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<p>Breast cancer has emerged as the leading malignancy among Indian women, with a notable subset of cases linked to inherited genetic predisposition. Germline testing is a vital tool for identifying individuals at elevated risk, guiding targeted therapies such as PARP inhibitors, and informing preventive strategies through family-based screening. However, population-specific data from India remain limited, and most studies have focused narrowly on <i>BRCA1/2</i>. In this study, we employed high-depth germline whole exome sequencing to comprehensively evaluate cancer susceptibility in 479 unselected Indian breast cancer patients sourced from a National Cancer Tissue Biobank. Pathogenic or likely pathogenic variants were identified in 24.6% of the cohort, including 8.35% in <i>BRCA1/2.</i> Notably, 67% of these findings were in non-<i>BRCA</i> genes, including HRR and tumor suppressor genes, which would be missed by <i>BRCA</i>-only testing. The unbiased, broad-panel approach enabled evaluation of emerging susceptibility genes such as <i>RECQL</i>. Additionally, we identified two clinically significant <i>DPYD</i> variants (c.1679T &gt; G and c.1905 + 1G &gt; A), associated with fluoropyrimidine toxicity risk. Beyond cancer risk, medically actionable secondary findings were detected in 21.7% of individuals, with variants in non-oncology genes listed in ACMG SF v3.2. Together, these findings highlight the genetic heterogeneity of hereditary breast cancer in India and demonstrate the clinical utility of comprehensive germline testing. While targeted multi-gene panels may suffice in clinical settings, whole-exome sequencing provides additional benefits by uncovering ancestry-specific susceptibility genes and actionable variants relevant for therapy and prevention in genetically diverse populations.</p>

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Germline mutational landscape in a large cohort of Indian breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月1日

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  • John Peter,
  • Bani Jolly,
  • Rajdeep Raha,
  • Jayalakshmi Jothi,
  • Avrajit Chakraborty,
  • Swaminathan Ganapathi Raman,
  • Selvi Radhakrishnan,
  • Sridhar Sivasubbu,
  • Vinod Scaria,
  • Sundarasamy Mahalingam

摘要

Breast cancer has emerged as the leading malignancy among Indian women, with a notable subset of cases linked to inherited genetic predisposition. Germline testing is a vital tool for identifying individuals at elevated risk, guiding targeted therapies such as PARP inhibitors, and informing preventive strategies through family-based screening. However, population-specific data from India remain limited, and most studies have focused narrowly on BRCA1/2. In this study, we employed high-depth germline whole exome sequencing to comprehensively evaluate cancer susceptibility in 479 unselected Indian breast cancer patients sourced from a National Cancer Tissue Biobank. Pathogenic or likely pathogenic variants were identified in 24.6% of the cohort, including 8.35% in BRCA1/2. Notably, 67% of these findings were in non-BRCA genes, including HRR and tumor suppressor genes, which would be missed by BRCA-only testing. The unbiased, broad-panel approach enabled evaluation of emerging susceptibility genes such as RECQL. Additionally, we identified two clinically significant DPYD variants (c.1679T > G and c.1905 + 1G > A), associated with fluoropyrimidine toxicity risk. Beyond cancer risk, medically actionable secondary findings were detected in 21.7% of individuals, with variants in non-oncology genes listed in ACMG SF v3.2. Together, these findings highlight the genetic heterogeneity of hereditary breast cancer in India and demonstrate the clinical utility of comprehensive germline testing. While targeted multi-gene panels may suffice in clinical settings, whole-exome sequencing provides additional benefits by uncovering ancestry-specific susceptibility genes and actionable variants relevant for therapy and prevention in genetically diverse populations.