Dataset Information

Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer.

ABSTRACT: Mucinous colorectal carcinomas (MC) constitute 10% of colorectal malignancies. Recently, an increased risk of colorectal cancer has been demonstrated in germline BRCA1/2 mutation carriers. Furthermore, BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of MC tumors. Here, we investigate the relationship between BRCA mutations and mucinous histology in colorectal carcinoma patients, using both an existing cohort of sequenced colorectal tumors and a prospective case-control study comparing MC and conventional adenocarcinoma (AC) patients tested for BRCA mutations. We discovered that MC tumors exhibit a statistically significantly higher incidence of BRCA mutations in addition to a higher average mutation count when compared to AC tumors in the existing cohort. The strongest predictor of the mutation count was mucinous histology, independently of other variables including microsatellite instability. Contrary to our hypothesis, the first association did not recur in the prospective case-control study, likely due to our pathological definition of MC tumors and small sample size. Finally, we observed a higher tumor mutational burden (TMB) in MC tumors compared with AC tumors. We suggest that the association between MC histology, BRCA mutations, and increased TMB may open the door to the utilization of simple tests (such as histopathologic characterization) to detect patients who may benefit from immunotherapy in colorectal cancer.

SUBMITTER: Harpaz N

PROVIDER: S-EPMC7196997 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer.

Harpaz Noa N Gatt Yair Eli YE Granit Roy Zvi RZ Fruchtman Hila H Hubert Ayala A Grinshpun Albert A

Journal of oncology 20200425

Mucinous colorectal carcinomas (MC) constitute 10% of colorectal malignancies. Recently, an increased risk of colorectal cancer has been demonstrated in germline BRCA1/2 mutation carriers. Furthermore, BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of MC tumors. Here, we investigate the relationship between BRCA mutations and mucinous histology in colorectal carcinoma patients, using both an existing cohort of sequenced colorectal tumors a ...[more]

PMID: 32377194

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Project description:BACKGROUND: Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer. METHODS AND RESULTS: The total number of synonymous and non-synonymous exome mutations (Nmut), and the presence of germline or somatic mutation in BRCA1 or BRCA2 (mBRCA) were extracted from whole-exome sequences of high-grade serous ovarian cancers from The Cancer Genome Atlas (TCGA). Cox regression and Kaplan-Meier methods were used to correlate Nmut with chemotherapy response and outcome. Higher Nmut correlated with a better response to chemotherapy after surgery. In patients with mBRCA-associated cancer, low Nmut was associated with shorter progression-free survival (PFS) and overall survival (OS), independent of other prognostic factors in multivariate analysis. Patients with mBRCA-associated cancers and a high Nmut had remarkably favorable PFS and OS. The association with survival was similar in cancers with either BRCA1 or BRCA2 mutations. In cancers with wild-type BRCA, tumor Nmut was associated with treatment response in patients with no residual disease after surgery. CONCLUSIONS: Tumor Nmut was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.

Dataset Information

Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer.

Publications

Mucinous Histology, <i>BRCA1/2</i> Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer.

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