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

James M Chan; Mark Clendenning; Sharelle Joseland; Peter Georgeson; Khalid Mahmood; Jihoon E Joo; Romy Walker; Julia Como; Susan Preston; Shuyi Marci Chai; Yen Lin Chu; Aaron L Meyers; Bernard J Pope; David Duggan; J Lynn Fink; Finlay A Macrae; Christophe Rosty; Ingrid M Winship; Mark A Jenkins; Daniel D Buchanan

doi:10.1007/s10689-023-00351-2

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

Fam Cancer. 2024 Mar;23(1):9-21. doi: 10.1007/s10689-023-00351-2. Epub 2023 Dec 8.

Authors

James M Chan^{1

2}, Mark Clendenning^{1

2}, Sharelle Joseland^{1

2}, Peter Georgeson^{1

2}, Khalid Mahmood^{1

2

3}, Jihoon E Joo^{1

2}, Romy Walker^{1

2}, Julia Como^{1

2}, Susan Preston^{1

2}, Shuyi Marci Chai^{1

2}, Yen Lin Chu^{1

2}, Aaron L Meyers^{1

2}, Bernard J Pope^{1

2

3}, David Duggan⁴, J Lynn Fink^{5

6}, Finlay A Macrae^{7

8}, Christophe Rosty^{1

2

9

10}, Ingrid M Winship^{8

11}, Mark A Jenkins^{2

12}, Daniel D Buchanan^{13

14

15}

Affiliations

¹ Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
² Centre for Cancer Research, University of Melbourne, The University of Melbourne, Parkville, VIC, Australia.
³ Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, Australia.
⁴ Quantitative Medicine and Systems Biology Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
⁵ Faculty of Medicine, Frazer Institute, The University of Queensland, Brisbane, QLD, Australia.
⁶ Australian Translational Genomics Centre, Queensland University of Technology, Brisbane, QLD, Australia.
⁷ Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, VIC, Australia.
⁸ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia.
⁹ Envoi Pathology, Brisbane, QLD, Australia.
¹⁰ School of Medicine, University of Queensland, Herston, QLD, Australia.
¹¹ Department of Medicine, The University of Melbourne, Parkville, VIC, Australia.
¹² Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia.
¹³ Colorectal Oncogenomics Group, Department of Clinical Pathology, Melbourne Medical School, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia. daniel.buchanan@unimelb.edu.au.
¹⁴ Centre for Cancer Research, University of Melbourne, The University of Melbourne, Parkville, VIC, Australia. daniel.buchanan@unimelb.edu.au.
¹⁵ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia. daniel.buchanan@unimelb.edu.au.

Abstract

Genetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, 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 variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43: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 the RNF43 variant met the 2019 World Health Organization (WHO²⁰¹⁹) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 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 findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Keywords: BRCA1; Colorectal cancer; Digenic inheritance; FCCTX; Germline pathogenic variant; RNF43; Serrated polyposis syndrome.

MeSH terms

BRCA1 Protein / genetics
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Mutation
Ubiquitin-Protein Ligases / genetics

Substances

BRCA1 protein, human
BRCA1 Protein
RNF43 protein, human
Ubiquitin-Protein Ligases