About genetic mutations are one of the main causes of cancer; they interrupt the normal processes that control cell growth, causing cell growth and the formation of tumors. Fortunately, only a small but significant percentage of human cancers are hereditary. Today, it is estimated that about 7% of mammary carcinomas, 10% of ovarian tumors, about 10% of colo-rectal tumors and about 20% of medullary thyroid tumors have an eredo-familial component. In these tumors, DNA mutations occur at the level of germ cells or reproductive cells and can therefore be transmitted to the offspring. The individual will have at birth that genetic defect on one or more genes in all the cells of the organism, and will therefore be predisposed to develop a neoplasia when, during the course of life, other mutations will add to the predisposing one or he will expose himself to conditions that may favor them (cigarette smoke, other carcinogens, environmental substances, etc.).
Identifying the genetic mutations responsible for tumors is part of the same strategy to diagnose and treat them. It is known that specific genes are mutated in a large number of neoplasms; many specific mutations have been recognized and can now be detected with specific laboratory methods. For example, tests are available to detect mutations for the p53 protein, which is involved in at least 60% of all human neoplasms; then for K-Ras, which has mutated in most of the lung, stomach and pancreas cancers; p16 and B-Raf proteins for the diagnosis of melanoma; of the BRCA1 and BRCA2 proteins, for predisposition and / or mutation in breast and ovarian carcinomas; of the MLH1 and MSH2 proteins for the diagnosis of hereditary colon cancer and the APC protein for familial adenomatous polyposis. These are just some of the known mutations that occur on cancer cells in humans. And now, researchers may have added another candidate to the list: FANCM.
The research indicated that mutations in the FANCM gene are not, contrary to current knowledge, related to Fanconi anemia, which is a hereditary disease of the bone marrow. However, the researchers report that mutations in the FANCM gene are associated with early cancer development and chemotherapy toxicity. FANCM is a gene that has been linked to the development of Fanconi anemia, after which in 2005 the research identified mutations of the FANCM gene – called biallelic mutations – in patients with the disease. Previous studies have indicated that biallelic mutations also cause DNA errors that increase susceptibility to breast cancer in particular. In the new studies, researchers sought to gain a better understanding of the disease from FANCM mutations. This result would not be an absolute novelty, since Fanconi anemia is already known to predispose partients to develop no onlly leukemias, but some solid cancers as well.
The first study was conducted by Dr. Massimo Bogliolo, from the Center for Research on the Biomedical Network of Rare Diseases (CIBERER) and the Universitat Autònoma de Barcelona in Spain, and published in the journal Genetics in Medicine. Bogliolo and colleagues used genomic sequencing to analyze cells derived from three patients who had mutations in the FANCM gene. However, the study showed that people showed no abnormalities in the blood or bone marrow, but mutated cells for the tumor of the head and neck. Furthermore, these patients had high toxicity in response to chemotherapy. The loss-of-function mutations in the FANCM therefore cause a cancer predisposition syndrome clinically distinct from Fanconi anemia.
The second study, conducted by Javier Benítez, also of CIBERER, included five women with biallelic mutations in the FANCM gene. By supporting early studies, Benati and colleagues found that women did not develop Fanconi anemia, showed a high susceptibility to breast cancer and chemotherapy toxicity. Instead, the biallelic mutations in the FANCM gene cause a type of cancer predisposition syndrome, rather than Fanconi anemia. Based on their results, monitoring of patients with FANCM gene mutations was recommended due to their increased susceptibility to cancer. They also warn that care should be taken when dealing with these problems with chemotherapy, because if the patient has a biallelic mutation for FANCM, it could make it more vulnerable to the more pronounced and toxic effects of chemo itself.
Two posthumous studies, on the other hand, presented data on how the mutation of FANCM is most likely linked to the development of ovarian cancer. One of them, homozygous, was isolated in a women with primary ovarian failure not related to any known syndrome. The other study, based on large-scale genomic molecular screening (GWAS), correlated the FANCM gene to a high probability that it is involved in the appearance of primitive ovarian carcinomas. It is curious, instead, how an Italian research group has found a correlation between mutations of the FANCM gene and male breast cancer, which is extremely rarer than that of women, but for which no responsible causes have ever been found, nor its own genetic markers.
More data will be needed, especially on the mechanisms with which the mutated FANCM protein causes the appearance of tumors, but even more intriguing will be to respond because it exposes to greater toxic effects of anticancer drugs.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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