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Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer
Author(s) -
Evans Daniel R.,
Venkitachalam Srividya,
Revoredo Leslie,
Dohey Amanda T.,
Clarke Erica,
Pennell Julia J.,
Powell Amy E.,
Quinn Erina,
Ravi Lakshmeswari,
Gerken Thomas A.,
Green Jane S.,
Woods Michael O.,
Guda Kishore
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23549
Subject(s) - missense mutation , biology , germline , genetics , penetrance , germline mutation , allele , colorectal cancer , population , gene , cancer , mutation , phenotype , medicine , environmental health
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 ∼2‐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.