A molecular taxonomy of tumors independent of tissue-of-origin

Peter T Nguyen; Simon G Coetzee; Daniel L Lakeland; Dennis J Hazelett

doi:10.1016/j.isci.2021.103084

A molecular taxonomy of tumors independent of tissue-of-origin

iScience. 2021 Sep 3;24(10):103084. doi: 10.1016/j.isci.2021.103084. eCollection 2021 Oct 22.

Authors

Peter T Nguyen¹, Simon G Coetzee¹, Daniel L Lakeland², Dennis J Hazelett^{1

3}

Affiliations

¹ The Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Lakeland Applied Sciences LLC, Los Angeles, CA 91001, USA.
³ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

Abstract

Cancer is an organism-level disease, impacting processes from cellular metabolism and the microenvironment to systemic immune response. Nevertheless, efforts to distinguish overarching mutational processes from interactions with the cell of origin for a tumor have seen limited success, presenting a barrier to individualized medicine. Here we present a pathway-centric approach, extracting somatic mutational profiles within and between tissues, largely orthogonal to cell of origin, mutational burden, or stage. Known predisposition variants are equally distributed among clusters, and largely independent of molecular subtype. Prognosis and risk of death vary jointly by cancer type and cluster. Analysis of metastatic tumors reveals that differences are largely cluster-specific and complementary, implicating convergent mechanisms that combine familiar driver genes with diverse low-frequency lesions in tumor-promoting pathways, ultimately producing distinct molecular phenotypes. The results shed new light on the interplay between organism-level dysfunction and tissue-specific lesions.

Keywords: Bioinformatics; Cancer; Genomics.