Abstract
The incidence of early-onset colorectal cancer (CRC), which affects people under
50, is increasing for unknown reasons. Additionally, no underlying genetic cause is
found in 20%–30% of patients suspected of having familial CRC syndrome. Whole
exome sequencing (WES) has generated evidence for new genes associated with
CRC susceptibility, but many patients remain undiagnosed. This study applied WES
in five early-onset CRC patients from three unrelated families to identify novel
genetic variants that could be linked to rapid disease development. Furthermore, the
candidate variants were validated using Sanger sequencing. Two heterozygote varia-
tions, c.1077-2A>G and c.199G>A, were found in the MSH2 and the MLH1 genes,
respectively. Sanger sequencing analysis confirmed that these (likely) pathogenic
mutations segregated in all the affected families’ members. In addition, we identified
a rare heterozygote variant (c.175C>T) with suspected pathogenic potential in the
MAP3K1 gene; formally the variant is of uncertain significance (VUS). Our findings
support the hypothesis that CRC onset may be oligogenic and molecularly heteroge-
neous. Larger and more robust studies are needed to understand the genetic basis of
early-onset CRC development, combined with novel functional analyses and omics
approaches.
