PRIMARY OBJECTIVES:
I. To evaluate the impact of loss of p21 and mutations in p53 on the relationship between higher intake of a Western dietary pattern (manifested by higher red meat and total fat intake and lower n-3 polyunsaturated fatty acids, fruit and vegetable intake) and colon cancer recurrence/mortality. (B1)
II. To evaluate the impact of mutated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras), mutated p53, phorphorylated (phospho)-v-akt murine thymoma viral oncogene homolog 1 (Akt) overexpression, and p27 loss on the relationship between each of obesity, physical activity and dietary glycemic intake and colon cancer recurrence/mortality. (B1)
III. To evaluate the impact of tumoral cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) overexpression, high tumor microvessel density and intact p21 on the relationship between aspirin use and colon cancer recurrence. (B1)
IV. To define the association of type and extent of genomic instability with clinical outcome in stage III colon cancers treated with resection and adjuvant chemotherapy (CALGB 89803). (B2)
V. To assess the ability of a prognostic gene expression signature to stratify stage II colorectal cancer patients into those who will experience relapse within five years post surgery (high risk) and those who will experience five-year disease free survival (low risk), without additional treatment. (B3)
VI. To determine whether there is a significant relationship between the risk of recurrence and the continuous 12-gene recurrence score (RS) as measured by the growth hormone insufficiency (GHI) assay of gene expression, using the pre-specified genes and Recurrence Score algorithm. (B4) VII. To determine whether there is a significant relationship between the risk of recurrence and the continuous 15-gene RS2 as measured by the GHI assay of gene expression, using the pre-specified genes and second-generation Recurrence Score algorithm. (B4)
VIII. To assess the methylation status of mutL homolog 1 (MLH1), o-6-methylguanine-DNA methyltransferase (MGMT), and Werner syndrome (WRN) in tumors obtained from patients enrolled in both treatment arms of CALGB 89803. (B5)
IX. Determine the expression of DNA repair pathway proteins assessed by methylation-specific polymerase chain reaction (MSP) assays as well as the expression of DNA repair proteins that are known to interact with these epigenetically silenced DNA repair proteins using validated immunostaining assays. (B5)
X. Recognition of cytosine phosphate guanine (CpG) island methylator phenotype (CIMP) genes. (B5)
XI. To understand the relationship between tumor gene methylation status and epigenetic silencing of DNA repair pathway genes. (B5)
XII. To examine newly identified prognostic biomarkers (long interspersed nucleotide element 1 \[LINE-1\] methylation, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha \[PIK3CA\] mutation, v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\] mutation, fatty acid synthase \[FASN\] expression and vitamin D receptor \[VDR\] expression) in stage III colon cancers (CALGB 89803) with detailed lifestyle, treatment and follow-up data and correlate them with survival. (B6)
SECONDARY OBJECTIVES:
I. To define the association of type and extent of genomic instability with microsatellite instability and p53 mutations, which have previously been characterized in these tumors by Drs. Warren and Bertagnolli. (B2)
II. Associations with other markers will be determined at some future time once they have been characterized by collaborators. (B2)
III. To determine whether the 12-gene RS provides significant information beyond clinical and pathologic measures, including T stage, mismatch repair system (MMR) status, number of lymph nodes examined, tumor grade, and lymphovascular invasion. (B4)
IV. To determine whether the 15-gene RS2 provides significant information beyond the clinical and pathologic measures, including T stage, MMR status, number of lymph nodes examined, tumor grade, and lymphovascular invasion. (B4)
V. To compare the risk of recurrence between the high and low recurrence risk groups based on pre-specified percentile cut-points for the 12-gene RS. (B4)
VI. To compare the risk of recurrence between the high and low recurrence risk groups based on pre-specified percentile cut-points for the 15-gene RS2. (B4)
VII. To determine, for each of a panel of selected new genes (up to 768 genes), whether there is a significant relationship between gene expression and recurrence-free interval (RFI). (B4)
VIII. To define the association of CIMP and methylated genes with other genetic alterations and tumor-specific characteristics. (B5)
IX. To study the influence of diet and other lifestyle factors on cancer recurrence and treatment-related toxicity in patients participating in this trial. (B6)
OUTLINE:
Previously collected tissue samples are analyzed for K-ras mutations; COX-2, phospho-AKT, and VEGF overexpression; microvessel density; association of genomic instability with microsatellite instability and p53 mutations; and methylation status of MLH1, MGMT, and WRN and to identify prognostic biomarkers by LINE-1 hypomethylation, PIK3CA mutation, BRAF mutation, FASN expression, and VDR expression via immunohistochemistry, polymerase chain reaction (PCR), RT-PCR, and microarray.
