dogma,
of specific disease diagnoses for patient assessment. and how cell signaling and communication occur.
Oncology nurses must develop a specialized plan This knowledge is essential for oncology nurses. It
of care, identify appropriate interventions with per- helps them anticipate cancer symptoms in patients
sonalized goals for effectiveness, and be educated and understand how treatments work, and provides
on evaluating outcomes. a basic foundation for developing individualized

Key Points
▶ Eight hallmarks have been identified to assist caregivers and providers in understanding how cancer develops.
These include self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis with lim-
itless replicative potential, sustained angiogenesis, tissue invasion, metastasis, reprogramming energy metab-
olism, and evasion of the immune response. Two enabling traits, genome instability and mutation plus tumor-
promoting inflammation, were also added. Nurture is now included because it can cause genetic alterations of
cancer. These nurture sources include obesity, lack of exercise, poor diet, and social habits.

▶ Carcinogenesis occurs in three stages: initiation, promotion, and progression. Some sources suggest a fourth
state, malignant conversion.

▶ Some environmental and chemical human carcinogens are so strong that they can disrupt inflammation resolu-
tion and contribute as a hit, contributing to the two-hit theory of DNA damage.

▶ The central dogma is the backbone of molecular biology and includes the three core processes of DNA replica-
tion, transcription, and translation.

▶ Driver variants, like those found in TP53, are commonly associated with cancer development. Passenger vari-
ants are found with cancer but do not offer growth advantage and seem to be only along for the ride. Checkpoint
gatekeepers function at specific points in the active phases of the cell cycle before the S phase and M phase to
guarantee the accuracy of the genome and cell processes. If an error is present, the TP53 retinoblastoma tumor
suppressor protein will cause cell cycle arrest for repair or programmed cell death (apoptosis) if too much dam-
age has occurred.

▶ An oncogene is a variant form of a gene from a healthy cell that can cause cancer. Oncogenes can be inherited
or caused by exposure to cancer-causing substances in the environment.

▶ Phenotypic changes occur through loosening or tightening the chromatin.

▶ Visualized chromosomes seen during karyotyping are sister chromatids.

▶ Epigenetic modifications occur along a splice of DNA and histones using chemical tags. Methyl groups can be
added at the C and G nucleotides (CpG islands) to cause silencing or stopping of transcription. Other chemical
tags can be added and close the gaps to all transcription.
 Chapter 1. Genomics of Cancer | 25

Key Points
▶ Methylation levels are lower in malignant cells than in healthy cells.

▶ Physiologic changes found in healthy cells changed to malignant cells include altered mobility of outside mem-
brane components, modified contact adhesion and inhibition of movement, altered surface charge density, and
the ability of cancer cells to hide due to increased lectin agglutinability (stickiness) of leukocytes.

▶ Failure of resolution, via pro-resolving lipid mediators, is essential in pathogenesis and a unifying component of
many underlying chronic inflammatory diseases such as obesity.

▶ Carcinogens are chemical substances, or a mixture of chemical substances, that induce cancer after inhalation,
ingestion, dermal application, or injection.

treatment plans. Understanding the biology of triple-negative breast cancer. Cells, 8(12), Article 1492.
cancer is integral for people new to oncology or https://​doi.org/10.3390/cells8121492
Donehower, L.A., Soussi, T., Korkut, A., Liu, Y., Schultz, A.,
those who want to review and close some gaps in
Cardenas, N., … Wheeler, D.A. (2019). Integrated analy-
knowledge. sis of the TP53 gene and pathway alterations in the can-
cer genome atlas. Cell Reproduction, 28(5), 1370–1384.
The author would like to acknowledge Matthew Ted- https://doi.org/10.1016/j.celrep.2019.07.001
Dou, X., Tong, P., Huang, H., Zellner, L., He, Y., Jia, Q., …
der, PhD(c), for his contribution to this chapter that Liao, D.J. (2020). Evidence for immortality and autonomy
remains unchanged from the previous edition of this in animal cancer models is often not provided, which
book. causes confusion on key issues of cancer biology. Journal
of Cancer, 11(10), 2887–2920. https://doi.org/10.7150​
/jca.41324
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Chapter 1 Study Questions

1. Which type of cancer cell is the only one with the 4. An example of incomplete penetrance is which of
ability to establish a new tumor? the following?
A. Cancer endothelial cell A. A small boy alone on a playground without
B. Cancer hematopoietic cell his mother
C. Cancer stem cell B. Three adults and two small children playing
D. Cancer stromal cell football in the fog and rain
C. Two teenagers playing football who cannot
2. Which of the phases in the central dogma make a touchdown in the rain
includes designation of a new protein? D. Children who can be heard in the fog but
A. Translation cannot be seen
B. Replication
C. Transcription 5. The use of positron-emission tomography scans
D. All of the above in identifying cancer is based on which character-
istic of malignancy?
3. A new tumor suppressor protein has recently A. Cytoskeletal changes
been discovered. What could be a possible func- B. Changes to cellular metabolism
tion of this new protein? C. Increased angiogenesis
A. A transcription factor for epidermal growth D. Evasion of apoptosis
factor
B. A tyrosine kinase in the RAS–RAF pathway
C. An inhibitor of NF1 function
D. An upregulator of BAX expression