BRCA2 Mutation Carriers, Reproductive Factors and Breast Cancer
Background: Germline mutations in the BRCA genes dramatically increase the risk of breast cancer. In the general population, breast cancer risk is affected by age at menarche, by age at first birth, by the number of births and by the duration of breast feeding. Whether this is true for mutation carriers is not clear.
Methods: In a case-control study, nested in a population-based cohort of the Icelandic Cancer Detection Clinic, two groups of cases were defined, matched on year of birth, on age at diagnosis and on age when giving information on reproductive factors: 100 carriers of the Icelandic founder BRCA2 mutation 999del5, and 361 BRCA2-negative cases. The mean age at diagnosis was 48 years. There were 1000 women in a matched group of unaffected controls. Conditional logistic regression was used for the analysis.
Results: An increased number of births was associated with a decreased risk of breast cancer in BRCA2-negative cases but not in BRCA2-positive cases. A negative association between risk and duration of breast feeding was observed only in the mutation carriers. These associations were not statistically significant, but the effects of the two variables differed significantly according to mutation status (P = 0.007 and P = 0.045 for interaction with number of births and with duration of breast feeding, respectively). This was maintained when limiting the analysis to women diagnosed older than the age of 40 years.
Conclusion: The association between breast cancer and the number of pregnancies and between breast cancer and the duration of breast feeding was not the same for carriers and noncarriers of a detrimental BRCA2 mutation. In the context of other epidemiological and laboratory studies, this may indicate that the product of the BRCA2 gene has a function relating to the differentiation of epithelial tissue in the breast.

Mutations in the BRCA1 and BRCA2 genes dramatically increase the risk of breast cancer. Numerous mutations in each gene have been found in most populations studied, but only one mutation in each gene has been identified to date in the Icelandic population of 285,000; a rare mutation in the BRCA1 gene, and a much more frequent mutation in the BRCA2 gene. The BRCA2 mutation (999del5) is present in 7-8% of unselected breast cancer patients in Iceland, and it has a much higher prevalence (24%) in women diagnosed younger than 40 years of age. The mutation explains around 40% of the increased breast cancer risk in first-degree relatives of Icelandic breast cancer patients and all excess risk of prostate cancer and ovarian cancer in relatives of breast cancer patients. The estimated breast cancer risk in mutation carriers at the age of 70 years is 37-44%.

The two BRCA genes code for large proteins that are involved in basic cellular functions such as DNA repair, cell cycle control and transcription. Why the effects of mutations in these genes are mainly specific for cancers that are hormonally related, such as breast cancer, ovarian cancer and prostate cancer, is presently an important unanswered question. There are indications that the product of the BRCA1 gene has a role in oestrogen-receptor signalling, and recent results suggest that the BRCA2 gene may have a function relating to terminal differentiation of breast epithelial cells.

An increasing age at menarche, a low age at first birth, an increasing parity and breast feeding are associated with a reduced risk of breast cancer in the general population. However, after each pregnancy there is a transient increase in the risk of breast cancer. The strength and direction of the effects of pregnancies are therefore related to time since last birth, and thus present differently according to whether the women studied are at a fertile age. Furthermore, these associations may be affected by a disrupted function of either of the BRCA genes but the picture emerging from the few studies published to date is still far from being clear. Further studies in this field are important as they may increase our understanding of the function of the BRCA genes, as well as the effects of modifying factors on the risk in mutation carriers.

Familial breast cancer has been extensively studied at the Icelandic Cancer Society for more than two decades . The present study used information on 100 breast cancer cases carrying the Icelandic BRCA2 mutation, who were compared with breast cancer cases without the mutation and with unaffected controls. All participants had contributed information on reproductive risk factors, before diagnosis of the cases, in the cohort study of the Cancer Detection Clinic (CDC) of the Icelandic Cancer Society. The hypothesis of the present study was that the associations between breast cancer and age at menarche, pregnancies and breast feeding would be different for women with and without the mutation.