Cancer Susceptibility Dependent on Sex, Mutational Status, and Family History Among Patients With Lynch Syndrome

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Investigators examined the associations between family history and certain clinical factors in patients who carry LS and have a previous history of cancer.

Cancer surveillance among patients with Lynch syndrome (LS) should include familial burden, sex, and genetic assessment, according to results of a cohort study, published in Gastroenterology.

Patients from 2 cohorts (laboratory: n=3828; clinic: n=607) with LS were assessed between 2006 and 2013 by researchers from Harvard Medical School for clinical characteristics and genetic status of 4 LS genes for their association with cancer diagnoses.

Laboratory- and clinic-based participants were 63.5% and 68.0% women, aged median 50.0 and 50.0 years, 59.3% and 82.5% were White, and 83.2% and 61.1% had a previous cancer diagnosis, respectively. Pathogenic germline variants (PGVs) were detected in MutS homolog 2 (MSH2; n=1639; n=180), MutL homolog 1 (MLH1; n=1346; n=137), MutS homolog 6 (MSH6; n=670; n=145), postmeiotic segregation 1 homolog 2, mismatch repair system component (PMS2; n=145; n=138), or epithelial cell adhesion molecule (EPCAM;n=28; n=7) genes, respectively.

Among the laboratory-based cohort, male sex was associated with increased odds of sebaceous neoplasms (odds ratio [OR], 1.83; 95% CI, 1.30-2.58), colorectal (OR, 4.82; 95% CI, 4.06-5.72), small bowel (OR, 3.84; 95% CI, 2.17-6.77), gastric (OR, 2.96; 95% CI, 1.55-5.64), and urinary tract (OR, 1.93; 95% CI, 1.37-2.73) cancers.

MSH2/EPCAM PGVs were associated with a personal history of sebaceous neoplasms (OR, 4.33; 95% CI, 2.44-7.67), gastric (OR, 5.22; 95% CI, 1.20-22.65), urinary (OR, 3.98; 95% CI, 2.37-6.68), small bowel (OR, 2.53; 95% CI, 1.03-6.18), and colorectal (OR, 1.77; 95% CI, 1.46-2.13) cancers. MLH1 PGVs were associated with a personal history of gastric (OR, 6.56; 95% CI, 1.51-28.54) and colorectal (OR, 3.46; 95% CI, 2.81-4.27) cancers.

Patients with a first or second degree relative (FDR/SDR) with a specific cancer had increased odds for sebaceous neoplasia (OR, 7.39 per FDR/SDR; 95% CI, 2.71-20.15), small bowel (OR, 3.17 per FDR/SDR; 95% CI, 1.65-6.12), urinary tract (OR, 2.72 per FDR/SDR; 95% CI, 2.02-3.67), pancreaticobiliary (OR, 2.10 per FDR/SDR; 95% CI, 1.21-3.65), gastric (OR, 1.93 per FDR/SDR; 95% CI, 1.24-3.02), and endometrial (OR, 1.37 per FDR/SDR; 95% CI, 1.21-1.56) cancers.

Among the clinic-based cohort, odds were increased among men with a personal history of colorectal cancer (OR, 3.39; 95% CI, 2.33-4.92), those with MLH1 PGVs with a personal history of colorectal cancer (OR, 3.50; 95% CI, 2.09-5.84) and sebaceous neoplasms (OR, 5.56; 95% CI, 1.75-17.65), those with MSH2/EPCAM PGVs with a personal history of sebaceous neoplasm (OR, 11.98; 95% CI, 4.38-32.74), urinary tract (OR, 3.74; 95% CI, 1.37-10.23), colorectal (OR, 2.53; 95% CI, 1.60-3.99), and endometrial (OR, 1.79; 95% CI, 1.03-3.11) cancers, and a family history of urinary tract (OR, 2.03 per FDR/SDR; 95% CI, 1.28-3.22) and endometrial (OR, 1.49 per FDR/SDR; 95% CI, 1.12-1.98) cancers.

This study was biased by the high proportion of White women and may not be generalizable to a more diverse patient population.

These data indicated that in addition to family history, sex and genetic status of LS genes should be taken into account when formulating a cancer surveillance plan for patients with LS.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

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Biller LH, Horiguchi M, Uno H, Ukaegbu C, Syngal S, Yurgelun MB. Familial burden and other clinical factors associated with various types of cancer in individuals with Lynch syndrome. Gastroenterol. Published online March 25, 2021. doi: 10.1053/j.gastro.2021.03.039.