In a patient with rectal cancer, what genetic testing is recommended and how should the results guide surveillance and management?

Genetic Testing in Rectal Cancer

All patients with newly diagnosed rectal cancer should undergo universal tumor testing with immunohistochemistry (IHC) for mismatch repair (MMR) proteins or microsatellite instability (MSI) testing to identify Lynch syndrome and guide both treatment decisions and family screening. 1

Initial Tumor-Based Testing Strategy

Universal somatic testing is the cornerstone of genetic evaluation for rectal cancer patients:

• Perform IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2) or MSI testing on all rectal cancer specimens at diagnosis 1
• This testing serves dual purposes: identifying candidates for immunotherapy (MSI-H/dMMR tumors respond to pembrolizumab or dostarlimab rather than chemoradiotherapy) and detecting hereditary Lynch syndrome 2
• If MMR deficiency is detected, proceed with reflex testing for BRAF mutation and MLH1 promoter hypermethylation to distinguish sporadic from hereditary cases 1

Critical distinction: MSI-H is rare in rectal cancer (only a few percent) compared to colon cancer where it occurs in approximately 13% of cases, making positive findings particularly significant 3

Age-Stratified Germline Testing Approach

For patients under 30 years with rectal cancer:

• If dMMR tumor: perform constitutional Lynch syndrome panel testing first, followed by somatic tumor panel if germline testing is negative 1
• If pMMR tumor: proceed directly to constitutional CRC multigene panel testing 1

For patients 30-50 years with rectal cancer:

• Consider multigene panel testing based on family history, tumor characteristics, and clinical suspicion for hereditary syndrome 4
• Even without identified germline mutation, patients diagnosed under age 50 should receive enhanced surveillance: standard post-CRC surveillance for 3 years, then 5-yearly colonoscopy until eligible for national screening 1

Lynch Syndrome Confirmation and Management

When Lynch syndrome is confirmed or suspected:

• Colonoscopic surveillance every 2 years for all Lynch syndrome patients 1
• Stratify surveillance initiation by gene: begin at age 25 for MLH1/MSH2 carriers, age 35 for MSH6/PMS2 carriers 1
• Screen for Helicobacter pylori and provide eradication therapy if positive 1
• Advise daily aspirin use, which reduces CRC risk in Lynch syndrome patients 1

Surgical implications for Lynch syndrome patients with rectal cancer:

• Standard low anterior resection is reasonable when abdominoperineal excision can be avoided, despite residual colon being at high risk for metachronous neoplasia 1
• For MSH6 or PMS2 mutations: insufficient evidence supports extended colectomy over segmental resection 1
• For MLH1 or MSH2 mutations: balance metachronous cancer risk against functional consequences, patient age, and wishes when deciding between segmental versus extended colectomy 1

Lynch-Like Syndrome Evaluation

For dMMR tumors without BRAF mutation/hypermethylation and no germline MMR variant:

• Perform somatic tumor testing with CRC gene panel 1
• If double somatic MMR variants identified: manage patient and first-degree relatives based on family history of CRC criteria 1
• If zero or one somatic mutation found: manage patient and first-degree relatives as per Lynch syndrome protocols 1

Family History-Based Testing

When family history suggests hereditary CRC:

• Assess MMR status in tumor tissue from close affected family member for all patients referred with family history of CRC 1
• Verify reported polyposis history by reviewing histopathology/endoscopy reports confirming minimum 10 adenomas or serrated lesions in first-degree relative 1
• For high-risk families (3+ first-degree relatives with CRC across >1 generation): perform 5-yearly colonoscopy from age 40 to 75 years 1

Polyposis Syndrome Considerations

Although less common in rectal cancer specifically:

• Familial adenomatous polyposis (FAP) requires APC testing when ≥10 adenomas present 1, 5
• MUTYH-associated polyposis (MAP) testing for biallelic MUTYH variants when adenomatous polyposis phenotype present 4
• Serrated polyposis syndrome is phenotype-driven (no causative genes identified); exclude other polyposis syndromes by gene panel if patient <50 years, multiple affected kindred members, or dysplasia present 1

Common Pitfalls to Avoid

• Do not skip universal tumor testing: Even though MSI-H is rare in rectal cancer, missing it has profound treatment implications (immunotherapy vs. chemoradiotherapy) 2
• Do not assume negative germline testing excludes hereditary syndrome: If family history strongly suggests hereditary CRC but mutation testing is negative, still implement the same surveillance and management as for confirmed mutation carriers 5
• Do not overlook family screening: Once germline mutation identified, first-degree relatives require predictive testing and appropriate surveillance 5, 6
• Do not forget non-colorectal surveillance in Lynch syndrome: While gastric/small bowel/pancreatic surveillance should only occur in clinical trials, endometrial and urinary tract cancers are part of the syndrome spectrum 1, 7

Documentation Requirements

• Record MMR/MSI status in pathology report for every rectal cancer 1
• Document family history across at least three generations when hereditary syndrome suspected 6
• Ensure genetic counseling occurs before germline testing to discuss implications of results 6, 4