Genetics, Mathematics, and Colorectal Cancer 

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Investigators have identified three new genetic ‘hotspots’ linked to colorectal cancer,...,which may provide new insight into the biology of colorectal cancer and present new therapeutics targets for treatment.

Two recent study reports in colorectal cancer explored new data on genetic precursors to the disease and outcome predictors once treatment is initiated.

New Genetic Links to Colorectal Cancer Are Identified

Investigators from Vanderbilt-Ingram Cancer Center, Nashville, and colleagues in China, South Korea, and Japan have identified three new genetic “hotspots” linked to colorectal cancer. One of the genetic loci is in close proximity to CCND2, the gene encoding cyclin D2, which plays a critical role in cell-cycle progression and has been shown to be overexpressed in colorectal tumors.

Another variant is located near the PITXI gene, a tumor-suppressor gene that may activate TP53 and regulate the activity of the enzyme telomerase. And the third variant includes two genes, HAO1 and PLCB1. PLCB1 has been previously shown to be overexpressed in colorectal cancer tissue. Results from the study were published in Nature Genetics.1

The researchers analyzed 5,252 colorectal cancer cases and 9,071 control samples from the Asia Colorectal Cancer Consortium to identify novel colorectal cancer risk factors. The three variants found may provide new insight into the biology of colorectal cancer and present new therapeutic targets for treatment, according to the study.

Mathematical Model May Help Predict Response to Chemotherapy

A new mathematical model that measures the amount of stress required for a cancer cell to die without harming healthy tissue may help scientists better predict which patients with colorectal cancer will respond to chemotherapy, according to a new study published in Cancer Research.2

Apoptosis is believed to be a hallmark of cancer resistance to chemotherapy. Previous studies have shown that an essential step in apoptosis—the process that leads to mitochondrial outer membrane permeabilization (MOMP)—is controlled by different members of the Bcl-2 family of proteins. Because some Bcl-2 proteins promote apoptosis and some prevent it, and those proteins that have the same effects on apoptosis work in parallel and can substitute for each other, it is difficult to predict whether cells are likely or unlikely to die.

Researchers from the Royal College of Surgeons in Ireland developed a tool that incorporates patient-specific molecular data sets. They studied the Bcl-2 proteins, determined levels of the individual proteins, and then put the levels into a mathematical model that calculated what genotoxic stress level is needed to achieve apoptosis.

The researchers applied their model predictor, called DR_MOMP, to protein profiles in tumor tissue and matched normal tissue samples from 26 patients with colorectal cancer and found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. The differences, according to the study, were sufficient to differentiate clinical responders from nonresponders “with high confidence.”

The finding may provide a clinical decision-making tool that predicts treatment responses in patients with colon cancer. The researchers hope to validate DR-MOMP in other cancer types and in larger patient cohorts. ■


1. Jia WH, Zhang B, Matsuo K, et al: Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer. Nature Genetics 45:191-196, 2012.

2. Lindner AU, Concannon CG, Boukes GJ, et al: Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy. Cancer Research 73:519-528, 2013.