DOI: 10.4103/crst.crst_260_23 ISSN: 2590-3233

Pan-cancer analysis of the spectrum of homologous recombination DNA repair (HRR) pathway genes in the Indian population: A retrospective observational study

Nasreen Parween, Trisha Dutta Gupta, Paridhy Vanniya Subramanyam, Nishtha Ajit Singh Tanwar, Archana S Narayana, Shabnam Hussain, Nusrath Fathima, Saranya Rangan, Ashwini Prakash, Sharanya Jayaraman, Vyomesh Javle, Pooja Gowda, K Anju, Linu Varghese, Peddagangannagari Sreekanthreddy, Raj Nagarkar, G Chithrathara, Vinusarathy, Rohit Raghunath Ranade, Saikrishna Kolluru, Sankar Srinivasan, Sudip Shrestha, Tushar Patil, Vashisht Maniar, Ashish Joshi, Sutapa Biswas, Ganesh Chandra Subuddhi, Ghanashyam Biswas, Raja Thirumalairaj, Amit Joshi, Kshitij D Rishi, Hitesh M Goswami, Vidya H Veldore
  • Cancer Research
  • Oncology (nursing)
  • Drug Guides
  • Oncology
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Background:

Homologous recombinant repair (HRR) deficit and the associated sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi) has been well studied in breast, ovarian, prostate, and pancreatic cancers, but very little is known about it in other cancer types.

Objectives:

We sought to understand the spectrum of HRR mutations in various cancer types, with the goal of identifying therapeutic targets in lesser-explored cancers.

Materials and Methods:

In this retrospective study conducted between January 2021 and December 2022, we analyzed a cohort of 659 patients with various cancer types with mutations in 15 HRR genes using next generation sequencing, at 4baseCare Onco Solutions Pvt. Ltd., Bengaluru, Karnataka, India.

Results:

We identified a total of 825 gene variants, including 366 likely pathogenic/pathogenic mutations (44.4%), with BRCA1 (196 variants; 22.8%), BRCA2 (183 variants; 21.3%), and ATM (157 variants; 18.3%) being prevalent. Germline and somatic mutations were prevalent in BRCA1 (114 variants; 60.3%) and BRCA2 (46 variants; 24%), respectively. Recurrent mutations were identified in 8 genes, including BRCA1, BRCA2, BRIP1, BARD1, CDK12, CHEK2, PALB2 and RAD54L. BRCA1 and BRCA2 mutations were observed in breast, gynecologic, and musculoskeletal cancers; ATM and BRCA2 in gastrointestinal and biliary tract cancers, respiratory, and head-and-neck cancers; BRCA2 and CDK12 in genitourinary cancers. Additionally, co-occurring mutations (in genes such as BRCA1-BRIP1, ATM-BRCA2, ATM-BRIP1) and known therapeutically significant mutations were identified.

Conclusions:

The presence of therapeutically significant HRR mutations across a broad spectrum of cancer types in our study suggests that these mutations can possibly be targeted, especially in cancers where there is a paucity of therapeutic targets. Further, non-BRCA HRR genes, such as ATM and CDK12, could play a more prominent role than previously recognized.

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