Contributions from evolution studies related to cancer and its treatment.
Mounting discoveries about the astoundingly complex essence of cancer—that its causes lie in multitudes of genes (of evolution) gone awry—are also pointing the way toward treatments aimed at direct intervention with a unique set of genetic errors. In the October, 2008 issue of Nature journal, medical scientists reported having identified 26 key mutated genes linked to lung cancer alone. This diversity, and the underlying genes as core to the problem, means that the historical blunt force triumvirate of treatment—surgery, chemotherapy, and radiation—are no longer the only tools for treatment; and medicine is moving towards a much more highly individualized set of treatment regimens.
About a quarter of breast cancers are especially aggressive with an excess of HER2 gene copies. The gene causes an overproduction of a certain protein on the cell surface that serves as a receptor for a growth-spurring substance. Knowledge of that gene from study of the genomes of breast cancers and their rapid-growing evolution, has been utilized to make a drug (Herceptin) that blocks the receptors. The same kind of basic research has shown the genetic mutations of several other cancers including brain, ovarian, and pancreatic (with 63 mutations) tumors; and scientists are seeking ways around the function of the tumor cells and for means of penetrating their defenses. For example, a drug called Gleevee has proved effective in blocking signals that encourage cell replication in certain leukemia patients, and lung cancer drugs, Tarceva and Iressa, target the growth factor EGFR apparently by blocking expressions of mutations of EGFR. Unfortunately, as with bacterial resistance to antibiotics, the tumors find ways (by natural selection) to evade the drugs, and a medical evolutionary arms race (co-evolution) goes on.
Prostate cancer (Photo credit: Wikipedia)
Craig Jordan, PhD., at the University of Rochester Medical Center, is working on cancer tumor stem cell eradication including Tykerb, a drug that can selectively eliminate a number of breast cancer stem cells based on fundamental studies using the knowledge and methodology gleaned from evolutionary studies. Gleevee may work well because it eliminates leukemia stem cells. Researchers at Fred Hutchinson labs have identified a potential protein biomarker for ovarian cancer called HE4, now in use to determine how far a tumor has advanced and is being studied for clinical screening.
Prostate cancer affects 1 in 7 men for an approximate 14% lifetime risk in the general population. Using data and methods from evolutionary cellular biology/genetics several papers (see below) have focused on the 5% of prostate cancers that occur in “hereditary prostate families”—defined by either 3 or more affected first degree relatives, or three successive generations with disease, or 2 relatives diagnosed under 56 years of age. First degree relatives of affected men, in general, have a 2-3 fold increased risk for the disease. The genetic basis of prostate cancer is complex; and it appears likely that many different genes modify risk. No single gene with major cancer susceptibility has yet been identified. Unlike breast and colon cancer, where a very small number of highly penetrant genes account for some of the disease in high-risk families, a single high-risk prostate cancer gene will likely be very rare and account for an even smaller proportion of cases.
In one study, using techniques of basic evolutionary study, the genetic variant on chromosome 8q24 had an odds ratio of 1.62, meaning that an individual is 1.62 times more likely to get prostate cancer if he has that variant than a man who does not. The variant was present in 19% of affected men and in 13% of the general population of men of European ancestry. Of all men in the population with prostate cancer, 8% can attribute their prostate cancer to this particular gene variant (which results from mutational changes over time). In men of African ancestry, the variant had a similar odds ratio of 1.6; however, it was found in 41% of men with the disease and 30% of the general population. Therefore, twice as many men of African ancestry with prostate cancer (16%) as compared to European ancestry with the same disease, have this predisposition.
In a subsequent study, a second gene variant was identified in the same 8q24 region. Taken together, the two variants contribute a joint population attributable risk of 11-13% for men of European ancestry and 31% for men of African ancestry. Mutations in the BRCA1 or BRCA2 genes are associated with a 3-7 fold increased risk of prostate cancer by age 70. BRCA2 testing in one study of 263 men with prostate cancer identified a mutation in 6—a 2.3% frequency. Evaluation of gene CHEK 2 on chromosome 22 in one study detected variants in 4.8% of 578 prostate cancer patients and none in any of the control group. Although the identification of prostate cancer markers (above and beyond PSA) is limited and in the rather early stages of development, these and other genetic markers are part of active research projects in basic laboratories to produce diagnostic test materials that can identify prostate cancer early enough and accurately enough to prevent growth beyond the prostate capsule and metastasis [Amundadottir, L.T., et. al., A Common Variant Associated with Prostate Cancer in European and African Populations. Natural Genetics 38(6): 652-658, 2006. Foulkes, W.D., Inherited Susceptibility to Common Cancers. New England Journal of Medicine 359; 2143-2153, 2008. Gudmundsson, J., et. al, Genome-wide Association Study Identifies a Second Prostate Cancer Susceptibility Variant at 8q24, Natural Genetics 39(5): 631-637, 2007].