High detection rate for BRCA2 mutations in male breast cancer families from North West England

33 families with a history of male breast cancer aged 60 or less or with a family history of male and female breast cancer were screened for the presence of BRCA2 mutations. 12 pathogenic BRCA2 mutations were identified (36%) in samples from an affected family member. All mutations segregated with disease where it was possible to check. Of the 14 families fulfilling BCLC criteria, 9 (64%) had mutations whilst only 3/16 (19%) of male breast cancer patients with less significant female breast cancer family history having a mutation. All 3 families with ovarian cancer and 3 families with multiple male breast cancer cases had BRCA2 mutations. These data are a further guide to how to prioritise samples for BRCA2 mutation analysis.     

BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic‐related mutations in BRCA1 associated with an increased risk of ovarian cancer

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP‐ribose) polymerase (PARP). Despite a number of small‐size hospital‐based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next‐generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population‐related without an apparent founder origin. This hot‐spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at‐risk relatives. Mutation carriers may also benefit from PARP‐targeted therapies.     

Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families

Familial aggregations of breast/ovarian cancer cases frequently depend on BRCA1/2 pathogenic mutations. Here we counselled 120 Italian breast/ovarian cancer families and selected 73 probands for BRCA1/2 mutation screening. Through this analysis we defined the prevalence of BRCA1/2 pathogenic mutations occurring in Italian breast/ovarian cancer families, enlarged the spectrum of Italian BRCA1/2 mutations by 15% and report on the identification of 13 novel variants, including two deleterious truncating mutations and two potentially pathogenic missense mutations, on the BRCA1 and BRCA2 genes. Finally in hereditary breast cancer families with three or more female breast cancer cases we observed a low mutation prevalence and a significant association with BRCA2 mutations.     

Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level. Irene Konstantopoulou and Theodore Rampias equally contributed to this work.     

A high frequency of germline <Emphasis Type="Italic">BRCA1/2</Emphasis> mutations in western Sweden detected with complementary screening techniques

Dominant inheritance is presumed in 6–10% of breast and ovarian cancers. Mutations in BRCA1 and BRCA2 genes are the most commonly identified causative genes in such families. The frequency of mutation carriers with breast/ovarian cancer depends on the population studied, and display considerable variation that coincides with ethnic and geographical diversity. Mutation analyses were performed in 143 families registered at the Cancer Genetic Counseling Clinic of western Sweden. In a thorough mutation screening procedure, the entire BRCA1 and BRCA2 genes were analyzed using a combination of complementary mutation detection techniques. Mutations in either BRCA1 or BRCA2 were detected in 36% (52 out of 143) of all screened families. All families were clinically evaluated regarding age at diagnosis, type of cancer and number of cancer cases in the family. Among high-risk families, the mutation detection rate was 39% (46 out of 117). The detection rate observed among families with cases of ovarian cancer (42 out of 62, 68%), was substantially higher than in families with only breast cancer (10 out of 81, 12%). Age at ovarian cancer did not seem to have an effect on the detection rate. The analyses revealed 11 frameshift mutations, 4 nonsense mutations and 2 large deletions. Notably, the BRCA1 c.3171ins5 mutation accounted for 34 of 52 (65%) identified mutations. Seven mutations are novel: BRCA1c.409_410del; c.1912T>G; c.2228_2229del; c.3029delA; c.3433delA, a large deletion covering exons 1–3 of BRCA1and one BRCA2 mutation; BRCA2c.6287_6290del. We have shown that the founder mutation BRCA1 c.3171ins5 has a great influence on western Swedish breast/ovarian cancer families along with a high number of mutations unique for the region. In order to achieve a high mutation detection rate we suggest a combination of several detection techniques.     

Genetic analysis of BRCA1 and BRCA2 in breast/ovarian cancer families from Aragon (Spain): two novel truncating mutations and a large genomic deletion in BRCA1

We screened BRCA1 and BRCA2 germline mutations in 60 high-risk breast and/or ovarian cancer patients and 20 relatives from Aragon (Spain) by DHPLC (Denaturing High Performance Liquid Chromatography) and direct sequencing of the entire coding sequence and the splicing sites of both genes. We have identified 17 different pathogenic mutations: 8 in BRCA1 and 9 in BRCA2 in 60 unrelated patients and 50% of relatives were carriers. The prevalence of pathogenic mutations in this study was 33.33%. Two truncating mutations are novel: c.5024_5025delGA in exon 16 of BRCA1 and c.2929delC in exon 11 of BRCA2 (numbered after GenBank U14680 and U43746). Multiplex Ligation Dependent Probe Amplification (MLPA) was performed for large mutational scanning of both genes and a large genomic deletion in BRCA1 was found (DelEx8-13). Furthermore, five mutations are described for the first time in Spanish population: c.1191delC, c.3478_3479delTT and c.6633_6637delCTTAA (BRCA1) and c.3972_3975delTGAG and 3908_3909delTG (BRCA2). Three mutations have been reported previously once in Spain: c.3600_3610del11 (BRCA1), c.5804_5807delTTAA (BRCA2) and c.9246C>A (BRCA2). The mutation c.5374_5377delTATG has been found before only in two unrelated families from Castilla-Leon, Spain (BRCA2). Frequent mutations described in Spanish population have also been present: c.187_188delAG, c.5242C>A and c.5385insC in BRCA1 and c.3492_3493insT and c.9254_9258delATCAT in BRCA2. c.5242C>A, 3972_3975delTGAG and c.5804_5807delTTAA were the recurrent mutations found. Fifteen different unclassified variants were identified (25% families). Although specific BRCA1 and BRCA2 mutations are recurrently reported as a result of genetic founder effects we conclude that heterogeneous ethnicity increases the variety of mutations that can be found in Spanish populations.     

The variants BRCA1 IVS6-1G>A and BRCA2 IVS15+1G>A lead to aberrant splicing of the transcripts

The majority of BRCA1 and BRCA2 deleterious mutations and variants of unknown significance have been identified in genomic DNA and their effects at the mRNA level have not been reported. Our aim was to ascertain the pathological effect of the BRCA1 IVS6-1G>A (c. 302-1G>A) and the BRCA2 IVS15+1G>A (c. 7617+1G>A) variants detected in Spanish breast/ovarian cancer families. Sequencing of cDNA from the BRCA1 IVS6-1G>A allele revealed an inappropriate splicing of exon 7. The analysis of the BRCA2 IVS15+1G>A allele showed the skipping of exon 15. Both alterations predicted the appearance of premature stop codons. Our findings highlight the importance of studying mutations at DNA and RNA levels in order to clarify the effect of the suspected mutation and to provide adequate counseling for breast/ovarian cancer families. An RNA analysis published online recently, showed that the BRCA2 IVS15+2T>G caused skipping of exon 15 in RNA isolated from skin fibroblasts [Vreeswijk MPG, Kraan JN, van der Klift HM et al (2008) Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat Published Online. doi:].     

Mutation analysis of <Emphasis Type="Italic">PALB2</Emphasis> in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>-negative breast and/or ovarian cancer families from Eastern Ontario,Canada

Background

PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient.

Methods

The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario.

Results

We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del – major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations.

Conclusions

PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.     

High Incidence of 4153delA <Emphasis Type="Italic">BRCA1</Emphasis> Gene Mutations in Lithuanian Breast- and Breast-ovarian Cancer Families

Summary BRCA1 and BRCA2 gene mutations confer a high lifetime risk to breast and ovarian cancers. We have screened cancer patients from 13 families with at least three breast and/or ovarian cancers from Lithuania for 5382insC, C61G and 4153delA BRCA1 gene mutations. One of three mutations was found in 9 of the 13 studied families (69%). 4153delA was the most frequently detected and accounted for 56% of all identified mutation. 5382insC and C61G accounted for 33% and 11% of found mutations, respectively. Significantly higher, than in other populations, incidence of 4153delA indicates that this may be founder BRCA1 mutation characteristic for Lithuanians. Our analysis shows that testing of 4153delA, 5382insC, C61G BRCA1 mutations should be extremely effective and inexpensive tool in testing Lithuanian population aimed to identify individuals with high risk of breast and ovarian cancers.     

A common Greenlandic Inuit BRCA1 RING domain founder mutation

Germ-line mutations in the tumour suppressor proteins BRCA1 and BRCA2 predispose to breast and ovarian cancer. We examined 32 breast and/or ovarian cancer patients from Greenland for mutations in BRCA1 and BRCA2. Whereas no mutations were identified in 19 families, 13 families exhibited a BRCA1 exon 3 nucleotide 234 T > G mutation, which has not previously been reported in the breast cancer information core (BIC) database. The mutation changes a conserved cysteine 39 to a glycine in the Zn²⁺ site II of the RING domain, which is essential for BRCA1 ubiquitin ligase activity. Eight of the families had members with ovarian cancer, suggesting that the RING domain may be an ovarian cancer hotspot. By SNP array analysis, we find that all 13 families share a 4.5 Mb genomic fragment containing the BRCA1 gene, showing that the mutation originates from a founder. Finally, analysis of 1152 Inuit, representing almost ~2% of the total Greenlandic Inuit population, showed that the frequency of the mutation was 1.0%. We conclude that the BRCA1 nucleotide 234 T > G is a common Greenlandic Inuit founder mutation. The relative high frequency in the general population, together with the ease of screening and possibility to reduce mortality in gene carriers, may warrant screening of the Greenlandic Inuit population. Provided screening is efficient, about 5% of breast- and 13% of ovarian cancers, respectively, may be prevented. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

BRCA1 and BRCA2 mutation carriers in the Breast Cancer Family Registry: an open resource for collaborative research

The Breast Cancer Family Registry is a resource for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. This resource is available to researchers worldwide for collaborative studies. Herein, we report the results of testing for germline mutations in BRCA1 and BRCA2. We have tested 4,531 probands for mutations in BRCA1 and 4,084 in BRCA2. Deleterious mutations in BRCA1 and BRCA2 were identified for 9.8% of probands tested [233/4,531 (5.1%) for BRCA1 and 193/4,084 (4.7%) for BRCA2]. Of 1,385 Ashkenazi Jewish women tested for only the three founder mutations, 17.4% carried a deleterious mutation. In total, from the proband and subsequent family testing, 1,360 female mutation carriers (788 in BRCA1, 566 in BRCA2, 6 in both BRCA1 and BRCA2) have been identified. The value of the resource has been greatly enhanced by determining the germline BRCA1 and BRCA2 mutation statuses of nearly 6,000 probands.     

BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases

Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included in this study, carried the CHEK2 1100delC, IVS2+1G>A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy.     

The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified

To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese. Wen-Feng Li and Zhen Hu have contributed equally to this work.     

The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition

Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the “PS3,” “PM2,” “PM3,” and “PP3” criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a “likely pathogenic” variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.     

Nuclear morphometric features in benign breast tissue and risk of subsequent breast cancer

Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30–60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10–12 and exons 15–16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15–16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases.     

Selected Aspects of Molecular Diagnostics of Constitutional Alterations in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> Genes Associated with Increased Risk of Breast Cancer in the Polish Population

Objectives

This study was undertaken to determine: 1) Type and prevalence of founder mutations BRCA1 and BRCA2 genes in Polish families with strong aggregation of breast and/or ovarian cancer. 2) Risk of breast and/or ovarian cancer depending on type of BRCA1 gene mutation. 3) Prevalence of BRCA1 mutation and of other alleles presumably linked with predisposition to breast cancer in unselected Polish patients with breast cancer. 4) Risk of breast cancer in patients with 5972C/T polymorphism that alters the BRCA2 protein structure.

Summary of the results

1. Among 66 families from several regions in Poland with a strong aggregation of breast/ovarian cancer, founder mutation of the BRCA1 gene were disclosed in 34 families and of the BRCA2 gene in on family. Altogether, seven different mutations were disclosed. Five mutations were found in at least two families in this group. The most frequent mutation was 5382insC (18 families), followed by C61G (7 families) and 4153delA (4 families). 2. Among 200 families representative for Poland with strong aggregation of breast/ovarian cancer, mutation of the BRCA1 gene were found in 122 families (61%) and of the BRCA2 gene in seven families (3,5%). 119 out of 122 mutations of the BRCA1 gene (97,5%) were repeatable. Three recurrent mutations of the BRCA1 gene (5382insC, C61G, 4153delA) characteristic for the Polish population were disclosed in 111 families representing 86% of all pathogenic sequences of this gene. 3. The risk of ovarian cancer in carriers of the three most frequent recurrent mutation of the BRCA1 gene in Poland is similar (OR 43.6 for 5382insC and 50 for 4153delA). The risk of breast cancer is significantly different for 4153delA (OR 1) and for other mutations (OR 10.9). 4. Among 2012 unselected breast cancers diagnosed in hospitals of nine Polish cities, mutations of the BRCA1 gene (5382insC, C61G, 4153delA) were disclosed in 2.9% patients. CHEK2 alternation (1100delC, IVS2+1G>A, I157T) was discovered in 8.1% and NBS1 mutation (657del5) in 0.8% of the patients. The changes were more frequent in the study than the control group. However, the risk of breast cancer was significantly higher for only three of them. Two changes, namely 5382insC and C61G of the BRCA1 gene revealed a high penetrance (OR 6.2 and 15.0, respectively), while I157T of the CHEK2 gene was associated with a low risk of breast cancer (OR 1.4). Mutations of the BRCA1, CHEK2 and NSB1 genes were significantly more frequent in patients with breast cancer diagnosed prior to 50 years of age. The mean age at diagnosis was 47.2 years for carriers of the BRCA1 mutation, 50.7 years for NBS1 and 54.2 for CHEK2. The mean age at diagnosis in the group of patients without any if the mutations described above was 56.1 years. When breast cancer patients with the diagnosis before and after 50 years of age were compared, the greatest difference in the frequency of mutation was revealed for the BRCA1 gene (5.5% vs 1.5%).BRCA1 mutations were significantly more frequent I familial aggregates of the tumor (10.8%), but were also present in sporadic cases (1.8%). For the CHEK2 and NBS1 genes, there was no correlation between frequency and family history of cancer in probands. 5. A higher frequency of heterozygous carriers of 5972C/T polymorphism of the BRCA2 gene was demonstrated for breast cancer prior to 50 years of age (OR 1.4). the risk of breast cancer prior to 50 years of age was particularly high in 5972T/T homozygote (OR 4.7). This polymorphism was associated with breast cancer notable for intraductal growth.

Conclusions

1. Efficient molecular diagnostics of genetic predisposition to breast/ovarian cancer in Poland could be based on relatively simple tests disclosing some of the most frequent recurrent mutations of the BRCA1 gene. 2. The risk of breast cancer seems to be only slightly higher in carriers of some BRCA1 gene mutations. This finding should be taken into account during work on prevention schemes for carriers of the BRCA1 mutations. 3. 5382insC and C61G mutations of the BRCA1 gene are linked with high risk of breast cancer. Changes in the CHEK2 and NBS1 genes appear to be linked with a higher risk of breast cancers, particularly at young age. However, penetrance in this case is low. All patients with breast cancer should be tested for BRCA1 gene mutations because the percentage of mutations is also high in patients older than 50 years of age or without familiar aggregation of breast/ovarian cancer. 4. Polymorphic changes in the BRCA2 gene sequence previously regarded as non-pathogenic may nevertheless predispose, homozygotes in particular, to breast cancer. Apparently, the recessive character of these changes is responsible for the negative family history in most cases. The use of DNA tests is the only way to disclose increased risk of breast cancer in carriers of the 5972T/T mutation.

     

A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families

Pathogenic mutations in BRCA1 and BRCA2 have been reported in about 55–59% of breast and ovarian cancer (HBOC) families of French Canadian descent, where about 70% of families with more than two cases of ovarian cancer were mutation-positive. Given that specific subtypes of ovarian cancer are associated with mutation-positive families, we reviewed the features of 54 HBOC families of French Canadian descent that had histopathologically confirmed cases of invasive ovarian cancer where the BRCA1 and BRCA2 mutation status is known, and 27 families harbored germline mutations. The number of cases and ages of diagnosis of either breast cancers or ovarian cancers did not differ significantly in comparisons of mutation-positive and mutation-negative groups. However, the distribution of histopathological subtypes for the 79 cases of invasive epithelial cancer from the 54 HBOC families differed when grouped according to familial mutation status. The mutation-negative group had significantly more cases of the mucinous subtype of ovarian cancer when compared with the BRCA1 (P = 0.005) and BRCA2 (P = 0.017) mutation-positive groups. The presence of a mucinous subtype ovarian cancer in multiple young age of onset breast and/or ovarian mutation-negative HBOC cancer families warrants further investigation, as these families appear to exhibit features most consistent with BRCA1 and BRCA2 carrier status.     

BRCA1 and BRCA2 Mutations in Breast and Ovarian Cancer Syndrome: Reflection on the Creighton University Historical Series of High Risk Families

Over the last four decades, Henry Lynch has collected pedigrees and samples from high risk breast and/or ovarian cancer families, generating a unique resource for the study of breast cancer susceptibility. These families have made a major contribution to increasing our knowledge in the cancer genetic susceptibility field, allowing the discovery of a genetic association between breast and ovarian cancer predisposition, contributing to the mapping of the BRCA1 and BRCA2 genes, advancing the idea of the existence of other breast cancer susceptibility genes, allowing the evaluation of BRCA-associated cancer risks and psychosocial aspects of BRCA testing and so on. Ten years after the cloning of BRCA1 and BRCA2, we report the current status of these families and compare the observed BRCA1/2 mutation detection rate with the estimations obtained by linkage analysis of the Breast Cancer Linkage Consortium families.