Genomic and molecular features distinguish young adult cancer from later-onset cancer.

William Lee,Tomi Jun,Miriam Saffern,Zishan Wang,Kuan-Lin Huang

doi:10.1016/j.celrep.2021.110005

Abstract

SUMMARYYoung adult cancer has increased in incidence worldwide, but its molecular etiologies remain unclear. We systematically characterize genomic profiles of young adult tumors with ages of onset ≤50 years and compare them to later-onset tumors using over 6,000 cases across 14 cancer types. While young adult tumors generally show lower mutation burdens and comparable copy-number variation rates compared to later-onset cases, they are enriched for multiple driver mutations and copy-number alterations in subtype-specific contexts. Characterization of tumor immune microenvironments reveals pan-cancer patterns of elevated TGF-β response/dendritic cells and lower IFN-γ response/macrophages relative to later-onset tumors, corresponding to age-related responses to immunotherapy in several cancer types. Finally, we identify prevalent clinically actionable events that disproportionally affect young adult or later-onset cases. The resulting catalog of age-related molecular drivers can guide precision diagnostics and treatments for young adult cancer.

Highlights

In the US and multiple countries, cancer incidence and mortality have steadily declined in adults over the age of 50 (Bray et al, 2018; Siegel et al, 2020)
Early-onset colorectal cancer is known to be associated with germline mutations in mismatch repair (MMR) genes (Lynch syndrome) (Lynch et al, 2009; Pearlman et al, 2017), and germline mutations disrupting ATM, CHEK2, BRCA1/2, CDKN2A, and PALB2 may contribute to earlyonset colorectal carcinogenesis (Pearlman et al, 2017)
We found significant enrichment of GATA3-mutated luminal A BRCA in young adults (FDR = 3.11E-3, Figures 2B and S2B), as well as significant enrichment of TP53, IDH1, and ATRX-mutated (B) Subtype percentages between young adult and later-onset cases in non-female-specific cancer types

Summary

Introduction

In the US and multiple countries, cancer incidence and mortality have steadily declined in adults over the age of 50 (Bray et al, 2018; Siegel et al, 2020). The overall decline is coupled with a recent rise in the incidence of various cancer types among young adults, including colorectal, endometrial, gallbladder, multiple myeloma, pancreatic, and renal cancer, for individuals between 15 and 50 years old in the US (Sung et al, 2019) and worldwide (Gupta et al, 2020). Existing genomic and molecular studies of adult cancers comprise mainly later-onset individuals (Campbell et al, 2020; SanchezVega et al, 2018; Zehir et al, 2017), where alterations that are differentially prevalent in young adult cancers may be diluted. Multiple studies have confirmed a higher prevalence of germline mutations in BRCA1/2 and TP53 in early-onset breast cancer (Gomez-Flores-Ramos et al, 2017; Packwood et al., 2019; Peto et al, 1999). While studies have identified various germline predisposing variants associated with young adult cancer, large-scale investigation of their somatic genomic and molecular profiles is scarce

Results

Discussion

Conclusion