In this study, we evaluate the risk of cancers other than BC and OC, in a subset of BRCA1/2 mutation carrier females affected with BC and OC. We have found an approximately 2.5‐fold increase in risk of any other cancer in BRCA1/2 mutation carriers, and a threefold increase in CC, which was significant in BRCA1 but not in BRCA2 carriers. Additional analyses including only cancers diagnosed after BC/OC diagnosis were conducted to correct for possible treatment, surveillance and ascertainment biases. HRs of 4 were found for the risk of developing any other cancer and CC after BC/OC diagnosis among BRCA1 carriers; among BRCA2 carriers, HRs were not significant. In addition, lymphoma risk was highly elevated among BRCA2 carriers.
Two large studies estimated the risk of other cancers in BRCA1
mutation carrier families.1,2
In these studies, a fraction of the carriers were tested directly, and the probability of being a carrier was calculated for family members who were not tested. Risks were compared with lifetime risk or incidence in the general population. Both studies found elevated risk of cancers other than BC and OC. In agreement with our results, Thompson et al2
reported an OR of 2.3 (95% CI 1.93 to 2.75, p
0.01) for any other cancer in female carriers but not in males. Brose et al
on the other hand, found a higher cumulative age‐adjusted lifetime risk of diagnosis of any cancer in male carriers of BRCA1
mutations (26.1%, 95% CI 17.5% to 34.6%) than in carrier women (10.3%, 95% CI 7.2% to 13.3%); however, their analyses were based on 381 females and only 102 males. In BRCA2
carriers, a relative risk (RR) of 2.45 (95% CI 2.15 to 2.78, p<0.001) for all cancers except BC, OC and non‐melanoma skin cancer was found.4
It was suggested that the elevated cancer risk found in carrier families, which includes a large fraction of affected individuals, may be overestimated, because of genetic or environmental exposures that are risk factors for other types of tumours in addition to BC and OC, which cluster in these families.8,9
Our unique approach of comparison of BC/OC‐affected carriers with non‐carriers enabled us to evaluate the effect of BRCA
mutations controlling for these factors.
The strength of our study is the direct testing of all carriers and the high quality of verification of diagnosis of other cancer. In addition, we ascertained all participants in the same way, mainly due to BC or OC diagnosis and the Ashkenazi origin. The high frequency and ease of testing of Ashkenazi founder mutations yielded a series that is less selected on the basis of family history as opposed to previous studies.1,2,4,5,7
The ascertainment due to diagnosis of other cancer was probably low and equal in the two groups we compared, in addition, survival bias may have resulted in reduced incidence of other cancers in both groups and underestimation of the risks. The carrier group, especially BRCA1
mutation carriers, are younger, regarding both age of BC/OC diagnoses and average length of follow‐up; however, age at diagnosis of other cancer is similar to that for non‐carriers. Therefore, all estimated HRs were analysed from birth to age at onset of other cancers or last follow‐up.
CC was the major contributor to the elevated cancer risk we found in our carrier group. In BRCA1
carriers it was significantly fourfold higher, whereas the HR of 2.3 that was found in BRCA2
carriers was non‐significant. Similar HRs were found when only CCs diagnosed after BC/OC diagnosis were included. Several studies in high‐risk carrier families evaluated CC risk. Brose et al1
found a twofold increase in the risk of CC in BRCA1
carriers; separate analyses by gender were not reported. An older study by the BCLC5
reported a fourfold increase in the risk, whereas in a subsequent, much larger study,2
a twofold increased risk was found in female, but not in male, carriers. As the incidence of rectal cancer was markedly low, the authors suggested that the elevated risk could be attributable to OC cases misdiagnosed as CC. In BRCA2
carriers, risk of CC was not elevated.4
Recently, two large case–control studies in Ashkenazi patients with CC were reported.10,11
Neill et al10
found 2.4% (24/1002) of patients with CC to carry one of the three Ashkenazi founder mutations, compared with 1.9% (19/1038) in the controls, which translated to a non‐significant odds ratio of 1.24 (95% CI 0.68 to 2.26). A similar study11
among 586 Ashkenazi patients with CC reported an RR of 0.50 (95% CI 0.22 to 1.14) associated with these mutations.
Common risk modifiers for BC and colorectal cancer, such as diet14,15,16
as well as genetic modifiers clustering in high‐risk families, may result in elevated CC risk in carrier families, regardless of the BRCA1/2
carrier status. However, by comparing BC/OC‐affected carriers with affected non‐carriers who share those factors, we suggest a role, either additive or synergistic, of BRCA1/2
mutations in occurrence of CC in this subset group. It is important to note that individuals affected with CC, especially BRCA1
carriers in our series, were older than the whole study group. Therefore, probably, longer survival is required for CC development in BRCA1
carriers. In the case–control studies mentioned above,10,11
carriers affected with BC/OC are probably under‐represented owing to a high mortality rate at younger age, which may have resulted in a lower carrier rate.
- To evaluate the risk for cancers other than breast and ovarian cancers, we compared BRCA1/2 mutation carriers and non‐carriers, all affected with breast and/or ovarian cancer. Both groups share environmental and genetic cancer risk modifiers. Therefore, our unique approach enables us to assess the role of BRCA1/2 mutations in risk of other cancers in this subset group, which comprise a large proportion of the BRCA1/2 carrier population.
- BRCA1 carriers affected with breast and/or ovarian cancer were found to have a 2.5‐fold risk for any other cancer, and an approximately fourfold increase in risk for colon cancer.
- Among BRCA2 carriers, the increased risk for any other cancer and colon cancer did not reach statistical significance; however, lymphoma risk was markedly elevated.
The risk of lymphoma was markedly elevated among BRCA2
carriers, with an HR of 11.9 (95% CI 3.1 to 46.2, p
0.001), whereas HR among BRCA1
carriers was non‐significantly reduced. In agreement with our results, the BCLC study reported an RR of 1.91 (95% CI 0.81 to 4.49) for non‐Hodgkin's lymphoma and 1.48 (95% CI 0.4 to 5.48) for Hodgkin's disease in BRCA2
The corresponding RRs in BRCA1
were 0.23 (95% CI 0.09 to 0.60, p<0.001) and 0 (p
0.15), respectively. However, an RR of 2.6 was found for leukaemia and lymphomas, based on 649 patients with ovarian cancer (all BRCA1
Again, in a case–control study of 286 Ashkenazi Jewish patients with lymphoma, only two BRCA
carriers were found.12
Whether the elevated lymphoma incidence we and others4
observed in BRCA2
carriers is related to treatment, owing to the role of BRCA2
in double‐strand breaks repair, should be further investigated. Of the four BRCA2
carrier patients with lymphoma in our series, two were diagnosed with lymphoma and treated with irradiation before BC diagnosis, the other two were diagnosed 5 and 34 years after the diagnosis of BC, and the causative role of the treatment for BC in the development of lymphoma is less clear.
In conclusion, our findings show an elevated risk of other cancers, especially that of CC, in a subset BC/OC‐affected carriers. Our results partly explain the controversy between studies of high‐risk carrier families and the case–control studies conducted in the general population. We speculate that the affected carriers, which comprise the majority of the carrier population in studies of high‐risk families, are the main contributors to the elevated cancer risks found in these studies.1,2,3,4,5,6,7
In the case–control studies10,11
conducted in the general population, the BC/OC‐affected carriers with early onset of disease are under‐represented, owing to reduced survival. In the future, better treatment and surveillance in carriers may result in longer life expectancy and therefore higher risk for other cancers, especially CC, among carriers.