Over the last decade, oncology has served as a paragon for the application of clinical genomics towards the
diagnosis and treatment of disease. The availability of high-throughput technologies for clinical assessment,
coupled with emerging knowledge of the genomic aberrations that promote the growth and progression of
tumors, has revolutionized cancer medicine. In 2014, we initiated a prospective clinical sequencing initiative to
examine 341 (now 468) cancer associated genes in tumor and matched normal specimens from patients with
advanced cancer, a cohort which now exceeds 25,000. We have used these data to identify and report somatic
mutations to facilitate enrollment to genomically matched clinical trials and pathogenic germline alleles to reveal
familial cancer susceptibility. Yet, we lack a fundamental understanding regarding the extent to which germline
alterations promote and interact with somatic mutations to affect cancer progression and response to therapy.
There remains a transformative opportunity to integrate germline and somatic analysis to further inform prognosis
and treatment decisions. Moreover, somatic mutational patterns and signatures can be harnessed to discover
novel germline alleles of biological and clinical significance. Here, we propose to build upon our unique
prospective clinical sequencing initiative to gain a comprehensive picture of how germline and somatic alterations
interact to influence cancer initiation, progression and therapeutic response. Building upon extensive Preliminary
Data, we will pursue this goal through 3 specific aims: (1) establish the prevalence of germline risk alleles and
associated patterns of somatic mutations across cancers; (2) establish integrated germline-somatic clinical
biomarkers of tumor progression and response to DNA repair agents; (3) discover novel candidate pathogenic
alleles of biological and clinical significance. Within the timeframe of this grant, we will sequence tumor-normal
pairs from >70,000 patients under active treatment, providing an unprecedented opportunity to identify and
rigorously evaluate germline-somatic interactions and their relevance to clinical practice. We will leverage the
rich genomic and clinical data set collected through our existing clinical sequencing initiative to identify
pathogenic germline variants, tumor-specific zygosity changes, and co-occurring patterns of somatic mutations
in all solid tumor types. By integrating clinical annotations, family history and outcome data with the alterations
identified in each patient, we will identify novel functional alleles and clinically significant biomarkers of disease-
specific outcomes and therapeutic response. The lessons we learn here will facilitate new clinical guidelines and
diagnostic approaches for cancer patients and establish best practices for discovering and clinically validating
prognostic and predictive biomarkers at the intersection of germline and somatic genetics.
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