Investigating the landscape of rare germline variants in cancer – from cancer risk to treatment response

Abstract

The widespread adoption of next-generation sequencing has enhanced our capacity to accurately characterize disease-causing rare germline variants, particularly in oncology. In this thesis, we developed and employed a comprehensive rare germline variant analysis strategy to address challenges in analyzing large sequencing data and identify causal rare germline variants related to cancer susceptibility and treatment response, offering fresh perspectives in unraveling the genetic underpinnings of cancer and advancing personalized cancer therapy. We started by enlisting five families with an extensive history of cancer but lacking any detectable causal variant to account for the cancer clustering. We carried out whole-genome sequencing and thoroughly investigated both coding and non-coding regions, identifying candidate rare germline pathogenic variants shared by affected family members in known germline cancer predisposition genes. (Chapter 1) We then conducted a comprehensive case-control study of 1,356 renal cell carcinoma (RCC) patients and 16,512 ancestry-matched cancer-free controls, confirming links between certain germline pathogenic variants and elevated RCC risk while emphasizing the importance of fine-level population stratification. Additionally, we detected a high frequency of secondary somatic alterations in the same RCC risk genes, which manifested as earlier age of cancer onset. We also broadened our investigation for germline rare variants to encompass previously underexplored types of variants and uncovered potential germline causal cryptic splice and copy number variants in known RCC risk genes. (Chapter 2) Lastly, we analyzed both germline and somatic genomic features in whole exome- sequencing data from 28 high-grade serous ovarian cancer patients before and after platinum- based neoadjuvant chemotherapy (NACT) to elucidate the interplay between germline and somatic variants governing platinum response. We identified higher frequency of rare germline variants accompanied by somatic alterations in patients sensitive to NACT in DNA damage repair genes and other genes linked to platinum response. Moreover, our findings suggest that platinum-based chemotherapy selectively eliminates specific tumor populations presumably more sensitive to the treatment, resulting in reduced tumor heterogeneity after treatment. (Chapter 3) Collectively, our findings underscore the significance of rare germline pathogenic variants in determining cancer susceptibility and treatment response and provide valuable insights for refining strategies in cancer germline genetics studies.