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Real world evidence of germline alterations in women with Breast and Ovarian cancer beyond BRCA from South Asian population

Cancer Genetics and Therapeutics
  • Primary Categories:
    • Cancer
  • Secondary Categories:
    • Cancer
Introduction:
BRCA1/2 predominates the risk of hereditary breast-ovarian cancer in young women. However, analysis using broader gene panels may reveal non-BRCA1/2 mutations that may predispose to cancer. Here, we provide the results of our germline profiling method using a larger gene panel (Germline+ [213 genes], 4basecare) in breast and ovarian cancer patients from the South Asian population.

Methods:
The study includes 233 patients with a diagnosis of breast/ovarian cancer, where we identified clinically relevant alterations (Pathogenic/ Likely pathogenic/ Variants of Uncertain Significance with literature support) and classified as per ACMG guidelines. Germline+ panel sequencing was performed using Illumina sequencing at ~100X depth to identify novel biomarkers in Breast and Ovarian cancer patients.

Results:
47% (n=109) of these patients carried either BRCA1 or BRCA2 mutations. In the non-BRCA group, nearly 53% (n=123) of the patients carried mutations in the DNA repair pathway (ATM, RAD54L, BRIP1, FANCM, PALB2, CHEK2). We also found pathogenic variants in relatively uncommon genes like AXIN2, PPM1D and RET.

Variants were also reported in Receptor tyrosine kinase (CBL, PDGFRA, MET), cellular metabolism (SDHA, SDHB), chromatin remodeling (MRE11, ARID1A, NSD1) and Wnt/beta-catenin (APC, CTNNA1) pathway-based genes.

Conclusion:
Key findings from this study demonstrates, nearly 53% of the individuals with the clinical phenotype of hereditary breast and ovarian cancers are BRCA negative. However, they possess genetic alterations other than BRCA1/2 genes, which are associated with cancer risk predisposition. This study summarizes the findings of >200 cases of several intriguing familial presentation with non-syndromic genetic alterations in pathways such as DNA repair, receptor tyrosine kinase, cellular metabolism, chromatin remodelling and Wnt/beta-catenin.

Based on our observations, limited panel testing of the BRCA1/2 significantly reduces the diagnostic yield. Hence, we emphasize screening for rare genetic alterations in families with high risk of developing HBOC or other cancers. Though there are no standard guidelines/ recommendations for germline panel testing, implementation of broader gene panels would aid in risk assessment, selection of appropriate treatment option and better stratification of cancer patients in precision oncology practice.

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