Human Oncology & Pathology Program

Polymorphous low-grade adenocarcinoma (PLGA) is the second most frequent type of malignant tumor of the minor salivary glands. We identified PRKD1 hotspot mutations encoding p.Glu710Asp in 72.9% of PLGAs but not in other salivary gland tumors. Functional studies demonstrated that this kinase-activating alteration likely constitutes a driver of PLGA.

Somatic mutations in exon 2 of the MED12 gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumors (PTs) would harbor MED12 somatic mutations in a way akin to FAs. A collection of 73 fibroepithelial tumors (including 26 FAs, 25 benign PTs, 9 borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from FFPE blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumor and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs significantly less frequently harbored MED12 exon 2 somatic mutations than FAs, benign and borderline PTs. Although M...

Acinic cell carcinoma (ACC) of the breast is a rare form of triple-negative (that is, estrogen receptor-negative, progesterone receptor-negative, HER2-negative) salivary gland-type tumor displaying serous acinar differentiation. Despite its triple-negative phenotype, breast ACCs are reported to have an indolent clinical behavior. Here, we sought to define whether ACCs have a mutational repertoire distinct from that of other triple-negative breast cancers (TNBCs). DNA was extracted from microdissected formalin-fixed paraffin-embedded sections of tumor and normal tissue from two pure and six mixed breast ACCs. Each tumor component of the mixed cases was microdissected separately. Tumor and normal samples were subjected to targeted capture massively parallel sequencing targeting all exons of 254 genes, including genes most frequently mutated in breast cancer and related to DNA repair. Selected somatic mutations were validated by targeted amplicon resequencing and Sanger sequencing. Akin to other forms of TNBC, the most frequently mutated gene found in breast ACCs was TP53 (one pure and six mixed cases). Additional somatic mutations affecting breast cancer-related genes found in ACCs included PIK3CA, MTOR, CTNNB1, BRCA1, ERBB4, ERBB3, INPP4B and FGFR2. Copy number alteration analysis revealed complex patterns of gains and losses similar to those of TNBCs. Of the mixed cases analyzed,

In this study, we have investigated, by immunohistochemical technique, the expression and potential prognostic significance of survivin in a series of 49 clear cell type renal cell carcinoma (ccRCC). Survivin expression was significantly associated with poorly differentiated, advanced stages and more aggressive ccRCCs (p < 0.05). Patients with low survivin expression had statistically significant better survival rates than patients with high survivin expression (p < 0.05). This may be relevant for follow-up protocols design and/or alternative therapeutic approaches.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death. Despite the advances in diagnosis and management of HCC, the biology of this tumor remains poorly understood. Recent evidence highlighted long noncoding RNAs (lncRNAs) as crucial determinants of HCC development. In this study we report the lncRNA HOXA transcript at the distal tip (HOTTIP) as significantly up-regulated in HCC specimens. The HOTTIP gene is located in physical contiguity with HOXA13 and directly controls the HOXA locus gene expression by way of interaction with the WDR5/MLL complex. HOX genes encode transcription factors regulating embryonic development and cell fate. We previously described HOX genes deregulation to be involved in hepatocarcinogenesis. Indeed, we observed the marked up-regulation of HOXA13 in HCC. Here, by correlating clinicopathological and expression data, we demonstrate that the levels of HOTTIP and HOXA13 are associated with HCC patients' clinical progression and predict disease outcome. In contrast to the majority of similar studies, our data were obtained from snap-frozen needle HCC biopsies (n 5 52) matched with their nonneoplastic counterparts collected from patients who had not yet received any HCC-tailored therapeutic treatments at the time of biopsy. In addition, taking advantage of gain and loss of function experiments in liver cancer-derived cell lines (HuH-6 and HuH-7), we uncover a novel bidirectional regulatory loop between HOTTIP/HOXA13. Conclusion: Our study highlights the key role of HOTTIP and HOXA13 in HCC development by associating their expression with metastasis and survival in HCC patients, provides novel insights on the function of lncRNA-driven hepatocarcinogenesis, and paves the way for further investigation about the possible role of HOTTIP as a predictive biomarker of HCC. (HEPATOLOGY 2014;59:911-923)

Acinic cell carcinoma (ACC) of the breast is a rare form of triple-negative (that is, estrogen receptor-negative, progesterone receptor-negative, HER2-negative) salivary gland-type tumor displaying serous acinar differentiation. Despite its triple-negative phenotype, breast ACCs are reported to have an indolent clinical behavior. Here, we sought to define whether ACCs have a mutational repertoire distinct from that of other triple-negative breast cancers (TNBCs). DNA was extracted from microdissected formalin-fixed paraffin-embedded sections of tumor and normal tissue from two pure and six mixed breast ACCs. Each tumor component of the mixed cases was microdissected separately. Tumor and normal samples were subjected to targeted capture massively parallel sequencing targeting all exons of 254 genes, including genes most frequently mutated in breast cancer and related to DNA repair. Selected somatic mutations were validated by targeted amplicon resequencing and Sanger sequencing. Akin to other forms of TNBC, the most frequently mutated gene found in breast ACCs was TP53 (one pure and six mixed cases). Additional somatic mutations affecting breast cancer-related genes found in ACCs included PIK3CA, MTOR, CTNNB1, BRCA1, ERBB4, ERBB3, INPP4B and FGFR2. Copy number alteration analysis revealed complex patterns of gains and losses similar to those of TNBCs. Of the mixed cases analyzed,

Polymorphous low-grade adenocarcinoma (PLGA) is the second most common intra-oral salivary gland malignancy. The vast majority of PLGAs harbor a PRKD1 E710D hotspot somatic mutation or somatic rearrangements of PRKD1, PRKD2 or PRKD3. Given the kinase domain homology among PRKD1, PRKD2 and PRKD3, we sought to define whether PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements would be driven by somatic mutations affecting the kinase domains of PRKD2 or PRKD3. DNA was extracted from 8 microdissected PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements. Samples were thoroughly centrally reviewed, microdissected and subjected to Sanger sequencing of the kinase domains of PRKD2 and PRKD3 genes. None of the PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements harbored somatic mutations in the kinase domains of PRKD2 or PRKD3 genes. PLGAs lacking PRKD1 somatic mutations or PRKD gene family rearrangements are unlikely to harbor som...