Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort

Abstract

Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.

Figure 1

APC mutation spectrum and novel genotype-phenotype associations. The mutation distribution shows clustering of two thirds of all APC mutations in proximal Exon 15, with three Indian mutational hotspots (codon 935, 1061 and 1309) contributing to one third of all APC mutations. Large number of novel APC mutations (n = 15) and few novel genotype phenotype associations for codon 1228, 1346 and 1483 mutations.

Figure 2

A pragmatic stepwise screening strategy to improve mutation detection rates in FAP patients. Cumulative mutation detection rates with step wise screening of exons/genes most likely to be mutated in south Asian FAP cases. Arrows on left side shows the cumulative mutation detection rates in our cohort achieved after each step. In our cohort, the cumulative mutation detection rate did not change with NTHL1, POLD1 and POLE gene analysis it may increase the detection rate slightly in larger cohorts of APC and MUTYH negative adenomatous polyposis cases from different geo-ethnic background.