Dataset Information

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

ABSTRACT: Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n?=?7), primary aGCTs that subsequently recurred (n?=?9) and their matched recurrences (n?=?9), and aGCT recurrences without matched primary tumors (n?=?10) to targeted massively parallel sequencing of ?410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p?=?0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

SUBMITTER: Da Cruz Paula A

PROVIDER: S-EPMC7390666 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Da Cruz Paula Arnaud A da Silva Edaise M EM Segura Sheila E SE Pareja Fresia F Bi Rui R Selenica Pier P Kim Sarah H SH Ferrando Lorenzo L Vahdatinia Mahsa M Soslow Robert A RA Vidal August A Gatius Sonia S Przybycin Christopher G CG Abu-Rustum Nadeem R NR Matias-Guiu Xavier X Rubin Brian P BP Reis-Filho Jorge S JS DeLair Deborah F DF Weigelt Britta B

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20200312 8

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that ...[more]

PMID: 32203090

Similar Datasets

Project description:BACKGROUND:Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE:To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS:Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS:Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS:Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY:In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Dataset Information

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Publications

Genomic profiling of primary and recurrent adult granulosa cell tumors of the ovary.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets