GENE-North: Germline Next-Generation Sequencing to Uncover Pathogenic and Familial Cancer Genes in Solid Cancers (other than Breast and Ovary) in North India

In India breast and ovarian cancers have been the primary focus of germline testing but there is a growing body of evidence suggesting a significant hereditary component in other solid tumors such as renal cell carcinoma RCC colorectal endometrial pancreatic prostate thyroid lung head-neck rare tumors and gallbladder cancer GBC.

Renal cell carcinoma RCC and thyroid cancer are both known to have a hereditary component with 3 to 5 percent of RCC and up to 10 percent of differentiated thyroid cancers linked to pathogenic germline variants in cancer predisposition genes. While syndromic causes eg VHL FH FLCN in RCC RET in medullary thyroid carcinoma are well-characterised emerging evidence suggests that a significant proportion of patients even without classical high-risk features harbour pathogenic or likely pathogenic P/LP germline variants particularly in DNA damage response DDR and mismatch repair MMR genes.

Recent Indian data in advanced RCC demonstrate a 20 percent prevalence of germline P/LP variants of which nearly 80 percent would have been missed using conventional testing criteria. Comparable germline data for thyroid cancer in the Indian population are lacking.

Gallbladder cancer is notably more prevalent in the Gangetic belt Uttar Pradesh Bihar and North-East India. Although data is limited familial clustering and early-onset cases suggest potential germline predisposition possibly involving genes like TP53 BRCA1/2 MMR genes STK11 and CDKN2A. This warrants formal exploration.

Understanding the prevalence and spectrum of such variants in unselected patients across all stages is crucial for

Refining genetic testing guidelines relevant to the Indian population.

Identifying at-risk family members through cascade screening.

Exploring therapeutic implications for targeted therapies eg PARP inhibitors ICIs VEGF-TKIs RET inhibitors.

This multicentre study aims to evaluate the prevalence of germline pathogenic or likely pathogenic P/LP variants in unselected patients across a range of non-breast/ovary solid tumors.

Identifying at-risk family members through cascade screening.

Exploring therapeutic implications for targeted therapies eg PARP inhibitors ICIs VEGF-TKIs RET inhibitors.

This multicentre study aims to evaluate the prevalence of germline pathogenic or likely pathogenic P/LP variants in unselected patients across a range of non-breast/ovary solid tumors.