Study data published in Gastroenterology identified potential de novo pathogenic variants that may predispose adolescents and young adults to colorectal cancer (CRC). In a cohort of individuals diagnosed with CRC at age 25 years or younger, whole-exome sequencing (WES) revealed potential pathogenic variants in a substantial proportion of patients. Investigators thus advocated for broader sequencing efforts to further illustrate and identify pathogenic variants associated with early-onset CRC.

Genetic susceptibility is presumed to play a role in early-onset CRC, though prior research suggests only a small proportion of adolescents and young adults with CRC have a familial history of the disease. Further, polyposis and microsatellite instability are rare in young patients with CRC, meaning a pathogenic variant of the adenomatous polyposis coli (APC) gene and mismatch repair (MMR) deficiency are unlikely.

Thus, to explore the occurrence of inherited and de novo predisposing genes, investigators performed WES on germline DNA from 23 patients diagnosed with CRC before the age of 25 years. Germline DNA were also obtained from 14 patient-parent trios. Eligible patients did not have germline pathogenic variants in the APC or MMR genes. Three broad categories of variants were explored: (1) variants in known hereditary cancer-associated genes (HCGs), (2) hemizygous, homozygous, or potential compound heterozygous variants which occur infrequently in control populations (<0.15%), and (3) de novo variants from patient-parent trios.

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Among patients, the mean age at CRC diagnosis was 20 years. Probable pathogenic variants in HCGs were identified in 6 of 37 patients (16%). Specifically, 2 patients carried a TP53 variant and 1 patient carried a homozygous pathogenic splice site variant in BLM.

Three patients carried heterozygous pathogenic variants in genes not previously associated with CRC predisposition: 1 each for BRCA2, PALB2, and NF1. While BRCA2 and PALB2 are associated with breast cancer rather than CRC susceptibility, an enrichment in variants within these genes has been reported in certain adolescent cancers. Two patients carried heterozygous pathogenic variants on the recessive MUTYH and MSH3 genes. Finally, 1 patient carried a POLD1 frameshift variant.

Potential pathogenic de novo variants were observed in 7 patients (19%). Two of these variants were protein truncating, but were in genes not associated with disease. Three de novo variants were predicted to be “likely” pathogenic, but have not previously been associated with oncogenic processes. Two de novo missense variants were identified in the genes PRKCB and SOS2, which are known to be missense intolerant. Both these genes encode proteins which directly interact with Ras, which itself is frequently associated with malignancies.

In this sequencing study, WES combined with HCG analyses provided a potential “genetic diagnosis” for 19% of patients. To confirm the occurrence and role of these variants in early-onset CRC, further study is necessary.

“[T]his is the first study to describe that patients with CRC diagnosed at age 25 years or younger carry potentially pathogenic de novo variants in genes previously not associated with cancer that are well-conserved in pathways known to be involved in cancer development,” investigators wrote. “Broad implementation of patient-parent sequencing in individuals with extremely young onset of an adult type of cancer and international sharing of data…will help identifying (de novo) pathogenic variants that occur repeatedly in these CRC patients,” they concluded.


Jongmans MCJ, Zhang J; AYA-CRC study group, Kuiper RP, Hoogerbrugge N, Ligtenberg MJL, de Voer RM. Genetic cancer susceptibility in adolescents and adults 25 years or younger with colorectal cancer. Gastroenterol. Published online November 9, 2021. doi: 10.1053/j.gastro.2021.11.009