Whole-exome sequencing enhances diagnosis in young CRC patients

Whole-exome sequencing (WES) can improve diagnosis rates in young colorectal cancer (CRC) patients who show no pathogenic variants in mismatch repair (MMR) genes or in the adenomatous polyposis coli (APC) gene, reports a recent study.

The study included 23 patients and 14 patient-parent trios in whom no germline pathogenic MMR or APC mutations have been recorded. All patients had been diagnosed with CRC between 12 and 25 years of age.

WES found that six CRC patients (16 percent) harboured likely pathogenic variant in hereditary cancer-associated genes. Among these, two had a mutation in the TP53 gene, while another had a homozygous pathogenic splice variant in the BLM gene. Of note, three patients carried pathogenic variants in genes not traditionally associated with CRC risk. Moreover, seven CRC patients carried potentially pathogenic de novo CRC variants.

Similarly, 16 patients were flagged when researchers tested for novel CRC susceptibility genes, accounting for a recessive disease scenario. However, none of these variants showed a clear link to CRC.

Overall, a WES analysis on germline DNA revealed that in young CRC patients without known mutations in APC or in MMR genes, potentially pathogenic variants were highly prevalent and could aid timely genetic diagnosis in 19 percent of cases.

“Most genes in which we identified de novo variants are suggested to be intolerant to loss-of-function variants,” the researchers said. “To confirm that these genes play a role in early CRC development, these findings need to be confirmed in other patients with CRC.”

“Broad implementation of patient-parent sequencing in individuals with extremely young onset of an adult type of cancer and international sharing of data, for instance by gene-matching platforms, will help identify pathogenic variants that occur repeatedly in these patients with CRC,” they added.