RESUMEN
Characterizing moderate penetrance susceptibility genes is an emerging frontier in colorectal cancer (CRC) research. GALNT12 is a strong candidate CRC-susceptibility gene given previous linkage and association studies, and inactivating somatic and germline alleles in CRC patients. Previously, we found rare segregating germline GALNT12 variants in a clinic-based cohort (N = 118) with predisposition for CRC. Here, we screened a new population-based cohort of incident CRC cases (N = 479) for rare (MAF ≤1%) deleterious germline GALNT12 variants. GALNT12 screening revealed eight rare variants. Two variants were previously described (p.Asp303Asn, p.Arg297Trp), and additionally, we found six other rare variants: five missense (p.His101Gln, p.Ile142Thr, p.Glu239Gln, p.Thr286Met, p.Val290Phe) and one putative splice-altering variant (c.732-8 G>T). Sequencing of population-matched controls (N = 400) revealed higher burden of these variants in CRC cases compared with healthy controls (P = 0.0381). We then functionally characterized the impact of substitutions on GALNT12 enzyme activity using in vitro-derived peptide substrates. Three of the newly identified GALNT12 missense variants (p.His101Gln, p.Ile142Thr, p.Val290Phe) demonstrated a marked loss (>2-fold reduction) of enzymatic activity compared with wild-type (P ≤ 0.05), whereas p.Glu239Gln exhibited a â¼2-fold reduction in activity (P = 0.077). These findings provide strong, independent evidence for the association of GALNT12 defects with CRC-susceptibility; underscoring implications for glycosylation pathway defects in CRC.
Asunto(s)
Neoplasias Colorrectales/genética , N-Acetilgalactosaminiltransferasas/genética , Western Blotting , Línea Celular Tumoral , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Repeticiones de Microsatélite/genética , Proteínas Recombinantes/genéticaRESUMEN
A recent report detailed the occurrence of both somatic and constitutional variants in the GALNT12 gene, located at 9q22.33, in some colorectal cancer (CRC) patients. In this study, we investigate the occurrence of inherited deleterious variants in GALNT12 in 118 families referred to a cancer genetics clinic. We discovered two deleterious variants (c.907G>A (p.Asp303Asn); c.1187A>G (p.Tyr396Cys)) in 4/118 probands. The variants, which were not found in 149 control individuals (P = 0.0376), cosegregate with CRC and/or adenomatous polyps in other family members. The probability by chance that cosegregation of c.907G>A with CRC and/or adenomatous polyps occurred, in the two pedigrees combined, was 1.56%. Although this study does not provide irrefutable evidence that GALNT12 variants are highly penetrant alleles that predispose to CRC in the majority of unexplained hereditary CRC families, it does provide additional evidence to support an important role of these variants in a proportion of this considerable high-risk group.