Personalized Risk Assessments Could Play a Role in Detecting and Treating CRC Plus Lynch Syndrome

Utilization of risk modifiers could pave the way for personalized risk assessment, potentially resulting in early detection of and precision medicine for patients with colorectal cancer (CRC) who have Lynch syndrome, according to a study published in Lancet Oncology.

Investigators identified notable evidence of unknown familial risk factors that modified CRC risk for carriers of Lynch syndrome (P< .0001). The hazard ratios (HRs) per 1 polygenic standard deviation (SD) for carriers in Europe were 5.4 (95% CI, 2.9-9.9), 5.1 (95% CI, 3.5-7.4) for carriers in North America, and carriers in Australasia were 3.5 (95% CI, 2.0-5.9). This translates to patients in Europe being 5.4-fold increased risk of CRC for every SD in polygenic factors.

Moreover, 14% (95% CI, 10%-20%) of European men who carried MLH1 were estimated to have a CRC cancer penetrance of 40% to 60%, 23% (95% CI, 6%-42%) had a risk of less than 20%, and 33% (95% CI, 18%-51%) had a risk of more than 80%. Of the patients who were carriers of MLH1 or MSH2 variants—depending on gene, sex, and continent—7% to 56% had CRC cumulative risk less than 20%, 9% to 44% had a risk of more than 80%, and only 10% to 19% had a risk between 40% to 60%.

Existing clinical guidelines for individuals who are carriers of pathogenic variants of DNA mismatch repair genes are current based on age-specific cumulative risk of CRC for all carriers of variants within the same gene. Due to this, investigators set out to assess the variation in penetrance of CRC between variant carriers within the same gene by their sex and continent of residence.

In the retrospective cohort study, investigators collected data from the International Mismatch Repair Consortium that has 273 members from 122 research institutions around the world and are involved in Lynch syndrome research. Those with at least 3 members in their family and have 1 confirmed carrier of a pathogenic variant were admitted into the study. Investigators focused on several mismatch repair genes, including MLH1, MSH2, MSH6, or PMS2. Patients who had both parents test negative for pathogenic variants were excluded from the study.

Investigators allowed ungenotyped family members onto the study based on age, cancer status, and relationship to the carriers and non-carriers. Hazard ratios (HR) were used to measure the sex-specific, age-specific, gene-specific, and continent-specific cancer incidences for carriers divided by non-carriers. Additionally, polygenic SD was utilized to measure the variation of risk between carriers of the same sex, age, and mutated gene.

Data was collected between July 2014 to December 2018 from 5255 families, including 79,809 relatives, across 5 continents, notably Europe, North America, and Australia, and 22 countries. The patients enrolled on the study were carriers of MLH1 (n = 1829), MSH2 (n = 2179), MSH6 (n = 798), and PMS2 (n = 449).

Carriers who had MSH6 and PMS2 variants were estimated to have a cumulative risk of less than 20%. However, half of the men in North America who were included in the study had a risk of less than 20%. Only a small portion of patients had a risk of 80% or more.

A wide variation of risk was noted by investigators when the analysis focused on 250 families who carry a specific MSH2 variant known as c.942+3A>T. When investigators examined sex and continent of residence, about 9% to 15% of carriers had a risk of less than 20%, and 33% to 45% had a risk of over 80%. When investigators examined models with and without age, there was no differentiation in results.

Reference

International Mismatch Repair Consortium. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study. Lancet Oncol. 2021;22(7):1014-1022. doi:10.1016/S1470-2045(21)00189-3