Work led by Kodi Taraszka on identifying clinical and germline influences on Tumor Mutational Burden (TMB) and somatic copy number burden (CNB) is now out in The American Journal of Human Genetics. This was a collaboration with the Zaitlen Lab and Tempus.

A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden
K Taraszka, S Groha, D King, R Tell, K White, E Ziv, N Zaitlen, A Gusev. The American Journal of Human Genetics. 2024

Tumor Mutational Burden (TMB) is one of few FDA-approved biomarkers for immunotherapy and associated with clinical benefit, but the causes of variation in TMB remain poorly understood. CNB is also commonly associated with poor survival but the underlying mechanisms are unknown and heterogenous. In this work, we used two large tumor-sequencing cohorts with germline imputation to explore germline correlates of TMB and CNB. This study identified associations with patient demographics, genetic ancestry, and germline risk scores for smoking, tanning, educational attainment / socioeconomic status, and autoimmune conditions. In some cases, these associations modified the prognostic effect of TMB on clinical outcomes. These findings highlight the utility of germline variation as a tool for causal inference in oncology and motivate integration of TMB with other host-driven factors into a broader predictive model.

Schematic of associations with TMB and CNB across cancers (columns).

FR perturb-seq schematic