Increased Risk for Early-Onset CRC in Third-Degree Relatives

Even third-degree relatives of people with early-onset colorectal cancer (CRC) are at elevated risk for the disease, according to a new study that researchers say could influence screening recommendations.

Among first-degree relatives, there was a sixfold increased risk of developing the malignancy before age 50 in comparison with the general population. Among second- and third-degree relatives, the risk was 1.5 times higher.

Family history is a recognized risk factor for CRC. Roughly 1 in 10 cases of CRC in the United States occurs in people younger than 50 years. It has not been clear to what extent having relatives with early-onset CRC contributes to risk beyond familial syndromes and whether risk extends beyond first-degree relatives, according to study author Lisa A. Cannon-Albright, PhD, of the University of Utah School of Medicine, Salt Lake City, Utah, and colleagues.

The new findings suggest “that extended family history should be part of the discussion when making cancer screening decisions,” the researchers write. Their study appears in the August issue of Cancer Epidemiology.

The authors used the Utah Population Data Base (UPDB) to examine genealogies in which more than three generations were linked to the Utah Cancer Registry. The analysis comprised all CRC cases for which there were linked genealogy data.

Of the 1510 cases of early-onset CRC that the team identified, the risk for CRC was 6.00, 3.09, and 1.56 times higher than expected on the basis of UPDB disease rates for first-, second-, and third-degree relatives, respectively. All results were statistically significant.

The authors also found that individuals with a first-degree relative with early-onset CRC were at 2.64-fold higher risk for CRC at any age. The risk was 1.96-fold higher risk with a second-degree relative and 1.3-fold higher with a third-degree relative. In other words, “the risk for [early-onset] CRC is higher than the risk for CRC at any age, for all degrees of relatives shown,” the team writes.

“Significantly elevated risk for CRC at both locations (left or right) was observed for all degrees of relationship; however the confidence intervals are overlapping, suggesting no difference in risk of left- vs right-sided CRC,” they state.

The findings held up when the researchers used a genealogic index of familiality test instead of calculating relative risk. Although the authors were unable to exclude from the analysis people with inherited syndromes, they say that it is not likely that Lynch syndrome is driving the results, given that more than three quarters of the early-onset CRC cases were left-sided, “and Lynch primarily occurs in the proximal colon.”

The authors caution, however, that the majority of the study population were of Northern European ancestry, which could limit generalizability to other groups.

Currently, there are no screening guidelines for second- or third-degree relatives of persons with early-onset CRC unless Lynch syndrome or another genetic condition is identified, the researchers write.

The authors note that their findings suggest that early colonoscopy screening may be considered not only for first-degree relatives but also for second- and possibly third-degree relatives of persons who have early-onset CRC and that the findings could “influence future CRC screening recommendations.

“Relatives may also benefit from an evaluation with genetic counseling to assess underlying inherited conditions,” they write. “However, we note that there are important considerations in the need for resources to accomplish earlier population-based CRC screening.”

The study was supported by the Utah Cancer Registry, which is funded by the National Cancer Institute’s SEER Program, and the US Center for Disease Control and Prevention’s National Program of Cancer Registries. Additional support was provided by the University of Utah and Huntsman Cancer Foundation. The authors have disclosed no relevant financial relationships.

Cancer Epidemiol. 2021;73:101973. Abstract

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