What genes are responsible for colon cancer recurrence?

Genes Responsible for Colon Cancer Recurrence

Multiple genes are implicated in colorectal cancer recurrence, with key roles played by APC, KRAS, p53, mismatch repair genes (MSH2, MLH1, MSH6, PMS1, PMS2), and BRAF mutations, which collectively drive tumor progression and metastatic potential. 1, 2

Key Genetic Alterations Associated with Recurrence

Somatic Mutations in Primary Tumors

• APC and MCC (chromosome 5q): Critical in early adenoma formation and progression 1
• KRAS (chromosome 12p): Associated with 92% of CIMP2 subtype tumors with higher recurrence rates 3
• DCC (chromosome 18q): Involved in tumor progression 1
• p53 (chromosome 17p): Found in 71% of CIMP-negative cases, associated with aggressive disease 3
• BRAF mutations: Present in 53% of CIMP1 tumors, linked to distinct recurrence patterns 3

Mismatch Repair Genes

• MSH2, MLH1, PMS1, PMS2, and MSH6 (GTBP): Defects in these genes lead to microsatellite instability (MSI) 1
• MSI status is both prognostic and predictive of response to therapy, with MSI-high tumors generally having better prognosis but potentially reduced benefit from fluoropyrimidine-based adjuvant therapy 1

Molecular Subtypes and Recurrence Risk

Three distinct molecular subtypes of colorectal cancer have been identified, each with different recurrence patterns 3:

1. CIMP1 (CpG Island Methylator Phenotype 1):

   • Characterized by MSI (80%) and BRAF mutations (53%)
   • Low rates of KRAS (16%) and p53 mutations (11%)
   • Generally better prognosis but can recur

2. CIMP2:

   • High rate of KRAS mutations (92%)
   • Rare MSI, BRAF, or p53 mutations
   • Intermediate recurrence risk

3. CIMP-negative:

   • High rate of p53 mutations (71%)
   • Lower rates of MSI (12%) or mutations of BRAF (2%)
   • Higher recurrence risk, especially with p53 mutations

Gene Expression Panels for Recurrence Prediction

Several validated multigene assays can help predict recurrence risk 1:

1. Oncotype DX Colon:

   • 12-gene panel including:
     • Stromal genes: BGN, INHBA, FAP
     • Cell cycle genes: MK167, MYBL2, MYC
     • Genotoxic stress: GADD45B
     • Reference genes: ATP5E, GPX1, PGK1, UBB, VDAC2
   • Generates Recurrence Score® (1-100) correlating with likelihood of recurrence 1
   • Validated in QUASAR and NSABP C-07 trials 1

2. ColoPrint:

   • 18-gene expression classifier
   • Categorizes patients into low vs. high recurrence risk
   • Independent of other risk factors 1

3. ColDx:

   • 634-probe microarray assay
   • Identifies high-risk stage II patients with HR 2.53 for recurrence 1

Serum Biomarkers for Post-Surgical Surveillance

Serum detection of genetic mutations shows promise for monitoring recurrence 2:

• Serum APC and p53 mutations: Strongly correlated with lymph node metastasis and TNM stage
• Serum KRAS mutations: Associated with locoregional metastasis
• Serum p53 mutations: More frequently detected in peritoneal metastasis
• Patients positive for any of these serum markers show significantly higher postoperative recurrence rates 2

Clinical Implications

1. Genetic Testing Recommendations:

   • MSI testing should be performed for all patients younger than 50 years to assess for Lynch syndrome 1
   • Some institutions perform MSI testing reflexively on all colorectal tumors due to prognostic value 1

2. Treatment Decisions:

   • While multigene assays provide prognostic information, they have not yet demonstrated predictive value for chemotherapy benefit 1
   • The NCCN recommends assessment of KRAS, NRAS, and BRAF mutation status to guide treatment strategies 1

Emerging Genetic Factors

Recent research has identified additional genes involved in colorectal cancer predisposition and potential recurrence 4:

• RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43, and GREM1

Understanding the genetic trajectories from primary tumor to metastasis is crucial for distinguishing between indolent oligo-metastatic disease and aggressive poly-metastatic disease 5.