An update on APC I1307K homozygosity: observations from a large multigene panel testing cohort.

APC

The APC c.3902T>A (p.Ile1307Lys) susceptibility allele in the heterozygous or homozygous state, creating an unstable poly-adenine tract

The APC c.3902T>A (p.Ile1307Lys) allele is associated with 1.7-fold increased odds of colorectal adenocarcinoma in Ashkenazi Jewish heterozygotes, but the risk in homozygotes remains unknown and rests on very small published samples. Within a clinical diagnostic laboratory cohort, the authors compared 340 heterozygotes and 74 homozygotes with 372 individuals with MSH6-associated Lynch syndrome and 19,809 individuals negative for the I1307K allele, for MSH6 and for any other reportable pathogenic variant. Homozygotes showed a trend toward increased odds of colorectal cancer relative to the latter group (OR 2.48; p = 0.074), with no difference for heterozygotes (OR 0.94; p = 0.83). MSH6-positive individuals had higher odds than homozygotes in direct comparison (OR 3.54; p < 0.0001), a difference that disappeared in logistic regression (OR 1.19; p = 0.78). The authors conclude that sample size and selection bias preclude distinguishing a modestly increased risk from no risk at all.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This work should be read for what it is, a negative study: the main result (OR 2.48; p = 0.074) does not cross the significance threshold, and the authors themselves state they cannot distinguish a modest risk from no risk. The complete absence of signal in heterozygotes, contrary to the 1.7-fold figure in the literature, mainly illustrates the limits of a case-control design run inside a population already selected for testing, where the controls are themselves cancer genetics patients. Nothing changes in practice: I1307K homozygosity does not warrant Lynch-type surveillance, and the question of the true risk calls for a population-based cohort rather than another laboratory series.

Analysis by Dr Thibaut Benquey