Genetic Testing for Polyposis: Diagnosis & Treatment Guide

Quick Takeaways

• Polyposis is usually driven by inherited mutations in APC, MUTYH, or related genes.
• Genetic testing pinpoints the exact mutation, shaping surveillance and surgery plans.
• Choosing between single‑gene tests, multi‑gene panels, or whole‑exome sequencing depends on family history and clinical presentation.
• Positive results trigger tailored colonoscopic schedules, prophylactic colectomy options, and, in some cases, targeted drug trials.
• Genetic counseling before and after testing reduces anxiety and improves decision‑making.

Understanding Polyposis and Its Genetic Roots

Polyposis describes a condition where dozens to thousands of adenomatous polyps line the colon and sometimes the upper gastrointestinal tract. The sheer number of polyps dramatically raises colorectal cancer risk-often before age 40.

Two hereditary syndromes dominate the landscape:

• Familial Adenomatous Polyposis (FAP) - usually caused by a germline mutation in the APC gene. Patients develop >100 polyps in their teens.
• MUTYH‑associated Polyposis (MAP) - linked to biallelic mutations in the MUTYH gene. Polyps tend to appear later and in slightly lower numbers.

Other, less common genes (e.g., STK11 for Peutz‑Jeghers, BMPR1A for Juvenile Polyposis) also drive polyposis but account for a small slice of cases.

How Genetic Testing Works for Polyposis

When a clinician suspects hereditary polyposis-based on polyp count, age of onset, or family cancer patterns-they order a genetic test. The process typically follows these steps:

1. Blood or saliva sample collection from the patient (and sometimes affected relatives).
2. DNA extraction and quality check in a certified laboratory.
3. Sequencing using Next‑Generation Sequencing (NGS) platforms, which can read thousands of gene regions simultaneously.
4. Bioinformatic analysis to compare the patient’s sequences against reference genomes.
5. Interpretation by clinical geneticists, who classify variants as pathogenic, likely pathogenic, benign, likely benign, or VUS (variant of uncertain significance).

Turn‑around time varies: targeted single‑gene tests may return in 2‑3 weeks, while broader panels can take 4‑6 weeks.

Key Genes Involved: APC, MUTYH, and Beyond

The most frequent culprits are:

• APC gene - located on chromosome 5q22.2, encodes a tumor‑suppressor protein that regulates β‑catenin. Over 1,200 known pathogenic variants exist, many truncating mutations.
• MUTYH gene - sits on chromosome 1p34.1, encodes a DNA‑glycosylase involved in base‑excision repair. The two most common pathogenic variants in European populations are p.Tyr179Cys and p.Gly396Asp.
• Additional genes - STK11 (Peutz‑Jeghers), BMPR1A and SMAD4 (Juvenile polyposis), and DNA mismatch‑repair genes (MLH1, MSH2, MSH6, PMS2) linked to Lynch syndrome which can also present with multiple polyps.

Knowing which gene is mutated guides the clinician’s surveillance schedule and informs relatives about their own risk.

Choosing the Right Test: Panels vs Single‑Gene vs Whole‑Exome

Three main test formats dominate UK clinical practice:

When family history points clearly to APC or MUTYH, a single‑gene test saves money and simplifies interpretation. If the pattern is ambiguous-e.g., mixed family cancers or a low‑polyp burden-a panel or WES avoids repeated testing.

Interpreting Results: Positive, Negative, and VUS

A “positive” result means a pathogenic or likely‑pathogenic variant was found. This triggers cascade testing for first‑degree relatives, often via saliva kits.

A “negative” result does not guarantee safety. It could reflect: (a) a mutation in an untested gene, (b) a large genomic rearrangement missed by standard NGS, or (c) a de‑novo mutation that escaped detection. In such cases, clinicians may still recommend intensified surveillance based on phenotype.

Variants of uncertain significance (VUS) are the most frustrating. They lack enough evidence to be classified as harmful. Management usually follows the patient’s clinical picture until more data emerge-often through international databases like ClinVar.

Impact on Treatment Decisions: Surveillance, Surgery, and Targeted Therapies

Genetic information reshapes three core management pillars:

• Surveillance - APC carriers start colonoscopy at age 10‑12, repeating every 1‑2 years. MUTYH biallelic carriers begin at 25‑30 years, with 2‑3‑year intervals. Panel‑tested patients receive schedules tailored to the most penetrant gene identified.
• Prophylactic Colectomy - For classic FAP (≥100 polyps) or when polyps become high‑grade dysplasia, total proctocolectomy with ileal pouch‑anal anastomosis (IPAA) is standard. In MAP, surgery is reserved for refractory disease because polyps appear later.
• Targeted Therapies - Recent trials (2023‑2024) show COX‑2 inhibitors (e.g., celecoxib) can modestly reduce polyp burden in APC‑mutated patients. Ongoing studies explore PARP inhibitors for MUTYH‑deficient tumors.

All decisions should be made after a thorough genetic counseling session, ensuring patients understand benefits, risks, and lifestyle implications.

Practical Checklist for Patients and Clinicians

• Gather a three‑generation family cancer history before ordering any test.
• Schedule a pre‑test genetic counseling appointment.
• Decide on test type (single‑gene vs panel) based on phenotype.
• Ensure the laboratory is accredited by the UK Accreditation Service (UKAS) and participates in the UK Genetic Testing Network.
• After results, update the patient’s electronic health record with variant classification and recommended surveillance interval.
• Offer cascade testing to at‑risk relatives within 6 months of a positive result.
• Re‑evaluate management annually; consider re‑testing if a VUS later reclassifies.