A 42-year-old man with a personal history of colorectal cancer (diagnosed at age 38) and a family history of early-onset colorectal and endometrial cancers presents for genetic risk assessment. Which investigation is most appropriate to confirm Lynch syndrome (hereditary nonpolyposis colorectal cancer)?

Explanation

## Investigation of Choice for Lynch Syndrome Confirmation ### Clinical Presentation Clues - Early-onset colorectal cancer (age 38, <50 years) - Family history of early-onset colorectal AND endometrial cancer - No mention of polyposis These features are classic for Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC). **Key Point:** MSI testing and MMR immunohistochemistry on the tumor are the first-line investigations to screen for Lynch syndrome. Abnormal results warrant germline MMR gene sequencing for definitive diagnosis. ### Diagnostic Algorithm for Lynch Syndrome ```mermaid flowchart TD A[Early-onset CRC or family history of CRC/EC] --> B[MSI testing + MMR IHC on tumor] B --> C{MSI-High or MMR loss?} C -->|Yes| D[Germline MMR gene sequencing] C -->|No| E[Lynch syndrome unlikely] D --> F{Pathogenic mutation found?} F -->|Yes| G[Lynch syndrome confirmed] F -->|No| H[Consider other syndromes] ``` ### Why MSI and MMR IHC? | Investigation | Mechanism | Sensitivity | Specificity | |---|---|---|---| | **MSI testing** | Detects expansion of microsatellite repeats due to MMR deficiency | ~85% in Lynch syndrome | ~90% (some sporadic MSI-H tumors) | | **MMR IHC** | Detects loss of MLH1, MSH2, MSH6, or PMS2 protein expression | ~90% in Lynch syndrome | ~95% (directly reflects gene function) | | **Germline MMR sequencing** | Gold standard; identifies pathogenic mutation in MLH1, MSH2, MSH6, or PMS2 | ~95% in Lynch syndrome families | 100% (definitive) | | **Colonoscopy** | Detects polyps and cancers; does not identify genetic predisposition | N/A | N/A | | **Serum CEA** | Nonspecific tumor marker; reflects disease burden | Low sensitivity | Low specificity | **High-Yield:** Lynch syndrome accounts for 2–4% of all colorectal cancers. Germline mutations in MLH1 (~60%), MSH2 (~25%), MSH6 (~7%), or PMS2 (~3%) cause loss of mismatch repair function, leading to microsatellite instability (MSI-H) and early-onset, right-sided CRC with increased risk of endometrial, ovarian, and gastric cancers. **Clinical Pearl:** The revised Bethesda criteria recommend MSI/MMR testing for: - CRC diagnosed before age 50 - CRC with MSI-H histology - CRC in a patient with a Lynch syndrome-related cancer in the family - CRC in a patient with two Lynch syndrome-related cancers (CRC, endometrial, gastric, ovarian, urothelial, biliary, small bowel) **Mnemonic: MLH-MSH-PMS** — The four mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are mutated in Lynch syndrome; loss of function causes Microsatellite Instability and early-onset cancer. [cite:Robbins 10e Ch 7]