Studying the Tumor Biology and Genetics of Cancer - By Dr. Atallah
Traditionally, clinical and pathologic staging by TNM has been the primary method for determining prognosis as well as treatment & follow-up for colorectal and anal cancer. For example, good risk patients with stage III colon cancer have a proven survival with adjuvant oxaliplatin-based systemic chemotherapy.However, the role of adjuvant treatment for stage II colon cancer is less certain, and genetic differences such as loss of heterozygosity (LOH) and microsatellite instability have been described.These findings may result in important clinical applications – ie., deterining who will benefit from adjuvant chemotherapy for stage II colon cancer.Genetics and protein expression are currently in use to determine who will benefit from Erbitux (cetuximab).Erbitux, proven effective from stage IV, liver-metastatic colon cancer is not beneficial in patients with k-ras mutation and therefore this gene is routinely checked to assure patients have the k-ras wild-type prior to initiating therapy.
While TNM staging has provided the gold standard for determining prognosis and treatment ofmalignancies of the colon, rectum, and anus, it cannot address the inherent differences between tumors, including the biologic characteristics (ie, propensity to metastasize) and also their response to chemotherapeutics.
Research to date includes work research from Jen, et al. which has shown that patients with clinical stage II and III colon cancer who have demonstrable LOH on chromosome 18q21 have decreased 5-year survival (54% vs. 93% for patients with stage II disease).Therefore, LOH in 18q21 is a strongly predicts long-term survival. As reported by Potter and others, the presence of tandem dinucleotide repeats (microsatellites) in cancer cells is of clinical significance.As with autosomal dominant, hereditary non-polyposis colon cancer (HNPCC), the presence of mutations in mismatch repair genes during cell division can result in high microsatilite instability (MSI).Interestingly, MSI-high colon cancer tumors are associated with improved outcome when compared stage for stage with MSI-low, sporadic colon cancer.In a randomized trial, The Eastern Cooperative Oncology Group E5202 trail is currently investigating how MSI and LOH on chromosome 18q21 can be used prospectively to select patients with stage II colorectal cancer who will benefit from adjuvant FOLFOX with and without bevacizumab.
More recently, novel genetic markers and germline polymorphisms have been studied as an alternate method of obtaining prognostic information and treatment-predictive data.These new markers may also help identify unique molecular pathways which intern lead to target specific chemotherapeutics.Examples include polymorphisms in the interleukin-8 (IL-8) gene.IL-8 has been shown to be important in the angiogenesis of colorectal cancer, and polymorphisms at this locus are associated with a higher risk of local recurrence.Conversely, epidermal growth factor receptor (EGFR) genotypes and a higher number of cytosine-adenine dinucleotide repeats are associated with a significantly higher recurrence-free survival.Other markers which have been shown to correlate with colon cancer recurrence rates include intercellular adhesion molecule-1 (ICAM-1), tumor growth factor-beta (TGF-B), and fibroblast growth factor receptor-4 (FGFR-4).
Perhaps the latest advancement to date involves using RNA purified from tumor cells and thendetermining a gene expression profile or ‘signature’ by testing this sample against a DNA microarray including thousands of known transcripts.This allows for determination of which proteins are transcribed in a particular tumor (i.e., gene expression signature).In 2004, Wang, et al., reported the first gene expression profile obtained from 74 patients with stage II colon cancer.23-gene sitnatures where found to correlate with disease relapse and this data was prospectively validated with 78%accuracy (p = 0.003) on 36 patients.Eschrich, et al. also used microarray gene expression signatures to study colon cancer tumors and found that a 43-gene signature was identified which strongly correlated with 36-month overall survival in patients with Dukes B and C disease.Finally, Toshiaki et al. in 2009 reported that gene expression signatures can predict lymph node metastasis.In this study, 89 patients with colorectal cancer were studied and 73-gene transcription signatures were identified using DNA microarray techniques which allowed for an accuracy of prediction lymph node metastasis of 88.4%.