HNPCC

**Genetics/Pathophysiology:** Autosomal dominant germline mutation in a DNA mismatch repair gene: MLH1 (most common, along with MSH2), MSH2, MSH6, PMS2. EPCAM deletions can silence MSH2. MMR normally corrects base-pair mismatches and insertion/deletion loops generated by DNA polymerase during replication. Loss of function (second-hit "two-hit" mechanism in somatic cells) leads to accumulation of errors in short repetitive sequences (microsatellites) = microsatellite instability (MSI-high). Affected genes include TGF-beta receptor II and BAX, which drive carcinogenesis. Distinct from the APC/chromosomal instability pathway (FAP, sporadic CRC) and the CIMP/BRAF pathway (sporadic MSI tumors via MLH1 promoter hypermethylation).

**Clinical features:** - Colorectal cancer at young age (mean ~45 y), predominantly right-sided (proximal/ascending colon), often mucinous, poorly differentiated, with lymphocytic infiltrate; adenomas progress to carcinoma rapidly (accelerated adenoma-carcinoma sequence). Few polyps (not hundreds as in FAP). - Extracolonic cancers: endometrial (most common extracolonic; lifetime risk ~40-60% in women, may be sentinel cancer), ovarian, gastric, small bowel, urothelial/ureter/renal pelvis, hepatobiliary, pancreatic, brain (glioblastoma; Turcot variant), sebaceous adenoma/carcinoma and keratoacanthoma (Muir-Torre variant).

**Diagnosis:** - Clinical criteria: Amsterdam II ("3-2-1" or 3-3-2 rule): ≥3 relatives with Lynch-associated cancer, ≥2 successive generations, ≥1 diagnosed <50 y, one is a first-degree relative of the other two, FAP excluded. Revised Bethesda guidelines guide tumor testing. - Universal tumor screening of CRC (and endometrial) specimens: IHC for MMR proteins and/or MSI PCR. If MLH1 loss: test BRAF V600E mutation or MLH1 promoter hypermethylation; present = sporadic, absent = suspect Lynch → germline testing.

**Management/screening:** - Colonoscopy every 1-2 years starting at age 20-25 (or 2-5 years before youngest family member's diagnosis). - Women: consider endometrial biopsy/transvaginal ultrasound; prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing is complete. - Upper endoscopy for gastric cancer surveillance (consider H. pylori testing), urinalysis surveillance in some guidelines. - Aspirin chemoprevention has evidence for reduced CRC risk. - MSI-high/dMMR tumors respond well to immune checkpoint inhibitors (pembrolizumab, nivolumab) because of high neoantigen burden. - Treatment of CRC: surgery, often subtotal colectomy given metachronous risk.

**Boards pearls:** HNPCC = MMR defect, MSI, proximal colon, young, few polyps. FAP = APC mutation (chromosome 5q), 100s-1000s of polyps, near 100% CRC by 40 y. Endometrial cancer is the most common extracolonic malignancy. Compare: Peutz-Jeghers (STK11, hamartomas, mucocutaneous pigmentation), MUTYH-associated polyposis (autosomal recessive, base excision repair, G:C→T:A transversions), Gardner (FAP + osteomas, desmoids, epidermoid cysts).