BRCA Genes Linked to Prostate and Pancreatic Cancers

Faulty versions of the BRCA1 and BRCA2 genes are well known to increase the risk of breast cancer in men and women, and in ovarian cancer. Now BRCA1 and BRCA2 have been linked to several other cancers, including those that affect men.

A study published today in the Journal of Clinical Oncology has provided the strongest evidence to date of these links and helped researchers estimate more accurately the associated risk.

Since these genes were discovered in the mid-90s, numerous studies have explored possible links between BRCA1 and BRCA2 mutations and other cancers. However, these studies had small sample sizes, resulting in imprecise estimates of cancer risk. Being able to estimate the risks accurately is important for informing cancer prevention and screening strategies and providing genetic counselling to those at greatest risk. BRCA mutations are uncommon, impacting around 1 in 300-400 people in the population.

To further investigate these risk estimates, a team led by researchers at the University of Cambridge, funded by Cancer Research UK, analysed data from almost 3,200 families with one or more members with the BRCA1 mutation and almost 2,200 families with members carrying the BRCA2 mutation. The researchers examined the associations with 22 primary cancers. From the data, the researchers estimated that men who carry a BRCA2 mutation have a 27% risk of developing prostate cancer by the time they are 80 years old, more than double the rate compared to non-carriers. BRCA1 mutations were not associated with an increase in prostate cancer risk.

Carrying a defective copy of either BRCA1 or BRCA2 more than doubled an individual's risk of pancreatic cancer to 2.5-3% by age 80.

The mutations were also found to increase the risk of stomach cancer, though the researchers caution that because of the rarity of this form of cancer, the number of patients in their datasets was small.

Mutations in both genes significantly increased the risk of breast cancer in men, though the disease is still very rare, accounting for less than 1% of all male cancer cases in the UK. While a BRCA1 mutation increased a man's risk of developing breast cancer more than four-fold to 0.4% by age 80, a BRCA2 mutation increased this risk by 44 times to 3.8% by age 80. It is estimated that 38 out of 1,000 male carriers of the BRCA2 mutation will develop breast cancer by age 80.

The researchers were unable to find compelling evidence that mutations were linked to increased risk of some other cancers which were previously thought to be linked to faulty BRCA genes, such as melanoma.

Professor Antonis Antoniou from the Department of Public Health and Primary Care at the University of Cambridge, who led the research, said: "These large datasets of patients have allowed us to estimate with much greater accuracy the extent to which faulty BRCA1 and BRCA2 genes increase the risk of several cancers. We've known for some time that they're linked to breast and ovarian cancer, but there's been uncertainty about other cancers."

Professor Marc Tischkowitz from the Department of Medical Genetics at the University of Cambridge added: "The link between BRCA2 and prostate cancer and pancreatic cancer is now much clearer, thanks to the data we've analysed. We have also identified a potential link with stomach cancer, but this is based on small numbers and needs further study. Our data suggests that there is no strong link between BRCA2 and melanoma, which may provide greater clarity to BRCA2 gene carriers.

Cancers caused by inherited faulty BRCA genes are relatively rare, and other factors like age, smoking, diet and other preventable factors contribute to a person's risk. Improving our understanding of how faults in our genes are associated with certain cancers puts us in a much better position to pinpoint those at a higher risk of developing cancer.

References:

Li S, Silvestri V, Leslie G, Rebbeck TR, Neuhausen SL, Hopper JL, Nielsen HR, Lee A, Yang X, McGuffog L, Parsons MT, Andrulis IL, Arnold N, Belotti M, Borg Å, Buecher B, Buys SS, Caputo SM, Chung WK, Colas C, Colonna SV, Cook J, Daly MB, de la Hoya M, de Pauw A, Delhomelle H, Eason J, Engel C, Evans DG, Faust U, Fehm TN, Fostira F, Fountzilas G, Frone M, Garcia-Barberan V, Garre P, Gauthier-Villars M, Gehrig A, Glendon G, Goldgar DE, Golmard L, Greene MH, Hahnen E, Hamann U, Hanson H, Hassan T, Hentschel J, Horvath J, Izatt L, Janavicius R, Jiao Y, John EM, Karlan BY, Kim SW, Konstantopoulou I, Kwong A, Laugé A, Lee JW, Lesueur F, Mebirouk N, Meindl A, Mouret-Fourme E, Musgrave H, Ngeow Yuen Yie J, Niederacher D, Park SK, Pedersen IS, Ramser J, Ramus SJ, Rantala J, Rashid MU, Reichl F, Ritter J, Rump A, Santamariña M, Saule C, Schmidt G, Schmutzler RK, Senter L, Shariff S, Singer CF, Southey MC, Stoppa-Lyonnet D, Sutter C, Tan Y, Teo SH, Terry MB, Thomassen M, Tischkowitz M, Toland AE, Torres D, Vega A, Wagner SA, Wang-Gohrke S, Wappenschmidt B, Weber BHF, Yannoukakos D, Spurdle AB, Easton DF, Chenevix-Trench G, Ottini L, Antoniou AC. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. J Clin Oncol. 2022 Jan 25:JCO2102112. doi: 10.1200/JCO.21.02112. Epub ahead of print. PMID: 35077220.