Dataset Information

Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome.

ABSTRACT:

Aim of work

Reporting the incidence and the variants of BRCA1/2 mutations in ovarian cancer patients exploring their effects on the treatment outcomes.

Patients and methods

In total, 104 patients with epithelial ovarian cancer were prospectively recruited to the study. Analysis consisted of the sequencing of all the translated exons and immediately adjacent intronic regions of the BRCA1/2 genes. Responses to multiple lines of chemotherapy were assessed, as well as the effect of BRCA gene mutations on progression-free survival (PFS) and overall survival (OS).

Results

Pathogenic BRCA1/2 mutations were found in 21.15% of the patients. BRCA1 mutations represented 68.2% of the total mutations. Two novel BRCA1 mutations were identified. Age at diagnosis was a strong predictor of the presence of a pathogenic BRCA1/2 mutation. Patients with a family history of cancer had a higher incidence of BRCA mutations (P=0.005). As high as 72% of the patients with BRCA mutations were diagnosed at advanced stage. High-grade serous tumors have a higher incidence of pathogenic mutation (P=0.07). Response to neoadjuvant chemotherapy was high (93.9%). All patients underwent surgery which was optimal in 73.1% of the patients. As high as 85.6% of the patients received adjuvant chemotherapy. Relapse rate was 45.2%. Visceral metastasis was more often in BRCA carriers (P=0.01). Patients carrying pathogenic BRCA1/2 mutations had a longer median PFS of 42.43 months (95% CI 32.04-52.83) compared to 22.24 months (95% CI 14.83-29.58) for non-carriers (P=0.08). OS was 64.32 months (95% CI 38.09-90.06) for BRCA mutation patients versus 56.63 months (95% CI 50.05-63.21) (P=0.04) for non-carriers. In multivariate analysis, early stage at diagnosis and optimal debulking were the only independent predictors of better PFS and OS.

Conclusion

We documented a number of pathogenic BRCA1 and 2 mutations in this patients cohort; two novel mutations were detected. BRCA status seemed to affect survival in ovarian cancer patients.

SUBMITTER: Ashour M

PROVIDER: S-EPMC6626894 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome.

Ashour Mohamed M Ezzat Shafik Hanan H

Cancer management and research 20190708

<h4>Aim of work</h4>Reporting the incidence and the variants of <i>BRCA1</i>/2 mutations in ovarian cancer patients exploring their effects on the treatment outcomes.<h4>Patients and methods</h4>In total, 104 patients with epithelial ovarian cancer were prospectively recruited to the study. Analysis consisted of the sequencing of all the translated exons and immediately adjacent intronic regions of the <i>BRCA1/2</i> genes. Responses to multiple lines of chemotherapy were assessed, as well as th ...[more]

PMID: 31372034

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Project description:ObjectiveTo investigate the prevalence of BRCA1/2 gene variants and evaluate the clinical and pathological characteristics associated with these variants in Chinese Hakka breast cancer patients.MethodsA total of 409 breast cancer patients were analyzed based on next-generation sequencing results, with 337 categorized as non-carriers and 72 as carriers of BRCA1/2 variants. Data on the patients' BRCA1/2 gene mutation status, clinical and pathological characteristics, as well as menstrual and reproductive information, were collected, analyzed, compared, and tabulated. Logistic regression analysis was performed to explore the relationship between clinical characteristics and pathogenic variants.ResultsAmong the patients, 72 were identified as carriers of pathogenic or likely pathogenic variants in BRCA1/2, while 337 had likely benign or benign mutations. The BRCA1 c.2635G > T (p. Glu879*) variant was detected at a high frequency, accounting for 12.5% (4/32) of the BRCA1 mutations, while the c.5164_5165del (p.Ser1722Tyrfs*4) variant was common among the BRCA2 mutations, accounting for 17.5% (7/40). It was observed that a higher proportion of BRCA1 carriers had the triple-negative breast cancer subtype, whereas more BRCA2 carriers exhibited estrogen receptor (ER) + and progesterone receptor (PR) + subtypes. Multivariate logistic regression analysis revealed that a family history of cancer (OR = 2.36, 95% CI = 1.00-5.54), bilateral cancer (OR = 4.78, 95% CI 1.61-14.20), human epidermal growth factor receptor 2 (HER2)- (OR = 8.23, 95% CI 3.25-20.84), and Ki67 ≥ 15% (OR = 3.88, 95% CI 1.41-10.65) were associated with BRCA1/2 mutations, with the age at diagnosis, age at menarche, and premenopausal status serving as covariates.ConclusionsThe most common pathogenic variant of the BRCA1 and BRCA2 in breast cancer patients was c.2635G > T and c.5164_5165del, respectively. Additionally, a family history of cancer, bilateral cancer, HER2-, and Ki67 ≥ 15% were identified as independent predictors of BRCA1/2 pathogenic variants.

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.

Project description:A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age <50 years were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at age >60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95%CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.

Dataset Information

Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome.

Aim of work

Patients and methods

Results

Conclusion

Publications

Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome.

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