A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

Abstract

Mutations in the two breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for a varying fraction of breast cancer families in different populations (Szabo and King, 1997). Both BRCA1 and BRCA2 mutations are scattered throughout the large coding regions of the genes (Breast Cancer Information Core). In admixed populations, most mutations appear uniquely in single families only, making the mutation screening laborious and expensive. Furthermore, there is also evidence of other predisposing genes (Ford et al, 1998;Kainu et al, 2000). It is, therefore, important to find the clinical risk factors that could best predict the presence of BRCA1 and BRCA2 mutations, so that the screening could be directed to potential mutation carrier families. Several probability models for mutation detection have been developed. These are, however, based only on BRCA1 (Berry et al, 1997;Couch et al, 1997;Shattuck-Eidens et al, 1997), focus on specific founder mutations in the Ashkenazi population (Foulkers et al, 1999;Hodgson et al, 1999;Hopper and Jenkins, 1999), or require information such as penetrance estimations not available in all populations (Berry et al, 1997;Parmigiani et al, 1998; ChangClaude et al, 1999).Here we have developed a model for predicting the presence of a BRCA1 or BRCA2 mutation in families with 3 or more relatives affected with breast or ovarian cancer. We also compared this model with those of Shattuck-Eidens et al (1997) and Couch et al (1997) originally designed for BRCA1 only. Additionally, the frequency of BRCA1/2 mutations was studied in 295 families with two affected family members to evaluate the feasibility of genetic screening in families with moderate family history. PATIENTS AND METHODSThe cohort studied consisted of 148 families with 3 or more 1st or 2nd degree relatives affected with breast or ovarian cancer. The families were identified by patient interviews, and full pedigrees were constructed with the confirmation of all genealogy data through the Finnish population registration as well as diagnostic data through hospital records and/or Finnish Cancer Registry as previously described (Vehmanen et al, 1997a,b;Eerola et al, 2000). Additionally, 295 breast cancer cases with one 1st degree relative affected with breast or ovarian cancer and identified in the patient cohorts described in Eerola et al (2000) were also studied. In the following, these are called small families. The family history of these cases was based on information reported by the index patient. All patients participating in the study signed an informed consent before the blood sample for the genetic analysis was taken. This study has been approved by the Ethical Committees of Departments of Obstetrics and Gynaecology, and Oncology, HUCH, and appropriate permissions were obtained from the Ministry of Social Affairs and Health in Finland.The mutations identified by a complete mutation analysis of the whole coding sequences and exon/intron boundaries of the genes in 95 of these families have been previously reported...

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

“…Of the altogether 1182 invasive breast cancers, 36 tumours were from BRCA1 and 40 tumours from BRCA2 mutation positive families; 740 tumours were from other familial breast cancer patients and 366 from sporadic patients. BRCA1/2 mutations had been excluded for all the 428 cases with strong family history of cancer (three or more, first-or second-degree relatives with breast or ovarian cancer), as well as, for 154 of the 312 cases from families with two affected first-degree relatives (BRCA1/2 mutation screening described in Vehmanen et al, 1997;Vahteristo et al, 2001Vahteristo et al, , 2002. The study was performed with informed consents from the patients as well as permissions from the Ethics Committee (E8) of the Helsinki University Central Hospital and from the Ministry of Social Affairs and Health in Finland.…”

BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition

“…The first series included 888 unselected (described in detail in Syrjakoski et al 17 and Kilpivaara et al 18 ) and 946 familial 16 breast cancer patients collected at the Helsinki University Central Hospital in Southern Finland. BRCA1 and BRCA2 mutations have been excluded in all the 403 patients with a strong family history of cancer (three or more first-or second-degree relatives with breast or ovarian cancer in the family, including the proband) as well as in 291 cases with one affected relative as previously described 2,15,17 (also unpublished data). DNA from altogether 736 healthy female subjects collected at the same geographical region of Southern Finland was studied as healthy population controls.…”

“…Germline mutations in these genes are found in the majority of families (75 -80%) with both early-onset breast cancer and ovarian cancer, but in a considerably lower fraction of families with site-specific female breast cancer (no ovarian cancer or male breast cancer). 1,2 Recently, the CHEK2 1100delC and Ile157Thr have been identified as new low-risk breast cancer susceptibility alleles. 3 -5 It has been suggested that a substantial proportion of the remaining familial aggregation of breast cancer might be attributed to several such low penetrance alleles that act multiplicatively, and thereby form a polygenic basis for breast cancer predisposition.…”

No germline FH mutations in familial breast cancer patients

“…The major known high-penetrance predisposition genes BRCA1 and BRCA2 account for a large majority of families with multiple cases of early-onset breast cancer and ovarian cancer, but only a small fraction of familial breast cancer without these characteristics. 14,15 Genetic linkage studies have suggested breast cancer loci on chromosomes 2q32, 6q25, 8p21, and 13q22. 16 -19 So far, the putative susceptibility genes in these regions have not been identified.…”