Abstract PR002: Somatic mutation rates and strength of selection on driver genes change by age in melanoma

Abstract

Abstract The frequencies of driver mutations in melanoma vary in patients of different ages. However, it is unclear whether these differences in frequency are driven by variation in underlying mutation rates or by a changing selective regime in the aging body. Employing a bulk tumor sequence dataset from 5472 melanomas (459 whole-exome sequences and 5013 cancer gene-panel sequences) analyzed with the cancereffectsizeR package, we quantified somatic mutation rates and the strength of selection on somatic mutations, measuring the survival advantage conferred by a somatic mutation across the tumorigenic trajectory. Likelihood ratio tests were used to compare cancer effect sizes between age groups: <40 y/o, 40-59 y/o and ≥ 60 y/o. The proportion of cancer effect attributable to each mutational source was calculated by averaging over bootstrapped resample of mutational signature weights. Mann-Whitney U statistics were used to test the difference in signature weights and cancer effect sources across the groups.The underlying mutation rate increased with age, with a mean of 4.49e-6, 4.88e-6, 6.45e-6 in patients <40 y/o, 40-59 y/o and ≥ 60 y/o respectively. From the whole-exome and panel data, 23 variants differed significantly across age groups, among which BRAF V600E had the largest effect sizes, followed by NRAS Q61R, NRAS Q61K, NRAS Q61L. BRAF V600E were significantly larger in patients <40 y/o, while NRAS Q61R, NRAS Q61K, NRAS Q61L were significantly larger in patients 40-59 y/o and ≥ 60 y/o. Although underlying mutation rates and strengths of selection varied across age groups, the origin of melanomas from patients in all three age groups was predominantly attributed to UV light. These observations illuminate numerous theoretical questions regarding the origins of cancer at different ages. They are helpful to widespread implementation of prevention strategies. Moreover, understanding the relative strength of selection on driver mutations within patients at distinct ages is crucial for improving precision therapeutic interventions. Citation Format: Yihan Liu, Moein Rajaei, Jeff Mandell, Jeffrey Townsend. Somatic mutation rates and strength of selection on driver genes change by age in melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR002.