Pan-Cancer Interrogation of <i>MUTYH</i> Variants Reveals Biallelic Inactivation and Defective Base Excision Repair Across a Spectrum of Solid Tumors.

Abstract

Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene <i>MUTYH</i> predispose to colorectal cancer (CRC) and other cancers. The possible association of heterozygous variants with broader cancer susceptibility remains uncertain. This study investigated the prevalence and consequences of pathogenic <i>MUTYH</i> variants and <i>MUTYH</i> loss of heterozygosity (LOH) in a large pan-cancer analysis. Data from 354,366 solid tumor biopsies that were sequenced as part of routine clinical care were analyzed using a validated algorithm to distinguish germline from somatic <i>MUTYH</i> variants. Biallelic germline pathogenic <i>MUTYH</i> variants were identified in 119 tissue biopsies. Most were CRCs and showed increased tumor mutational burden (TMB) and a mutational signature consistent with defective BER (COSMIC Signature SBS18). Germline heterozygous pathogenic variants were identified in 5,991 biopsies and their prevalence was modestly elevated in some cancer types. About 12% of these cancers (738 samples: including adrenal gland cancers, pancreatic islet cell tumors, nonglioma CNS tumors, GI stromal tumors, and thyroid cancers) showed somatic LOH for <i>MUTYH</i>, higher rates of chromosome 1p loss (where <i>MUTYH</i> is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency. This analysis of <i>MUTYH</i> alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic <i>MUTYH</i> variants in cancer predisposition, a broader range of cancers may possibly arise in <i>MUTYH</i> heterozygotes via a mechanism involving somatic LOH at the <i>MUTYH</i> locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable.