Familial Clustering Of Breast Cancer Research Articles

Genetic variations in PTEN and their potential link to breast cancer

Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related deaths in women. The heritable component in familial clustering of breast cancer has been estimated to be 73% and the environmental proportion 27%. These high penetrance traits and the identification of the breast cancer-predisposing gene PTEN, warrant further research. In this analysis, we specifically looked at PTEN single nucleotide polymorphisms (SNPs) and their association with breast cancer.

Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer

Early breast development is a risk factor for breast cancer, and girls with a breast cancer family history (BCFH) experience breast development earlier than girls without a BCFH. To assess whether prepubertal androgen concentrations are associated with timing of breast development (analysis 1) and to compare serum androgen concentrations in girls with and without a BCFH (analysis 2). Prospective cohort study of 104 girls aged 6 to 13 years at baseline using data collected between August 16, 2011, and March 24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study, New York site. Analysis 1 included serum concentrations of dehydroepiandrosterone sulfate, androstenedione, and testosterone (free and total) measured before breast development and divided at the median into high and low categories. Analysis 2 included the degree of BCFH: first-degree was defined as having a mother with breast cancer and second-degree was defined as having a grandmother or aunt with breast cancer. Analysis 1 included age at onset of breast development measured using the Pubertal Development Scale (scores range from 1-4; scores ≥2 indicate breast development), and analysis 2 included serum androgen concentrations. We also assessed breast cancer-specific distress using the 8-item Child Impact of Events Scale. Our analyses included 36 girls for the prospective model, 92 girls for the cross-sectional model, and 104 girls for the longitudinal model. Of the 104 girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black, and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive BCFH. Girls with prepubertal androstenedione concentrations above the median began breast development 1.5 years earlier than girls with concentrations below the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001). Similar patterns were observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI, 9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P = .009), total testosterone (1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI, 9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P = .01). Compared with girls without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had 240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P = .01), 10% higher total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL; P = .01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL vs 0.3 pg/mL; P = .14). The dehydroepiandrosterone sulfate concentration did not differ between BCFH-positive and BCFH-negative girls but was elevated in girls with breast cancer-specific distress. Our findings suggest that androgen concentrations may differ between girls with and without a BCFH and that elevated hormone concentrations during adolescence may be another factor to help explain the familial clustering of breast cancer.

Genetic predisposition of six well-defined polymorphisms in HMGB1/RAGE pathway to breast cancer in a large Han Chinese population.

Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box‐1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well‐defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer‐free controls from Heilongjiang province, China. There were no deviations from Hardy–Weinberg equilibrium for all polymorphisms. In single‐locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624‐A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624‐GG genotype after adjustment (95% confidence interval or CI: 1.17–1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C‐T‐A and C‐A‐G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20–6.18 and 1.58–67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09–1.32 and 1.12–1.42; P < 0.001 and <0.001 respectively). Our findings altogether demonstrate a significant association between RAGE gene rs1800624 polymorphism and breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis.

Gene panel testing for hereditary breast cancer.

Inherited predisposition to breast cancer is explained only in part by mutations in the BRCA1 and BRCA2 genes. Most families with an apparent familial clustering of breast cancer who are investigated through Australia's network of genetic services and familial cancer centres do not have mutations in either of these genes. More recently, additional breast cancer predisposition genes, such as PALB2, have been identified. New genetic technology allows a panel of multiple genes to be tested for mutations in a single test. This enables more women and their families to have risk assessment and risk management, in a preventive approach to predictable breast cancer. Predictive testing for a known family-specific mutation in a breast cancer predisposition gene provides personalised risk assessment and evidence-based risk management. Breast cancer predisposition gene panel tests have a greater diagnostic yield than conventional testing of only the BRCA1 and BRCA2 genes. The clinical validity and utility of some of the putative breast cancer predisposition genes is not yet clear. Ethical issues warrant consideration, as multiple gene panel testing has the potential to identify secondary findings not originally sought by the test requested. Multiple gene panel tests may provide an affordable and effective way to investigate the heritability of breast cancer.

A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland

BackgroundGermline mutations of the CHEK2 gene have been reported to be associated with breast cancer. In this study, we analyzed the association of CHEK2 mutations with the risk of development of breast cancer in women of North-Central Poland.Methods420 women with breast cancer and 435 controls were tested for three protein truncating (IVS2 + 1G > A, 1100delC, del5395) and one missense (I157T) CHEK2 mutation. IVS2 + 1G > A and I157T mutations were identified by RFLP-PCR, 1100delC variant was analyzed using an ASO-PCR and del5395 mutation by multiplex-PCR. The statistical tests: the odds ratio (OR) and Fisher’s exact test were used.ResultsIn 33 out of 420 (7.9%) women consecutively diagnosed with breast cancer, we detected one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2 + 1G > A or del5395. Together they were not associated with the increased risk of breast cancer (North-Central control group: OR = 1.6, p = 0.124; the general Polish population: OR = 1.4, p = 0.109). This association was only seen for IVS2 + 1G > A mutation (OR = 3.0; p = 0.039). One of the three truncating CHEK2 mutations (IVS2 + 1G > A, 1100delC, del5395) was present in 9 of 420 women diagnosed with breast cancer (2.1%) and in 4 of 121 women (3.3%) with a history of breast cancer in a first- and/or second- degree relatives. Together they were associated with the increased risk of disease in these groups, compared to the general Polish population (OR = 2.1, p = 0.053 and OR = 3.2; p = 0.044, respectively). I157T mutation was detected in 25 of 420 women diagnosed with breast cancer (6.0%) and in 8 of 121 women (6.6%) with a history of breast cancer in first- and/or second- degree relatives. The prevalance of I157T mutation was 4.1% (18/435) in North-Central control group and 4.8% (265/5.496) in the general Polish population. However it was not associated with an increased risk of breast cancer.ConclusionObtained results suggest that CHEK2 mutations could potentially contribute to the susceptibility to breast cancer. The germline mutations of CHEK2, especially the truncating ones confer low-penetrance breast cancer predisposition that contribute significantly to familial clustering of breast cancer at the population level.

Mutation analysis of the BCCIP gene for breast cancer susceptibility in breast/ovarian cancer families

ObjectiveAbout 5%–10% of breast cancer is due to inherited disease predisposition. Currently, mutations in the BRCA1 and BRCA2 genes explain less than 25% of the familial clustering of breast cancer, and additional susceptibility genes are suspected. The BCCIP gene plays an important role in the regulation of gene transcription and cell proliferation and could be involved in the maintenance of genomic integrity. The BCCIP protein binds in mammalian cells to the longest conserved region of the BRCA2 protein and is required for BRCA2 stability and function, making a critical contribution to the function of BRCA2 in mediating homologous recombination. Variants in the BCCIP gene could affect the BRCA2 functionality and be associated to the familial breast/ovarian carcinogenesis. Therefore, BCCIP gene is a potential candidate for being involved in heritable cancer susceptibility. MethodsWe have screened the entire coding region and splice junctions of BCCIP in affected index cases from 215 Spanish breast/ovarian cancer families for germ line defects, using direct sequencing. ResultsMutation analysis revealed 3 different intronic sequence changes. ConclusionsBased on the in silico and in vitro RNA analyses of these sequence alterations, none of them were predicted to be pathogenic or associated with cancer susceptibility.Our results indicate that BCCIP germ line mutations are unlikely to be a major contributor to familial breast/ovarian cancer risk in our population.

Deletion of Chromosomes 13q and 14q Is a Common Feature of Tumors with BRCA2 Mutations

IntroductionGermline BRCA1 or BRCA2 mutations account for 20–30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low.MethodsTo develop more efficient approaches to screening we have compared the gene expression and genomic profiles of BRCA2-mutant breast tumors with those of breast tumors lacking BRCA1 or BRCA2 mutations.ResultsWe identified a group of 66 genes showing differential expression in our training set of 7 BRCA2-mutant tumors and in an independent validation set of 19 BRCA2-mutant tumors. The differentially expressed genes include a prominent cluster of genes from chromosomes 13 and 14 whose expression is reduced. Gene set enrichment analysis confirmed that genes in specific bands on 13q and 14q showed significantly reduced expression, suggesting that the affected bands may be preferentially deleted in BRCA2-mutant tumors. Genomic profiling showed that the BRCA2-mutant tumors indeed harbor deletions on chromosomes 13q and 14q. To exploit this information we have created a simple fluorescence in situ hybridization (FISH) test and shown that it detects tumors with deletions on chromosomes 13q and 14q.ConclusionTogether with previous reports, this establishes that deletions on chromosomes 13q and 14q are a hallmark of BRCA2-mutant tumors. We propose that FISH to detect these deletions would be an efficient and cost-effective first screening step to identify potential BRCA2-mutation carriers among breast cancer patients without a family history of breast cancer.

Breast cancer susceptibility: current knowledge and implications for genetic counselling

Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

A family history of breast cancer will not predict female early onset breast cancer in a population-based setting

BackgroundAn increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting.MethodsAn unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer.ResultsThe risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12–10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83–5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33–9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30.ConclusionApplying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age.

Time to Check CHEK2 in Families With Breast Cancer?

Time to Check <i>CHEK2</i> in Families With Breast Cancer?

Hereditary breast and ovarian cancer.

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.

Breast cancer susceptibility after BRCA1/2: finding the genes and potential practical applications

2006, 8(Suppl 2):S1 (DOI 10.1186/bcr1544)Background Epidemiological studies have shown that only about 20%of the familial clustering of breast cancer is explained by the knownhighly penetrant mutations in BRCA1 and BCRA2. We have set out tosearch for the genes for the remaining 80%. Twin studies indicate apredominant role of shared genes rather than a shared environment;the patterns of occurrence of breast cancer in families are consistentwith a major polygenic component.Methods We have assembled a population based set of 5,000 breastcancer cases and 5,000 controls from the East Anglian population. Wehave simple clinical and epidemiological information, including familyhistory, and samples of blood and paraffin embedded tumour.We have used association studies based on single nucleotidepolymorphisms, first with candidate genes and then in a genome-widescan of 266,000 single nucleotide polymorphisms, to search for theputative predisposing genes. We have as yet searched only forcommon variants (frequency >5%).Results We have modelled the effects of polygenic predisposition inthe East Anglian population, and have shown that the model predicts awide distribution of individual risk in the population, such that half of allbreast cancers may occur in the 12% of women at greatest risk.Both the candidate gene-based and genome-wide scans have providedprovisional identification of a number of novel susceptibility genes, andthese are currently being confirmed by a world-wide consortium ofindependent laboratories totalling 20,000-plus cases and controls. Nosingle gene so far identified contributes more than 2% of the totalinherited component, consistent with a model in which susceptibility isthe result of a large number of individually small genetic effects.

Remarks on the BOADICEA model of genetic susceptibility to breast and ovarian cancer

Sir, With much interest we read the paper by Antoniou and colleagues (British Journal of Cancer, October 18, p 1580). These researchers described the development of a genetic model for familial breast cancer, named BOADICEA, which takes into account the simultaneous effects of BRCA1, BRCA2 and other genes. There is a considerable need for such predictions for purposes of management of women referred to genetic clinics and for the considerations of eligibility of any prophylactic interventions in both the clinical and research settings. The BOADICEA model requires a computer program for risk estimation, which is not easy to use in clinical practice. Moreover, such a model is mostly hard to understand for clinicians. Understandable risk estimation should, however, be available to clinicians, so that they know what they are actually doing while estimating disease risks. Our concern about this aspect of the BOADICEA model was illustrated in Figure 3. The authors presented a woman aged 40 years and unaffected with cancer. Her mother and maternal aunt developed ovarian cancer and two other maternal aunts developed breast cancer before the age of 50 years. This family is a good example of a typical Hereditary Breast and Ovarian Cancer (HBOC) family. The risk for breast cancer in these families is increased because of the combination of both breast and ovarian cancers in the family, which highly points to BRCA1 mutations. The BRCA1 mutation probability as predicted by the BOADICEA model is high, 40.9%. The model then predicted her risk of breast cancer at only 13%. For a clinician, this risk estimation is hard to understand and feels illogical. It seems that in the risk prediction by Antoniou et al (2004) the presence of ovarian cancer is not important for the estimation of the breast cancer risk for this woman. The authors did not discuss this point. Recently, Jonker et al (2003) have published a genetic model to predict someone's breast cancer risk based on the family history of breast and ovarian cancer. This model can be considered as an extension of the Claus model combined with the BRCAPRO model (Claus et al, 1991; Parmigiani et al, 1998). In the Jonker et al model, the familial clustering of breast and ovarian cancer is explained by three genes, BRCA1, BRCA2 and a hypothetical third gene BRCAu. This third gene was modelled to explain all familial clustering of breast cancer unaccounted for by the BRCA1 and BRCA2 genes. The model parameters were estimated using published estimates of population incidence and relative risks. As well as the BOADICEA model, the Jonker et al model is not easy to use in clinical practice. For this reason, we extended the easy-to-use Claus tables into the ‘Claus plus method' based on the Jonker model (Claus et al, 1994; Van Asperen et al, 2004). Our method uses the Claus tables, but also incorporates information on the presence of ovarian cancer, bilateral breast cancer and whether there are more than two affected relatives. The formula we obtained simplifies risk estimation in familial breast cancer: The formula starts with an intercept of 0.08. This is the population risk for breast cancer and the basis for further risk estimation. The value of the Claus table should be multiplied by 0.4. The formula subsequently includes the information on ovarian cancer, bilateral breast cancer and more than two affected relatives. These characteristics in the formula are one or zero. This new method might offer a good alternative for breast cancer risk estimation in clinical practice. The ‘Claus plus method' is an easy applicable method for hand-written pedigrees and at the moment it is widely used in the Dutch cancer clinics. Based on the ‘Claus plus method', the predicted risk of breast cancer of the 40-year-old woman in Figure 3 in the Antoniou paper was 31%. Although we are still working on the validation of our method, this risk figure is more in agreement with the risks as observed in typical HBOC families. The authors have mentioned several improvements to be made for their multi-purpose BOADICEA model like genotype-specific incidence rates, risk for other cancers and allele frequencies. Besides this, we would like to recommend paying attention to the applicability for clinical practice. To attain full development for the BOADICEA model, the authors should be in close contact with the ultimate users in clinical practice.

Contribution of the Defective BRCA1, BRCA2 and CHEK2 Genes to the Familial Aggregation of Breast Cancer: a Simulation Study Based on the Swedish Family-Cancer Database

The known breast cancer susceptibility genes only account for 20% to 25% of the excess familial risk of the disease [1]. The present study assessed the contribution of BRCA1/2 mutations and CHEK2 variants to the relative risk of breast cancer for women with affected mothers or sisters. The familial relative risks were estimated by Poisson regression based on the Swedish Family-Cancer Database. The Database was also used to calculate the distribution of life expectancy, the number of daughters per family and the age specific cumulative risk of female breast cancer. This information, together with the penetrances of BRCA1, BRCA2 and CHEK2 from the literature, was used to simulate the familial clustering of breast cancer under different scenarios. The excess risk explained by BRCA1, BRCA2 and CHEK2 decreased steeply with the age at diagnosis of the cancers. Around 40% of the familial risk for cases diagnosed before the age of 50 years was associated with BRCA1/2 mutations. In contrast, roughly 85% of the familial risk of breast cancer diagnosed before the age of 69 years remained unexplained. The contribution of CHEK2 to familial breast cancer was small.

Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study.

We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out.

Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the development of breast cancer.

The capacity of peripheral blood lymphocytes to repair X-ray-induced DNA damage, manifest as chromatid damage 30-90 min after G2-phase X-irradiation, was measured among available members of a family exhibiting a cluster of breast-cancer cases occurring in one generation. The cancer patients had been exposed to repeated chest fluoroscopic examinations during early childhood and adolescence. The development of breast cancer was correlated with DNA repair proficiency and history of radiation exposure. The results of the family study provide preliminary support for the hypothesis that a deficiency in repair of X-irradiation DNA damage may be a susceptibility factor for the development of breast cancer. This hypothesis, however, requires confirmation in a larger study. Studying the combined effect of susceptibility factors and environmental exposures may enhance our knowledge of the etiology of breast cancer and provide leads for effective prevention strategies aimed at reducing exposures or altering susceptibility to unavoidable exposures.

BREAST-CANCER-PRONE FAMILIES

Three breast-cancer-prone families are reported. It is strongly suggested that familial clustering of breast cancer is related to genetic factors. In family S, five family members of two generations were diagnosed as having breast cancer, and one had thyroid cancer metachronously. In family K, four family members of two generations were diagnosed as having breast cancer, and moreover, gastric cancer, colon cancer, uterine cancer and ovarian cancer were seen in family members. In family A with a breast cancer patient as the proband, gastric cancer, colon cancer, uterine cancer and ovarian cancer were seen in six members of two generations. According to an analysis of the organs from which cancer originated in these three cancer-prone families, it was suggested that there was only chronological difference between breast-cancer-prone families with organ specificity and other cancer-prone families. The clinical significance noting familial clustering of cancer is to detect high-risk groups for cancer. Screening and follow-up of the members of cancer-prone families may help to detect early cancerous lesions and to make early therapeutic decisions.