Hereditary breast and ovarian cancer.

Abstract

Familial breast cancer was first recognized in the Roman medical literature of 100 AD [1]. The first documentation of familial clustering of breast cancer in modern times was published by Broca, who reported 10 cases of breast cancer in 4 generations of his wife's family [2]. In the middle of the nineteen nineties it was proven at the molecular level that a substantial number of breast and ovarian cancers has hereditary monogenic aetiology [3,4]. Evaluation of frequency of pedigree-clinical signs characteristic for strong aggregations of breast/ovarian cancers among consecutive cases of cancers of these organs as well as analyses of cancer incidence in monozygotic twins indicate that about 30% of breast and ovarian cancers develop because of a strong genetic predisposition [5]. In other breast/ovarian cancers the significance of genetic factors was underestimated. However, recently it has been possible to show the characteristic constitutional background influencing development of cancer also in patients sporadic neoplasms. Therefore now scientists think that in almost all patients cancer a certain genetic background should be detectable, although influencing cancer risk to a various degree. Genetic abnormalities strongly related to cancer are called high risk changes (genes) and abnormalities influencing cancer development to a lower degree are called moderate risk changes (genes). Most frequently strong genetic predisposition to breast/ovarian cancers are related to mutations in the BRCA1 and BRCA2 genes and most often it appears as syndromes of hereditary breast cancer -site-specific (HBC-ss), hereditary breast-ovarian cancer (HBOC) and hereditary ovarian cancer (HOC). In family members of families HBC-ss syndrome only breast cancers but not ovarian cancers are observed. In HBOC syndrome families both breast and ovarian cancers are diagnosed, and in HOC syndrome only ovarian but not breast cancers are detected. Operational clinical-pedigree criteria which we use in order to diagnose definitively or with high probability the discussed syndromes are summarized in Table ​Table1.1. In the vast majority of cancer cases related to moderate risk genes family history is negative. HBC-ss, HBOC and HOC syndromes are clinically and molecularly heterogeneous. Mutations in the BRCA1 and BRCA2 genes are the most frequent cause of these syndromes. Table 1 Pedigree-clinical diagnostic criteria of HBC-ss, HBOC and HOC syndromes [6] BRCA1 syndrome In this syndrome women carry a germline mutation in the BRCA1 gene. Carriers of a BRCA1 mutation have approximately 50-80% lifetime risk of breast cancer and 40% risk of ovarian cancer [7]. We estimate that these risks are 66% for breast cancer and 44% for ovarian cancer in the Polish population (Table ​(Table2).2). Both risks appear to be dependent on the type and localization of the mutation [8-10]. Our findings suggest that the risk of breast cancer in women 5382insC is two times higher than in women 4153delA. Table 2 Risk of breast and ovarian cancer in BRCA1 mutation carriers in Poland [8] Incomplete penetrance of BRCA1 suggests that other factors, genetic and non-genetic modifiers, are important in carcinogenesis in the mutation carriers. The risk of ovarian cancer is modified by VNTR locus for HRAS 1 and is increased 2-fold in BRCA1 carriers harbouring one or two rare alleles of HRAS 1 [11]. We reported that the 135G>C variant in the RAD51 gene is strongly protective (OR = 0.5) against both ovarian and breast cancer [12,13]. Carriers of a BRCA1 mutation are also at about 10% lifetime risk of fallopian tube and peritoneal cancers [14]. These data about the frequency of ovarian cancer in BRCA1 carriers appear to reflect the combined frequency of ovarian, fallopian tube and peritoneal cancers, because these tumours were diagnosed as ovarian cancers in the past, and because they share similar morphology and cause elevated levels of the marker CA 125. The risk of cancer at other sites may be increased in carriers of a BRCA1 mutation as well, but the evidence is controversial and needs further studies. Breast and ovarian cancer in BRCA1 carriers have particular clinical characteristics. The mean age at onset of breast cancer is about 42-45 years [15,16] and of ovarian cancer is about 54 years [17,18]. 18-32% of breast cancers are bilateral [19,20]. These are rapidly growing tumours: >90% of cases have G3 grade at the time of diagnosis and almost all ovarian cancers in women a BRCA1 mutation are diagnosed in FIGO stage III°/IV°. Medullary, atypical medullary, ducal and oestrogen receptor negative (ER) breast tumours are common in BRCA1 carriers. BRCA1 mutation-positive tumours constitute about 10-15% of all ER-breast cancers [21-23]. Most carriers of a BRCA1 mutation report a positive family history of breast or ovarian cancer (Figure ​(Figure1).1). However, 45% of BRCA1 carriers report a negative family history, mainly because of paternal inheritance and incomplete penetrance (Figure ​(Figure3)3) [20]. Figure 1 Family HOC syndrome and diagnosed constitutional 4153delA BRCA1 gene mutation. Figure 3 Patient ovarian cancer and detected 5382insC BRCA1 mutation from family negative family history.