hereditary nonpolyposis colorectal cancer

**Pathophysiology** - Inheritance: autosomal dominant. Germline loss-of-function mutation in one allele of a mismatch repair gene; the "second hit" (somatic loss of the normal allele) causes loss of MMR function (Knudson two-hit model). - Genes: MLH1 and MSH2 (most common), MSH6, PMS2. EPCAM deletions silence MSH2 by promoter hypermethylation. - Normal MMR function: MutS homologs (MSH2/MSH6) recognize base-pair mismatches and small insertion/deletion loops; MutL homologs (MLH1/PMS2) recruit the machinery to excise and resynthesize the DNA. This corrects replication errors during S phase. - Loss of MMR leads to accumulation of errors in repetitive DNA sequences (microsatellites), producing microsatellite instability (MSI-high). Mutations in genes with microsatellite repeats (e.g., TGFBR2, BAX) drive tumorigenesis. - Mechanism differs from FAP/APC: Lynch follows the MSI (mismatch repair) pathway, not the chromosomal instability (APC → KRAS → p53) pathway.

**Clinical features** - Colorectal cancer at a young age (mean ~45), with proximal (right-sided/cecum, ascending colon) predominance. Tumors are often mucinous or poorly differentiated, with prominent lymphocytic infiltrate. - Few polyps (hence "nonpolyposis"), but adenomas progress to carcinoma faster (~2-3 years vs ~10 years in sporadic disease). - Extracolonic cancers: **endometrial cancer** (the most common extracolonic cancer, and often the sentinel cancer in women), ovarian, gastric, small bowel, urothelial (ureter/renal pelvis), hepatobiliary, pancreatic, and brain (glioblastoma, as in Turcot syndrome). Sebaceous adenomas/carcinomas and keratoacanthomas occur in the Muir-Torre variant.

**Diagnosis** - Clinical criteria: Amsterdam II criteria ("3-2-1 rule" or the 3-2-1 rule of 3 relatives, 2 generations, 1 diagnosed before age 50) and revised Bethesda guidelines (used to select tumors for testing). - Universal tumor screening: immunohistochemistry (IHC) for MMR protein loss and/or MSI PCR testing on all colorectal (and endometrial) cancers. - If MLH1 loss on IHC: test for BRAF V600E mutation or MLH1 promoter hypermethylation. These indicate **sporadic** MSI cancer, not Lynch. If BRAF is wild-type/no hypermethylation, proceed to germline testing. - Confirm with germline genetic testing.

**Management** - Colonoscopy every 1-2 years beginning at age 20-25 (or 2-5 years before the youngest affected relative's diagnosis). - Women: consider endometrial biopsy surveillance; prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete. - Consider upper endoscopy surveillance for gastric cancer, and urinalysis per risk. - Aspirin chemoprevention has evidence of reduced risk. - Colorectal cancer treatment: segmental or total colectomy depending on the case. MSI-high/dMMR tumors respond well to immune checkpoint inhibitors (pembrolizumab, nivolumab), and they show reduced benefit from 5-FU monotherapy in stage II disease.

**High-yield comparisons** - FAP: APC mutation (5q21), hundreds to thousands of polyps, near 100% cancer risk by ~40 yrs, prophylactic colectomy. - Lynch: MMR genes, few polyps, ~80% lifetime CRC risk, right-sided predominance. - Lynch is the most common hereditary CRC syndrome (~3-5% of all CRC). - Sporadic MSI cancers: usually older patients with MLH1 promoter hypermethylation and BRAF mutation.