Colon Cancer Genetics Overview

Colon Cancer Genetics Overview

• Colorectal cancers have high mutational burdens; familial predisposition is seen in approximately 20% of cases.
• Family history assessment is crucial. One first-degree relative with CRC doubles the risk, and more than one increases risk fourfold. Family history of CRC before age 45 increases risk fourfold.
• Patients without family history may require colonoscopy every 6 years.
• Four molecular subtypes (CMS) of CRC exist: CMS1 (MSI immune type), CMS2 (canonical, chromosomally unstable), CMS3 (metabolically dysregulated), and CMS4 (mesenchymal, angiogenesis).

Lynch Syndrome (HNPCC)

• The most common genetic predisposition to CRC, affecting about 2-4% of CRC cases and 2.5% of endometrial cancers.
• Caused by germline mutations in MMR genes (MLH1, MSH2, MSH6, PMS2).
• Age of onset typically ranges from 42 to 61.
• Lifetime CRC risk varies by affected gene: MLH1/MSH2 (40-80%), MSH6 (10-22%), PMS2 (15-20%).
• Diagnosed using IHC (immunohistochemistry) or MSI (microsatellite instability) genetic testing (high specificity and sensitivity, with ~5% and ~10% false negative rates respectively).
• Absence of MLH1 expression in IHC warrants BRAF testing or MLH1 promoter methylation testing, as BRAF mutations may also cause decreased MLH1 expression.
• Universal or reflex MMR testing for all newly diagnosed cancers is recommended for prognostication, adjuvant therapy decisions (stage II), and treatment planning (stage IV).
• Screening: Colonoscopy starting at age 25, then every 1-2 years.

Familial Adenomatous Polyposis (FAP)

• Affects approximately 1% of CRC cases.
• Caused by an autosomal dominant mutation of the APC gene.
• Lifetime CRC risk is approximately 100%.
• Typical onset is between 20 and 30 years of age.
• APC gene testing is recommended in patients with a positive family history.

Other Syndromes

• MUTYH-associated polyposis: Autosomal recessive biallelic mutation of MUTYH; extracolonic cancer risk includes the duodenum.
• Polymerase Proofreading-Associated Polyposis (PPAP): POLE and POLD1 mutations; oligopolyposis (10-99 adenomas); extracolonic cancer risk includes the endometrium.
• Juvenile polyposis syndrome: Autosomal dominant; BMPR1A and SMAD4 mutations; smooth-appearing polyps; extracolonic cancer risk includes the stomach; small intestinal polyps possible; approximate lifetime CRC risk is 39%.
• Cowden syndrome: Autosomal dominant; PTEN mutation; extracolonic cancer risk includes breast, thyroid, endometrial, and renal cancers; clinical features include macrocephaly, trichilemmomas, and oral papillomas.
• Peutz-Jeghers syndrome: Autosomal dominant; STK11 mutation; extracolonic cancer risk includes stomach, pancreas, breast, ovary, and testicle; clinical feature is mucocutaneous pigmentation (potentially fades with age).
• Li-Fraumeni syndrome: Autosomal dominant; TP53 mutation; extracolonic cancer risk includes sarcomas, breast cancer, leukemia, and adrenal cancers.

Colon Cancer Pathology

• Intraoperative marking of non-peritonealized margins is mandatory.
• Lymph node examination (minimum 12) is correlated with survival (INT 0089).
• Lymph node ratio (positive/total) is associated with shorter overall survival and disease-free survival.
• Micrometastases (0.2-2mm tumor clusters in lymph nodes) and tumor deposits (tumor tissue along lymphatic pathways, but no residual lymph node tissue) are associated with poor prognosis. Tumor deposits in particular have high impact on node-negative patient survival.
• Perineural invasion (PNI) and tumor budding (small clusters of tumor cells on tumor edge) are also high-risk factors.

Genetic Testing in Colon Cancer

MSI/MMR Testing

• Universally tested in colon cancer, conducted only by CLIA-approved labs.
• Present in 15% of CRCs (3% Lynch syndrome, 12% sporadic).
• MMR genes ranked by prevalence: PMS2, MSH6, MLH1, MSH2.
• IHC testing: 83% sensitivity, 89% specificity; MSI PCR testing: 85% sensitivity, 90% specificity.
• Lynch syndrome prevalence: MSI-H (16%), MSI-I (2%), MSS (0.3%).
• IHC positive signifies absence of one or more MMR proteins; negative means all 4 MMR proteins present.
• MSI-H or IHC positive implies germline Lynch.
• If MLH1 is absent, test BRAF V600E or MLH1 promoter methylation.
• MSI-H is associated with poor differentiation, proximal colon involvement, mucinous histology, lymphocytic infiltration, low metastatic potential, good prognosis, and benefit from immunotherapy.
• For Stage II MSI-H, 5FU adjuvant therapy is not typically indicated

KRAS/NRAS/HRAS Testing

• Found in ~50% of sporadic cancers and 50% of colonic adenomas >1 cm; KRAS most common, and more often in proximal colon.
• Mutations happen later in tumor progression.
• Tested in all metastatic CRCs and selected non-metastatic CRCs.
• CLIA-88 approved labs only.
• KRAS/NRAS mutations prevent use of panitumumab and cetuximab.

BRAF Testing

• Found in ~10% of all colon cancers, more in smokers, associated with female sex, older age, right-sided tumors, and poor differentiation.
• Poor prognosis (reduces survival).
• Most common mutation is V600E.
• Tested by IHC.
• CLIA-88 approved labs only.
• BRAF mutations prevent use of EGFR inhibitors, but BRAF inhibitors may be indicated.

HER2 Testing

• Found in 2% of all CRCs and 5-6% of metastatic CRCs, more common in distal colon.
• If IHC positive, reflex FISH or NGS for amplifications.
• Anti-HER2 may be indicated.

NTRK Fusion Testing

• Very rare (0.3% of CRCs).
• NTRK inhibitors may be indicated.

Multigene Assays

• Used for prognosis, recurrence risk, and chemotherapy guidance.
• Oncotype DX Colon Cancer assay (7 genes): recurrence score (low, intermediate, high) predicts recurrence independent of TNM, MMR, or nodes.
• ColoPrint (18 genes): low or high risk graded.
• ColDx: 634-transcript microarray assay.
• CD3 and CD8+ T-cell density: assessed in stage III for chemotherapy success prediction.
• Post-surgical circulating DNA (ctDNA): PCR assay; positive results indicate increased recurrence risk and possible benefit from adjuvant chemotherapy.

This quiz covers the genetic aspects and predispositions associated with colorectal cancer, including the role of family history and mutations. It discusses the four molecular subtypes of CRC and the significance of Lynch Syndrome in hereditary cancer risk. Understanding these concepts is vital for assessing the risk and management of colorectal cancer.