Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells

Abstract

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing

“…We profiled with HiDEF-seq 17 blood, primary fibroblast, and lymphoblastoid cell line samples from 8 different cancer predisposition syndromes, including defects in nucleotide excision repair, mismatch repair, polymerase proofreading, and base excision repair ( Supplementary Tables 1-2 ). In these samples, we first confirmed HiDEF-seq’s fidelity for dsDNA mutations by measuring the expected dsDNA mutation burdens and signatures based on prior studies 30-34 —except for MUTYH blood samples from which we were unable to recover its known signatures, since as seen in prior studies, MUTYH blood has near normal mutation burdens 34 ( Extended Data Figs. 7a-d, and Supplementary Tables 2 and 4 ).…”

Somatic variation in normal tissues: friend or foe of cancer early detection?

“…It has been proposed that somatic mutations could reduce the efficiency of gene regulatory networks and increase cell-tocell transcriptional heterogeneity 70,71 . However, the high somatic mutation burden observed in carriers of germline POLE/POLD1 23 , MUTYH 72 or mismatch repair gene 73,74 defects does not lead to any appreciable sign of accelerated ageing, suggesting that a more complex relationship likely exists between mutation and aging. It is likely that J o u r n a l P r e -p r o o f multiple, and mostly independent, forms of molecular and tissue damage synergistically contribute to aging-related functional decline.…”

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

“…rs1707302 is 2.2 kb from the TSS of PIK3R3 and is an eQTL in monocytes of PIK3R3 ( 49 ) and also an sQTL of MUTYH in whole blood ( 35 ). MUTYH , which is involved in base excision repair, has recently been shown to alter somatic mutation rates in normal human cells ( 50 ) and alter the germline mutation rate in mice ( 51 ). The C allele of rs116750427, an intronic variant of PAX5 , was associated with reduced odds of acquiring a mutated chr9-37358292-A-G (OR = 0.61, P value = 5.7 × 10 −10 ).…”