Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family

We describe a multi-generation CRC-affected family segregating pathogenic variants in bothBRCA1, a gene associated with breast and ovarian cancer andRNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998 –2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variantBRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variantRNF43:c.988  C >  T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of theRNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing aBRAF p.V600 wildtype CRC. Loss of the wildtype allele for bothBRCA1 andRNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our f...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research