What are the epidemiological characteristics of Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC)?

From the Guidelines

Lynch Syndrome is a hereditary cancer predisposition condition affecting approximately 1 in 279 individuals worldwide, with a significantly elevated lifetime risk of developing colorectal cancer and endometrial cancer, and the most recent evidence suggests that individuals with Lynch Syndrome have a lifetime risk of up to 60% for endometrial cancer and up to 80% for colorectal cancer 1.

Key Points

• The syndrome is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM), with MLH1 and MSH2 mutations accounting for approximately 70-80% of cases 1.
• The average age of cancer diagnosis in Lynch Syndrome patients is 44-61 years, significantly younger than sporadic cases 1.
• The syndrome demonstrates autosomal dominant inheritance, meaning children of affected individuals have a 50% chance of inheriting the mutation 1.
• Screening recommendations include colonoscopy every 1-2 years beginning at age 20-25, and women should consider annual endometrial sampling and transvaginal ultrasound beginning at age 30-35 1.

Epidemiological Data

• About 2-4% of all colorectal cancers are attributed to Lynch Syndrome, with an estimated 800,000 to 1 million carriers in the United States alone 1.
• Individuals with Lynch Syndrome have a significantly elevated lifetime risk of developing colorectal cancer (up to 80% compared to 4.5% in the general population) and endometrial cancer (up to 60% in women compared to 2.7% in the general population) 1.
• The estimated age of presentation and cumulative risk for diagnosis through age 80 years depends on the P/LP variant, ranging from an average age of 49 to 50 years and cumulative risk of 13%–26% for PMS2 to an average age of 49 years and cumulative risk of 34%–54% for MLH1 P/LP variant 1.

Aggregate Data

• LS patients develop fewer colorectal adenomas by age 50 years (usually <3 neoplasms) and the adenocarcinoma sequence appears more rapid in LS with polyp to cancer dwell times estimated at 35 months compared with 10-15 years in sporadic cancer 1.
• LS patients have improved survival from CRC stage for stage compared with those with sporadic cancer, and they have a significantly increased risk for a wide variety of extracolonic malignancies 1.

From the Research

Epidemiological Data

• Lynch syndrome is one of the most common cancer susceptibility syndromes, with individuals having a 50%-70% lifetime risk of colorectal cancer and 40%-60% risk of endometrial cancer 2.
• The syndrome is caused by germline mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2, and in some cases, 3' end deletions of the EPCAM gene 2.
• Lynch syndrome underlies approximately 5% of endometrial cancers and ∼1% of ovarian cancers 3.

Aggregate Data

• A study of 605 consecutive cases of primary endometrial cancer found that 40 cases were MMR-deficient, nonmethylated, with only 25% occurring in women below 50 years of age 4.
• Another study of 55 women with Lynch syndrome who underwent combined colonoscopy and endometrial biopsy screening found that endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma, while colonoscopy removed 71 colorectal polyps, of which 29 were tubular adenomas 5.
• The combined screening approach was found to be feasible, less painful, and effective in detecting (pre)cancerous lesions, with no interval endometrial or colorectal cancers detected 5.

Screening and Detection

• Regular screening for Lynch syndrome reduces CRC-related mortality, but high CRC incidence during regular colonoscopy screening suggests the possibility of nonpolypoid carcinogenesis 6.
• Universal screening of all newly diagnosed endometrial cancers is recommended, as a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters 4.
• The algorithm for screening endometrial carcinomas for Lynch syndrome remains a subject of debate, with some studies supporting universal screening and others proposing a hybrid approach informed by clinicopathologic features 3.