Molecular characterization of mucinous ovarian carcinoma

Abstract

Mucinous ovarian carcinoma (MOC) is a rare, chemoresistant tumor known to share pathologic features with tumors of the gastrointestinal and pancreaticobiliary tracts. To better understand the genomic and proteomic landscapes of invasive MOCs, we identified somatic mutations and proteins expression in a single institution cohort and compared these results with data from TCGA tumor projects.

Twenty-six tumors consistent with primary invasive MOC after expert pathology review and with available paired tumor and normal tissue were identified from institutional databases between July 2001 and July 2012. DNA extracted from FFPE or fresh frozen samples underwent next generation sequencing with a combination of a candidate gene assay (37 genes), the MSK-IMPACT assay (341 genes), transcriptome sequencing, and whole exome sequencing. Copy number alterations were identified using data from the MSK-IMPACT assay, whole exome sequencing or Affymetrix SNP 6.0 arrays. Immunohistochemistry (IHC) was performed using optimized antibodies for six proteins to confirm the diagnosis of MOC (ER, PR, CK7, CK20, CDX-2, PAX8) and seven proteins to correlate with mutation status and copy number alterations (p53, ARID1A[Baf250a], PTEN, PMS2, MSH6, HER2, p16). Mutation data for other TCGA tumor types was obtained from the cBio Cancer Genomics Portal (cbioportal.org).

The median age of the cohort was 58 years (range 20-86 years). Most (19/26, 73%) of the tumors were stage I. Somatic TP53 and KRAS mutations were the most common seen and were identified in 18 (69%) cases each, with a co-mutation rate of 50% (13/26). Other commonly mutated genes include ARID1A,PTEN, and PIK3CA. Homozygous deletions of CDKN2A were found in 27% (7/26). ERBB2 alterations were identified in 19% (5/26) and consisted of three amplifications and two mutations. Mutations in at least one potentially targetable gene were identified in 42% (11/26) of tumors. IHC was concordant with sequencing results in 154/182 (85%) of stained cases. Pancreatic, colorectal, lung adenocarcinoma, endometrial, and stomach cancers have the highest frequency of KRAS mutations. Co-mutations of KRAS and TP53 occur most commonly in pancreatic (59%) and colorectal (21%) carcinomas. CDKN2Ahomozygous deletions are also found at a similar frequency in pancreatic adenocarcinomas (28%). When evaluating the mutation rates of the five most commonly mutated genes in our MOC cohort with colorectal, pancreatic, gastric and high-grade serous ovarian carcinomas (HGSOC) in the TCGA datasets, pancreatic adenocarcinoma showed the most similarity. HGSOC showed little similarity to the MOCs.

KRAS and TP53 co-mutation are common in invasive MOCs. Other commonly mutated genes include ARID1A, PTEN, and PIK3CA. Potentially targetableERBB2 alterations were identified in several cases. Despite anatomic distinctions, the mutational landscape of MOC shares similarities with that of pancreatic adenocarcinoma including frequent CDKN2A deletions andKRAS/TP53 co-mutation. The suggested shared molecular pattern with pancreatic adenocarcinoma offers potential to guide future developmental therapeutics.