Genetic differences in familial adenomatous polyposis syndrome in a Hungarian population: A prospective single center study

Abstract

BACKGROUND

Familial adenomatous polyposis (FAP) is a disorder of autosomal dominant inheritance that is responsible for around 1% of colorectal cancer (CRC) cases.

AIM

To determine the mutation profile of FAP-specific to the Hungarian population.

METHODS

This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP (aFAP). Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes. To identify larger deletions and insertions, a multiplex amplifiable probe hybridization technique was used. The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.

RESULTS

A total of 26 index patients with clinically suspected FAP (n = 21) and aFAP (n = 5) were enrolled. APC gene alterations were confirmed in 92.31% of the cases (region 1B deletion, n = 2; whole-gene deletion, n = 4; frameshift mutation, n = 2; nonsense mutation, n = 5, and splice mutation, n = 1), with the remaining two cases having CHEK2 and MSH3 gene alterations. According to pathogenicity, 21 cases had pathogenic mutations, 6 cases had likely pathogenic mutations, and 16 cases had variants of unknown significance (VUS). The most frequent of the latter were the POLE (n = 5) and PIEZO1 (n = 4) gene variants.

CONCLUSION

Germline mutations in the APC gene were confirmed in more than 90% of Hungarian patients with clinically suspected FAP. Although the role of VUS genes is unclear, they are highly likely to play a role in the development of CRC.

Keywords: Polyposis syndrome; Genomics; Familial adenomatous polyposis; Genetic testing; APC; Germline mutation; Colorectal cancer

Core Tip: This prospective single-center study assessing the mutation profile of 26 Hungarian patients with clinically suspected familial adenomatous polyposis (FAP) or attenuated FAP confirmed APC gene mutations in over 90% of cases, confirming its critical role in FAP development. Variants of uncertain significance, particularly in POLE and PIEZO1, were also frequently detected and may contribute to colorectal cancer risk, though their clinical relevance remains unclear, highlighting the need for further research and genotype-phenotype correlation.