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

ABSTRACT: Young 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.

SUBMITTER: Lee W

PROVIDER: S-EPMC8631509 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Lee William W Wang Zishan Z Saffern Miriam M Jun Tomi T Huang Kuan-Lin KL

Cell reports 20211101 7

Young 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 ...[more]

PMID: 34788626

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Project description:PurposeClinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution.Experimental designThis is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference.ResultsThirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data.ConclusionsAoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.

Dataset Information

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

Publications

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

Similar Datasets

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