These days, the ways of reducing our risk of getting cancer are essential habits — wearing sunscreen, staying away from tobacco and avoiding exposure to carcinogens. However, despite the fact that these precautions can help prevent the vast majority of environmentally caused cancers, 5 to 10% of all cancer patients do not have such an easy way of preventing their fate. These are the patients who have a family history of cancer caused by inherited genetic mutations. In other words, these patients receive genes from their parents that are hardwired to increase the likelihood of tumor formation and cancer onset. As you may have heard from the recent buzz about genetic testing for the BRCA mutations, which are hereditary mutations that increase one’s risk for ovarian and breast cancers, it is imperative for people with family members affected by such cancers to determine whether they are also carriers of the mutations. Doing so would allow affected patients to take preventative measures, like mastectomies, to prevent the onset of the cancer, or to take care in family planning to avoid the risk of passing the mutations to their children.
These patients receive genes from their parents that are hardwired to increase the likelihood of tumor formation and cancer onset.
Currently, discerning whether a cancer is hereditary is a difficult process, and involves meticulous and often conjectural processes. For example, one such procedure is pedigree mapping, in which a specialist attempts to trace similar instances of the cancer in family members. Assembling pedigree maps is difficult when it is uncertain whether deceased extended family members had succumbed to a particular cancer. Another procedure, which involves analyzing biopsy samples from tumors, is a promising avenue for diagnosing hereditary cancers. However, most of the genetic sequences that cause hereditary cancers have not yet been discovered.
Professor Alison Gammie of the Department of Molecular Biology is using the yeast Saccharomyces cerevisiae as a model organism to solve this problem. “It may seem surprising to investigate human diseases in an organism as tiny and simple as yeast,” says Gammie. “But Saccharomyces cerevisiae’s genome bears many similarities to the human genome. In fact, the tiny yeast produces many of the same biomolecules and proteins as humans because most of the genetic sequence has been conserved in evolution.” Professor Gammie’s lab staff specializes in creating mutations in the yeast genome though selective breeding and analyzing their effects on protein production. As a simple organism, yeast also allows for fast testing for the presence of mutations and their locations in the genome. Because the crystal structures of the proteins coded in the yeast genome are already known, it is possible to link the effects of mutations in specific areas of the genome with structural changes of conformation, specifically the clustering of the amino acid side chains of the protein.
Professor Gammie is applying her work with Saccharomyces cerevisiae to investigate the genetic basis of colon cancer. Tumors that develop in colon cancer are often resistant to conventional chemotherapy because of low levels of mismatch repair proteins, which are naturally occurring proteins in organisms that repair tumor-causing mutations. Gammie’s lab is investigating the effect of mutations on the ubiquitin proteasome degradation pathway, a biochemical reaction process in which ubiquitin, a type of DNA mismatch repair protein, is degraded. According to Gammie, ubiquitin is degraded more rapidly when a mutation in its coding sequence gives rise to an aberrant protein conformation. The possible therapeutic applications of this research indicate the groundbreaking work in cancer research that is being carried out in Gammie’s lab — the most important of which includes development of a drug to inhibit this pathway, thus restoring normal mismatch repair activities in the cells of colon cancer patients, and drugs that will bolster the efficacy of conventional chemotherapy treatments. “Eventually,” says Gammie, “we hope to better understand hereditary cancer formation and contribute to cancer treatments beyond the realm of heritable cancers.”