A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.

Hongchen Cai ,Su Kit Chew ,Emily L Ashkin ,Laura Andrejka ,King L Hung ,Emily G Shuldiner ,Charles Swanton ,Le Cong ,Claudia Lee ,Christopher W Murray ,Dmitri A Petrov ,Wen‐Yang Lin ,Nicholas W Hughes ,Christopher D Mcfarland ,Min K Tsai ,Chuan Li ,Christian A Kunder ,Maryam Yousefi ,Rui Tang ,Leo C Chen ,Monte M Winslow

doi:10.1158/2159-8290.cd-20-1325

Abstract

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.This article is highlighted in the In This Issue feature, p. 1601.

Highlights

Cancer initiation and development is a multi-step process driven in large part by cancer cellintrinsic alterations [1]
To characterize the functional landscape of tumor suppression, we selected 48 known and putative tumor suppressor genes to investigate using Tuba-seq in a model of oncogenic KRAS-driven lung cancer (Fig. 1A; Methods). These genes were chosen based on multiple criteria including their mutational frequency in lung adenocarcinoma from The Cancer Genome Atlas (TCGA), GENIE, and TRACERx datasets, their mutational frequency in pan-cancer genomic data, and the consistency of their mutational profiles with tumor suppressor activity (Fig. 1A and B; Supplementary Fig. S1A–E and Table S1)(2,4–7)
Sensitivity, and precision of Tuba-seq [26,27], we quantify the effects of inactivating a diverse panel of putative tumor suppressor genes in an autochthonous mouse model of oncogenic KRAS-driven lung cancer

Summary

Introduction

Cancer initiation and development is a multi-step process driven in large part by cancer cellintrinsic alterations [1]. Over the past several decades, cancer genome sequencing has contributed to our understanding of the genetic drivers of cancer and identified a large number of putative tumor suppressor genes [2,3,4,5,6,7,8]. Tumor suppressors regulate many different pathways and cellular processes Assessing their impact on tumor initiation and each step of cancer development distinguishes driver from passenger genes and highlights different pathways and processes that constrain carcinogenesis across the course of the disease [12,13]. In vivo functional genomic approaches are critical for understanding cancer evolution [14,15,16], interpreting clinical cancer genome sequencing data [17,18], and directing precision medicine approaches [19,20]

Methods

Results

Discussion

Conclusion