Cancer Genetics

Assist. Dr. Ceyhan CERAN SERDAR

Ankara Medipol University
School of Medicine
Department of Medical Biology and Genetics
• Cancer is one of the most common and serious diseases seen in
clinical medicine.
• There are 14 million new cases of cancer diagnosed each year and
over 8 millions deaths from the disease worldwide.
• Cancer is invariably fatal if it is not treated.
• Identification of persons at increased risk for cancer before its
development is an important objective of genetics research.
 NEOPLASIA
• Cancer is the name used to describe the more virulent forms of
neoplasia, a disease process characterized by uncontrolled cellular
proliferation leading to a mass or tumor (neoplasm).
• The abnormal accumulation of cells in a neoplasm occurs because of
an imbalance between the normal processes of cellular proliferation
and cellular attrition.
• For a neoplasm to be a cancer, however, it must also be malignant,
which means that not only is its growth uncontrolled, it is also
capable of invading neighboring tissues that surround the original
site (the primary site) and can spread (metastasize) to more distant
sites.
• Tumors that do not invade or metastasize are not cancerous but are
referred to as benign tumors, although their abnormal function, size
or location may make them anything but benign to the patient.
Cancer is not a single disease but rather comes in
many forms and degrees of malignancy. There are three
main classes of cancer:
• Sarcomas, in which the tumor has arisen in mesenchymal tissue, such
as bone, muscle, or connective tissue, or in nervous system tissue;
• Carcinomas, which originate in epithelial tissue, such as the cells
lining the intestine, bronchi, or mammary ducts; and
• Hematopoietic and lymphoid malignant neoplasms, such as
leukemia and lymphoma, which spread throughout the bone marrow,
lymphatic system, and peripheral blood.
• Within each of the major groups, tumors are classified by site, tissue
type, histological appearance, degree of malignancy, chromosomal
aneuploidy, and, increasingly, by which gene mutations and
abnormalities in gene expression are found within the tumor.
 GENETIC BASIS OF CANCER

• Driver and Passenger Gene Mutations

• Oncogenes and Tumor Suppressor Genes

➢ CANCER IN FAMILIES
➢ SPORADIC CANCERS
➢ APPLYING GENOMICS TO INDIVIDUALIZE CANCER THERAPY
➢ CANCER and THE ENVIRONMENT
GENETIC BASIS OF CANCER
Driver and Passenger Gene Mutations
➢By analyzing many thousands of samples obtained from more than
30 types of human cancer, researchers are building The Cancer
Genome Atlas, a public catalog of mutations, epigenomic
modifications, and abnormal gene expression profiles found in a wide
variety of cancers.
• General scheme for
development of a carcinoma
in an epithelial tissue such as
colonic epithelium.
• The diagram shows
progression from normal
epithelium to local
proliferation, invasion across
the lamina propria, spread to
local lymph nodes, and final
distant metastases to liver
and lung.
• Most mutations found through sequencing of tumor tissue appear to
be random, are not recurrent in particular cancer types, and probably
occurred as the cancer developed, rather than directly causing the
neoplasia to develop or progress. Such mutations are referred to as
“passenger” mutations.
• A subset of a few hundred genes has been repeatedly found to be
mutated at high frequency in many samples of the same type of
cancer or even in multiple different types of cancers, mutated in fact
far too frequently to simply be passenger mutations.
• These genes are thus presumed to be involved in the development or
progression of the cancer itself and are therefore referred to as
“driver” genes, that is, they harbor mutations (so-called driver gene
mutations) that are likely to be causing a cancer to develop or
progress.
• EXP: The TP53 gene encoding the p53 protein
• Many different genome alterations can act as driver gene mutations.
• In some cases, a single nucleotide change or small insertion or deletion can
be a driver mutation.
• Large numbers of cell divisions are required to produce an adult organism
of an estimated 1014 cells from a single-cell zygote.
• Given a frequency of 10−10 replication errors per base of DNA per cell
division, and an estimated 1015 cell divisions during the lifetime of an adult,
replication errors alone result in thousands of new single nucleotide or
small insertion/deletion mutations in the genome in every cell of the
organism.
• Some environmental agents, such as carcinogens in cigarette smoke or
ultraviolet or X-irradiation, will increase the rate of mutations around the
genome.
• If, by chance, mutations occur in critical driver genes in a particular cell,
then the oncogenic process may be initiated.
The Cellular Functions of Driver Genes
• The nature of some driver gene mutations comes as no surprise: the
mutations directly affect specific genes that regulate processes that
are readily understood to be important in oncogenesis. These
processes include;
• cell cycle regulation,
• cellular proliferation,
• differentiation and exit from the cell cycle,
• growth inhibition by cell-cell contacts, and
• programmed cell death (apoptosis).
• Other driver genes affect translation, for example, genes that encode
noncoding RNAs from which regulatory microRNAs (miRNAs) are
derived
• Many miRNAs have been found to be either greatly overexpressed or
down-regulated in various tumors, sometimes strikingly so. Because
each miRNA may regulate as many as 200 different gene targets,
overexpression or underexpression of miRNAs may have widespread
oncogenic effects because many driver genes will be dysregulated.
• Noncoding miRNAs that impact gene expression and contribute to
oncogenesis are referred to as oncomirs.
 Oncogenes and Tumor
Suppressor Genes
• The first category includes proto-oncogenes. These are normal genes
that, when mutated in very particular ways, become driver genes
through alterations that lead to excessive levels of activity. Once
mutated in this way, driver genes of this type are referred to as
activated oncogenes.
• The second, and more common, category of driver genes includes
tumor suppressor genes (TSGs), mutations in which cause a loss of
expression of proteins necessary to control the development of
cancers. To drive oncogenesis, loss of function of a TSG typically
requires mutations at both alleles.
 CANCER IN FAMILIES
• Although essentially all individuals are at risk for some cancer at some
point during their lives, many forms of cancer have a higher incidence
in relatives of patients than in the general population.
• In some cases, this increased incidence is due primarily to inheritance
of a single mutant gene with high penetrance.
• These mutations result in hereditary cancer syndromes following
mendelian patterns of inheritance.
• Among these syndromes, we currently know of approximately 100
different genes in which deleterious mutations increase the risk for
cancer many-fold higher than in the general population.
Activated Oncogenes in Hereditary Cancer Syndromes

Multiple Endocrine Adenomatosis, Type 2 (MEN2)

• is an autosomal dominant disorder characterized by a high incidence
of medullary carcinoma of the thyroid that is often but not always
associated with pheochromocytoma, benign parathyroid adenomas,
or both.
• Patients with the rarer type B variant, termed MEN2B, have, in
addition to the tumors seen in patients with MEN2A, thickening of
nerves and the development of benign neural tumors, known as
neuromas, on the mucosal surface of the mouth and lips and along
the gastrointestinal tract.
• The mutations responsible for MEN2 are in the RET gene.
• RET encodes a cell-surface protein that contains an extracellular
domain that can bind signaling molecules and a cytoplasmic tyrosine
kinase domain.
• The mutations in RET that cause MEN2A increase its kinase activity
even in the absence of its ligand (a state referred to as constitutive
activation).
Exp: Hirschsprung disease
 The Two-Hit Theory of Tumor Suppressor Gene
Inactivation in Cancer
• The hereditary form of the childhood cancer retinoblastoma might be
initiated when a cell in a person heterozygous for a germline mutation
in the retinoblastoma TSG, required to prevent the development of
the cancer, undergoes a second, somatic event that inactivates the
other retinoblastoma gene allele.
• As a consequence of this second somatic event, the cell loses function
of both alleles, giving rise to a tumor. In the sporadic form of
retinoblastoma, both alleles are also inactivated, but in this case, the
inactivation results from two somatic events occurring in the same
cell.
• This so-called two-hit model is now widely accepted as the
explanation for many hereditary cancers in addition to
retinoblastoma, including familial polyposis coli, familial breast
cancer, neurofibromatosis type 1 (NF1), Lynch syndrome, and Li-
Fraumeni syndrome.
Retinoblastoma in a
young girl, showing
as a white reflex in
the affected left eye
when light reflects
directly off the
tumor surface.
The second hit can be caused by a variety of genetic, epigenetic, or
genomic mechanisms.
 SPORADIC CANCER
• How does sporadic cancer occur?
• Activation of Oncogenes by Point Mutation
• Loss of Tumor Suppressor Gene in Sporadic Cancer
• Activation of Oncogenes by Chromosome Translocation
Ras Oncogene
• One of the first activated oncogenes discovered was a mutant RAS
gene derived from a bladder carcinoma cell line.
• RAS encodes one of a large family of small guanosine triphosphate
(GTP)–binding proteins (so-called G proteins) that serve as molecular
“on-off” switches to activate or inhibit downstream molecules.
• Remarkably, the activated oncogene and its normal counterpart
proto-oncogene differed at only a single nucleotide.
• The alteration led to synthesis of an abnormal Ras protein that was
able to signal continuously, thus stimulating cell division and changing
it into a tumor.
Ras Oncogene
• RAS point mutations are now known in many tumors, and the RAS
genes have been shown experimentally to be the mutational target of
known carcinogens, a finding that supports a role for mutated RAS
genes in the development of many cancers.
• To date, nearly 50 human proto-oncogenes have been identified as
driver mutations in sporadic cancer.
• Only a few of these proto-oncogenes have also been found to be
inherited in a hereditary cancer syndrome.
Activation of Oncogenes by Chromosome Translocation

• As pointed out previously, oncogene activation is not always the

result of a DNA mutation.
• In some instances, a proto-oncogene is activated by a
subchromosomal mutation, typically a translocation.
• More than 40 oncogenic chromosome translocations have been
described to date, primarily in sporadic leukemias and lymphomas
but also in a few rare connective tissue sarcomas.
• In some cases, translocation breakpoints lie within the introns of two
genes, thereby fusing two genes into one abnormal gene that
encodes a chimeric protein with novel oncogenic properties.

→BCR/abl translocation
Chronic Myelogenous Leukemia
• The translocation between chromosomes 9 and 22, the so-called
Philadelphia chromosome that is seen in chronic myelogenous
leukemia (CML).
• The translocation moves the protooncogene ABL1, a tyrosine kinase,
from its normal position on chromosome 9q to a gene of unknown
function, BCR, on chromosome 22q. The translocation results in the
synthesis of a novel, chimeric protein, BCR-ABL1, containing a
portion of the normal Abl protein with increased tyrosine kinase
activity.
The Philadelphia chromosome
translocation, t(9;22)(q34;q11).
The Philadelphia chromosome
(Ph1) is the derivative
chromosome 22, which has
exchanged part of its long arm
for a segment of material from
chromosome 9q that contains
theABL1 oncogene.
Formation of the chimeric BCR-
ABL1 gene on the Ph1
chromosome is the critical
genetic event in the
development of chronic
myelogenous leukemia.
TP53 in sporadic cancer
• Although Li-Fraumeni syndrome, caused by a dominantly inherited
germline mutation in the TP53 gene, is a rare familial syndrome,
somatic mutation causing a loss of function of both alleles of TP53 is
one of the most common genetic alterations seen in sporadic cancer.
• Mutations of TP53, deletion of the segment of chromosome 17p that
includes TP53, or loss of the entire chromosome 17 is frequently and
repeatedly seen in a wide range of sporadic cancers.
• These include breast, ovarian, bladder, cervical, esophageal,
colorectal, skin, and lung carcinomas; glioblastoma of the brain;
osteogenic sarcoma; and hepatocellular carcinoma.
RB1 in sporadic cancer
• The retinoblastoma gene RB1 is also frequently mutated in many
sporadic cancers, including breast cancer.
• For example, 13q14 LOH in human breast cancers is associated with
loss of RB1 mRNA in the tumor tissues.
• In still other cancers, the RB1 gene is intact and its mRNA appears to
be at or near normal levels, yet the RB1 protein is deficient.
• This anomaly has now been explained by the recognition that RB1 can
be down-regulated in association with overexpression of the oncomir
miR-106a, which targets RB1 mRNA and blocks its translation.
APPLYING GENOMICS TO INDIVIDUALIZE CANCER THERAPY

• Genomics is already having a major impact on diagnostic precision

and optimization of therapy in cancer.
• Gene expression profiling is used to guide diagnosis and treatment.
• Comparative hybridization techniques can be used to measure
simultaneously the level of mRNA expression of some or all of the
estimated 20,000 protein-coding genes in any human tissue sample.
• A measurement of mRNA expression in a sample of tissue constitutes
a gene expression profile specific to that tissue.
• Using such tools, one can organize the data to find groups of genes
whose expression seems to correlate, that is, increase or decrease
together, between and among the samples.
• Grouping genes by their patterns of expression across samples is
termed clustering.
Gene Expression Profiling in Cancer Prognosis
• Choosing the appropriate therapy for most cancers is difficult for
patients and their physicians alike, because recurrence is common
and difficult to predict.
• Better characterization of each patient’s cancer as to recurrence risk
and metastatic potential would clearly be beneficial for deciding
between more or less aggressive courses of surgery and/or
chemotherapy.
• For example, in breast cancer, although presence of the estrogen and
progesterone receptors, amplification of the human epidermal
growth factor receptor 2 (HER2) oncogene, and absence of metastatic
tumor in lymph nodes found on dissection of axillary lymphatics are
strong predictors of better response to therapy and prognosis, they
are still imprecise.
CANCER AND THE ENVIRONMENT

• By environment, we include exposure to a wide variety of different

types of agents—food, natural and artificial radiation, chemicals, even
which viruses and bacteria are colonizing the gut.
• The risk for cancer shows significant variation among different
populations and even within the same population in different
environments.
• The gastric cancer is almost three times as common among Japanese
in Japan as among Japanese living in Hawaii or Los Angeles.
• According to some estimates based chiefly on data from the
aftermath of the atomic bombings of Hiroshima and Nagasaki, as
much as 75% of the risk for cancer may be environmental in origin.
• In other cases, there appears to be a correlation between certain
exposures and risk for cancer, such as the benefits of dietary fiber or
low-dose aspirin therapy in lowering colon cancer risks.