For more than 25 years we have known that some variants of the BRCA1 and 2 genes increase the risk of breast and ovarian cancer: today it is clear to us that women with a hereditary mutation of the BRCA1 / 2 genes have between 50 and 80% more likely to get breast cancer later in life. As we also know that in those with defective BRCA1, the risk of ovarian cancer is between 24% and 40%, while if the mutation is BRCA2 the risk is between 11% and 18%, against 1 -2% of the general female population.
Not just breast and ovary
But over the years – starting in 1994, the year BRCA 1 and 2 were identified – it has been intuited and demonstrated that BRCA genes do not exclusively modify the risk of these two female cancers: although rare, these mutations are linked to other types of cancer: prostate, pancreatic and stomach.
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But by how much do they increase the risk? An international study coordinated by the University of Cambridge and the Molecular Medicine department of Sapienza in Rome, in collaboration with the international consortium CIMBA (Consortium for Investigators of Modifiers of BRCA1 / 2), has deepened and refined the estimates of risk associated with mutations in the BRCA genes of over 20 cancers using medical record data from over 5,000 families. The results of the research, which was also supported by the AIRC Foundation, are published on Journal of Clinical Oncology.
The largest case history in the world
“The analyzes were carried out on an international series of 3,184 families with BRCA1 mutations and 2,157 families with BRCA2 mutations – he explains in detail Valentina Silvestri of the Department of Molecular Medicine of Sapienza University of Rome and co-author of the study. “A series – added Silvestri – which is the largest currently available in the world and which has allowed us to accurately estimate the extent to which a hereditary mutation in BRCA1 or BRCA2 is associated with the risk of developing 22 different types of cancer, including taking into account age and gender “.
“The study has the merit of having investigated many cancers and of having focused the attention of medical oncologists on the possibility of extending the search for mutated BRCAs in other cancers other than those of the breast and ovary”, he comments Saverio Cinieri, president of Aiom, the Association of Italian medical oncologists, director of the Complex Operational Unit of Medical Oncology of the Antonio Perrino Hospital in Brindisi which is not involved in the research: “There are studies that already indicated the role of BRCA in pancreatic tumors and prostate, and male breast. We now have numerical risk data ”.
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And the BRCA genes
BRCA genes are tumor suppressors, that is, they encode proteins that protect DNA from the accumulation of mutations and, consequently, from cancer. However, when these fragments of the genome are mutated, the errors on the double helix increase, and with them also the probability that healthy cells will turn into cancer cells. It is estimated that in Italy there are about 150 thousand people with the BRCA 1 and / or BRCA 2 mutation.
As anticipated, the results of the study show that cancers associated with BRCA1 and BRCA2 include, in addition to those of the breast and ovary, also prostate, pancreatic and stomach cancers. However, associations with other types of neoplasms suggested by previous studies, for example that with melanoma, were excluded. Our data “cannot confirm this link,” he said Marc Tischkowitz, of the Cambridge Department of Medical Genetics and co-author of the publication.
In prostate cancer
From the data, the researchers estimated that men carrying a BRCA2 mutation have an approximately 27% risk of developing prostate cancer before age 80, more than double that calculated in non-carriers. In contrast, mutations in BRCA1 are not associated with an increased risk of prostate cancer.
In pancreatic and stomach cancer
“Having a defective copy of BRCA1 or BRCA2 doubles the risk of pancreatic cancer in both sexes – explains Laura Ottini, of the Department of Molecular Medicine of Sapienza and coordinator of the study. “Furthermore, we found – he added – that the mutations tripled the risk of stomach cancer in both men and women, although the number of patients in the dataset was rather limited due to the rarity of this form of cancer”.
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In male breast cancer
Breast cancer in men is a very rare disease, globally affecting about 1 in 100,000 men, although its incidence appears to have been increasing in the past two decades. Mutations in both genes significantly increase the likelihood of developing this form of cancer later in life. Especially BRCA2, whose mutation increases this risk by more than 40 times, while a mutation in BRCA1 quadruples it.
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Brca test, where are we?
As stated in the document “Recommendations for the implementation of the predictive and preventive BRCA test in breast, ovarian, pancreatic and prostate cancers”, published last May by AIOM, https://www.aiom.it /wp-content/uploads/2021/07/2021_Racc_testBRCA_predittivo-preventivo.pdf knowing if a patient is positive for the BRCA test allows you to choose a targeted therapy and to undertake primary and secondary cancer prevention paths. Where are we now with BRCA genetic testing? “In some regions – replies Cinieri – genetic evaluation is already being carried out also of relatives of women with breast cancer positive for the BRCA test and, recently, also of family members of men with breast cancer”.
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But “These results underline the usefulness of extending genetic tests to search for BRCA mutations to a wider audience, which includes both women and men – as Ottini points out:” The estimates we have provided in this study – he concludes – clarify the link between BRCA mutations and cancer risk and will be the basis for the development of increasingly effective and gender-specific prevention guidelines, in order to ensure the best clinical management for all patients and their families “.
Credits for the image: ANIRUDH on Unsplash