Age influences on the molecular presentation of tumours

Abstract

Cancer is often called a disease of aging. There are numerous ways in which cancer epidemiology and behaviour change with the age of the patient. The molecular bases for these relationships remain largely underexplored. To characterise them, we analyse age-associations in the nuclear and mitochondrial somatic mutational landscape of 20,033 tumours across 35 tumour-types. Age influences both the number of mutations in a tumour (0.077 mutations per megabase per year) and their evolutionary timing. Specific mutational signatures are associated with age, reflecting differences in exogenous and endogenous oncogenic processes such as a greater influence of tobacco use in the tumours of younger patients, but higher activity of DNA damage repair signatures in those of older patients. We find that known cancer driver genes such as CDKN2A and CREBBP are mutated in age-associated frequencies, and these alter the transcriptome and predict for clinical outcomes. These effects are most striking in brain cancers where alterations like SUFU loss and ATRX mutation are age-dependent prognostic biomarkers. Using three cancer datasets, we show that age shapes the somatic mutational landscape of cancer, with clinical implications.

Age-associated differences in the cancer molecular landscape

“…These analyses, however, focused on one cancer type and only a few molecular data types at a time. Recently, four independent studies performed pan-cancer analyses to shed light on the age-associated genomic, transcriptomic, and epigenomic patterns [11][12][13][14]. The age-related patterns of molecular alterations might suggest differences in the oncogenic mechanisms concerning the patient's age.…”

“…Age-related somatic mutation burden in tumors Increased age is associated with higher somatic mutations (single-nucleotide variants and small insertions/deletions) in most cancer types [11,12,14,[16][17][18], with an estimated increase of 0.077 mutations per megabase per year [12]. The spontaneous deamination of 5-methylcytosine to thymine (C>T) transitions, often referred to as the 'clock-like' mutational signature, dominates this age-related increase in mutation load.…”

“…likely to be found in older individuals [12]. The mutational signature related to APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like family) cytidine deaminase activity increases with age in melanoma [12] and prostate cancer [9].…”

“…likely to be found in older individuals [12]. The mutational signature related to APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like family) cytidine deaminase activity increases with age in melanoma [12] and prostate cancer [9]. In addition to somatic mutations, somatic copy-number alterations (SCNAs) also increase as a function of age in the pan-cancer analysis (Figure 1) [11,12].…”

“…The mutational signature related to APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like family) cytidine deaminase activity increases with age in melanoma [12] and prostate cancer [9]. In addition to somatic mutations, somatic copy-number alterations (SCNAs) also increase as a function of age in the pan-cancer analysis (Figure 1) [11,12]. Cancer-type-specific analyses revealed a significant positive association between SCNA level and age in a few cancer types, including low-grade glioma, endometrial, ovarian, and prostate cancers [11,12].…”