by Tom Wilemon

The first investigation to investigate genetic predisposition to early-onset colorectal cancer by race and ethnicity has identified several germline risk variants.

The study, which was published June 15 in Journal of Clinical Oncology, suggests that current multigene panel tests may not be representative of early-onset colorectal cancer risk in different populations. He found that there are racial and ethnic patterns for variants in the susceptibility genes APC, CHEK2, MLH1, PTEN and monoallelic MUTYH. However, no differences in overall prevalence were identified for young black and white patients, even though there are pronounced disparities in early-onset colorectal cancer between the two groups, which raises the possibility that ancestry-specific risk variants have yet to be identified.

Andreana Holowatyj, PhD, MSCI

As the incidence rates of early-onset colorectal cancer continue to increase and have a disproportionate impact among different populations, our findings are a timely reminder of the need for health equity considerations in the development of multigene panel tests, said corresponding author of the study, Andreana Holowatyj, PhD, MSCI, assistant professor of medicine at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.

The researchers looked for germline cancer susceptibility gene variants in 14 genes in five different populations: individuals who self-identified as Ashkenazi Jews, Asians, Blacks, Hispanics, and Whites and who were diagnosed with early-onset colorectal cancer among the 15 and 49 years old. They found that one in eight carried at least one pathogenic or probably pathogenic variant in a colorectal cancer susceptibility gene. Among groups, deleterious variants were found in 12.7% of Ashkenazi Jews, 9.5% of Asians, 10.3% of Blacks, 14% of Hispanics, and 12.4% of Whites. Ambry Genetics’ clinical-grade germline testing was conducted on a total of 3,980 patients. Over 1,000 of the patients identified as non-white, providing researchers with a first-of-its-kind opportunity for direct comparisons of germline genetic variants across different population groups.

Racial and ethnic patterns were defined for APC, CHEK2, MLH1, monoallelic MUTYH, and PTEN. The researchers also evaluated estimates for Lynch syndrome, an inherited disease that increases the risk of colorectal cancer. Prevalence varied markedly, from 3.2% among Ashkenazi Jewish patients to 9.9% for Hispanic patients.

The researchers noted in the article that no differences were observed in the overall prevalence of germline genetic characteristics between young black patients and white patients despite well-established outcome disparities.

This observation raises several questions for us about what factors might be driving the pronounced disparities in early-onset colorectal cancer outcomes between young black and white patients. If germline genetics contributes to racial differences in colorectal carcinogenesis and outcomes, then it is possible that we have not yet identified specific ancestry variants associated with the disease. It is known that beyond genetics, the interplay between biology, social determinants of health, and behaviors underlie distinct patterns of early-onset colorectal cancer across populations, Holowatyj said. Therefore, this work is an important first step towards a deeper dive into coupled germline and tumor whole genome sequencing in diverse populations to guide the discovery of potential genomic drivers and biomarkers for disease management.

The study’s other authors are Hannah Seagle, BS, Samantha Keller, BS, Sean Tavtigian, PhD, and Carolyn Horton, MS.

The research received support from the National Institutes of Health (K12 HD043483) from the Eunice Kennedy Shrive National Institute of Child Health and Human Development, the Ruth L. Kirschstein National Research Service Award (T32 HG008962) from the National Human Genome Research Institute, and a grant (P50 CA236733) from the National Cancer Institute.

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