Purpose: Biallelic germline pathogenic variants of the base excision repair (BER) pathway gene 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 variants and loss of heterozygosity (LOH) in a large pan-cancer analysis.
Materials And Methods: 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 variants.
Results: Biallelic germline pathogenic 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 , higher rates of chromosome 1p loss (where is located), elevated genomic LOH, and higher COSMIC SBS18 signature scores, consistent with BER deficiency.
Conclusion: This analysis of alterations in a large set of solid cancers suggests that in addition to the established role of biallelic pathogenic variants in cancer predisposition, a broader range of cancers may possibly arise in heterozygotes via a mechanism involving somatic LOH at the locus and defective BER. However, the effect is modest and requires confirmation in additional studies before being clinically actionable.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10901435 | PMC |
| http://dx.doi.org/10.1200/PO.23.00251 | DOI Listing |
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