Jolie genes: in breast cancer some mutations are more dangerous than others

Mutations on the BRCA1 and BRCA2 genes, which are associated with an increased likelihood of breast cancer, are not all the same: some appear to be more dangerous and reduce survival expectancy, while others seem to have a less negative impact on clinical outcome. This has been demonstrated for the first time by the large international BRCA BCY Collaboration study, conducted on women under 40 diagnosed with invasive breast cancer and coordinated by the University of Genoa - IRCCS Ospedale Policlinico San Martino and the University of Modena and Reggio Emilia, just published in the journal Annals of Oncology. The data are relevant because they will be able to help identify more accurately the real risk of patients with breast cancer and BRCA mutations, but above all because they will be able to guide clinical choices, intensifying treatment and controls in women with the most 'bad' mutations. These mutations are also known as 'Jolie genes' after the actress Angelina Jolie who decided to undergo preventive surgery (mastectomy and ovariectomy) after discovering she was a carrier.

"BRCA BCY Collaboration is an international study co-ordinated by Matteo Lambertini of the University of Genoa involving 109 Centres in 33 countries worldwide - explains Eva Blondeaux of the Clinical Epidemiology Unit of the IRCCS Ospedale Policlinico San Martino and co-author of the study -. This is a retrospective survey, in which characteristics and clinical outcomes of 3294 women under 40 who received a diagnosis of invasive breast cancer between 2000 and 2020 and were carriers of a BRCA1 or BRCA2 mutation were analysed. These two genes control DNA repair: when they are mutated, the DNA damage repair mechanism fails and consequently certain types of cancer develop more easily. This is why BRCA1 and BRCA2 mutations, which are hereditary, increase the lifetime probability of developing breast cancer by up to 80% and ovarian cancer by up to 40%. It is estimated that about one in ten breast neoplasms is due to defects in the BRCA1 or BRCA2 genes, but there are many possible mutations and until now it was not known whether the different genetic defects also lead to different clinical outcomes'.

The study filled the gap by analysing, among the thousands of possible BRCA mutations, the effect of individual possible variants on the survival of young patients diagnosed with invasive cancer. "We knew, for example, that BRCA1 mutations are more often found in triple-negative breast carcinomas, while BRCA2 mutations are more frequent in oestrogen receptor-positive tumours,' adds Angela Toss, a lecturer at the University of Modena and Reggio Emilia and a member of the Oncology Department of the University Hospital of Modena, co-author of the study. The new data go further, evaluating the influence of specific types of mutations. We were able to observe, for instance, that mutations that 'truncate' BRCA1 and BRCA2, making the protein shorter and more unstable, affect its functionality and lead to a worsening of survival in carrier patients, while mutations of a single DNA letter in BRCA1 or BRCA2, which change only one amino acid of the final protein, seem to be associated with a longer life expectancy. In summary, what seems to matter most is the consequence of the mutation on the actual functionality of the protein produced'.

"Identifying the associations between the type of mutation and the characteristics of breast cancer and its clinical outcomes, such as its aggressiveness, can help optimise treatment strategies,' Blondeaux and Toss conclude. 'For example, the presence of variants associated with a worse prognosis may suggest intensifying surveillance programmes, or even indicate the advisability of providing more or less intensive therapies depending on the impact the mutation may have on survival expectancy.