Novel BRCA2 pathogenic genotype and breast cancer phenotype discordance in monozygotic triplets

BRCA1/2 genes with high-penetrance are tumor suppressor and tumor susceptibility genes that play important roles in the homologous recombination mechanism in DNA repair and increase breast cancer risk. Variants in BRCA1 or BRCA2 are the main causes of familial and early-onset breast cancer. This study investigated pathogenic variant belonging to the BRCA2 gene splice region in monozygotic triplets. A 44-year-old woman was diagnosed with breast cancer when she was 32 years old. Her monozygotic sister had a history of breast cancer. No malignancy was detected in the third one of the monozygotic triplets. Sanger sequencing was used to evaluate the BRCA1/2 gene status of the patient and family members. It was figured out that they had the same genetic variant, a heterozygous germ-line splice region variant (c.7008-1G > C) in the BRCA2 gene. This novel splice region variant may be a new pathogenic variant of the BRCA2 gene. Its association with breast cancers needs to be further verified in more patient cases.     

Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing

Although an association between protein‐truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross‐sectional hospital‐based cohort of 108 moderate to high‐risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations.     

Is multiple SNP testing in BRCA2 and BRCA1 female carriers ready for use in clinical practice? Results from a large Genetic Centre in the UK

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82–1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33–0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.     

BRCA1 and BRCA2 mutation testing in Cyprus; a population based study

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast/ovarian cancer but were diagnosed with early onset breast cancer, ovarian cancer under the age of 60 or triple negative breast cancer. The spectrum of mutations identified in our patient cohort is different compared to other Mediterranean countries. Furthermore, several of the mutations detected are novel and have not been identified in other ethnic populations. This highlights the importance of operating a national reference center for cancer genetic diagnosis which offers services tailored to the needs of the Cypriot population.     

Androgen receptor expression in breast cancer patients tested for BRCA1 and BRCA2 mutations

Pristauz G, Petru E, Stacher E, Geigl J B, Schwarzbraun T, Tsybrovskyy O, Winter R & Moinfar F
(2010) Histopathology 57, 877–884 Androgen receptor expression in breast cancer patients tested for BRCA1 and BRCA2 mutations Aim: To assess the expression of receptors for androgen (AR), oestrogen (ER) and progesterone (PR) as well as human epidermal growth factor receptor type 2 (Her‐2/neu) status of breast carcinomas in breast cancer susceptibility gene (BRCA) BRCA1/2 mutation carriers and BRCA1/2 negative tested women. Methods: One hundred and thirty‐five breast cancers in women tested for BRCA1/2 mutations. Screening for BRCA1 and BRCA2 mutations was performed by direct sequencing of all BRCA1 and BRCA2 exons as well as the surrounding intronic sequences. Additionally, BRCA genes were analysed with multiplex ligation‐dependent probe amplification. Consecutive paraffin sections were examined immunhistochemically for AR, ER, PR and Her‐2/neu. Results: Of the 135 tumours, 43 (32%) were BRCA1‐related, 18 (13%) were BRCA2‐related and 74 (55%) were BRCA1/2‐negative. Seventy‐two per cent of the BRCA1‐related, 22% of the BRCA2‐related and 12% of the BRCA1/2‐negative tumours were triple (ER, PR, Her2neu)‐negative. Eighty‐four per cent of BRCA1 mutated cancers were high‐grade (G3) tumours. ARs were expressed in 30% (13 of 43) of BRCA1‐related, in 78% (14 of 18) in BRCA2‐related tumours and in 76% (56 of 74) in BRCA1/2 negative tumours. Twenty‐one per cent of ER‐negative BRCA1‐related tumours expressed androgen receptors. Conclusion: Approximately one in five BRCA1 mutated breast cancers negative for ER and PR express androgen receptors. Modulation of AR might open a new avenue for treating these high‐risk cancers.     

Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland

A number of genes other than BRCA1 and BRCA2 have been associated with breast cancer predisposition, and extended genetic testing panels have been proposed. It is of interest to establish the full spectrum of deleterious mutations in women with familial breast cancer.We performed whole‐exome sequencing of 144 women with familial breast cancer and negative for 11 Polish founder mutations in BRCA1, CHEK2 and NBS1, and we evaluated the sequences of 12 known breast cancer susceptibility genes. A truncating mutation in a breast cancer gene was detected in 24 of 144 women (17%) with familial breast cancer. A BRCA2 mutation was detected in 12 cases, a (non‐founder) BRCA1 mutation was detected in 5 cases, a PALB2 mutation was detected in 4 cases and an ATM mutation was detected in 2 cases. Polish women with familial breast cancer who are negative for founder mutations in BRCA1, CHEK2 and NBS1 should be fully screened for mutations in BRCA1, BRCA2 and PALB2. The PALB2 founder mutation c.509_519delGA should be included in the panel of Polish founder mutations.     

Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families?

Panchal S, Bordeleau L, Poll A, Llacuachaqui M, Shachar O, Ainsworth P, Armel S, Eisen A, Sun P, Narod SA. Does family history predict the age at onset of new breast cancers in BRCA1 and BRCA2 mutation‐positive families? Women who carry BRCA mutations are advised to begin breast cancer screening based on the age‐specific risks of breast cancer development. It is not clear to what extent the family history of breast cancer influences age of onset. We evaluated the use of family history to predict the age of breast cancer onset in BRCA mutation carriers. Pedigrees from an Ontario‐based registry were reviewed to identify the index case of breast cancer (most recent diagnosis) and other family cases of breast cancer. The youngest age of breast cancer diagnosis and mean age at breast cancer diagnosis in the other family cases were compared to the age of onset in the index case. The 260 BRCA1 and 213 BRCA2 pedigrees were reviewed. In BRCA2 families, the index case was diagnosed on average at 44.4 years when the youngest reported family case was less than or equal to 35 years, compared to 51.9 years when the earliest cases were diagnosed after age 50 (p = 0.04). A modest trend was seen for BRCA1 carriers, but this was not statistically significant. To a small extent, the onset of breast cancer in a BRCA2 mutation carrier can be predicted from her family history of cancer, however, the trend is modest and should not alter clinical recommendations regarding initiation of screening.     

High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer

Background: A higher frequency of skewed X chromosome inactivation has been reported in a consecutive series of young patients with breast cancer compared with controls of a similar age. Objective: To investigate the X inactivation pattern in patients with familial non-BRCA1/BRCA2 breast cancer (n = 272), BRCA1/BRCA2 germline mutations (n = 35), and sporadic breast cancer (n = 292). Methods: X inactivation pattern was determined by polymerase chain reaction analysis of the highly polymorphic CAG repeat in the androgen receptor (AR) gene. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially expressed one X chromosome. Results: Young patients with familial breast cancer had a significantly higher frequency of skewed X inactivation (11.2%) than young controls (2.7%) (p = 0.001). There was also a strong tendency for middle aged patients with sporadic breast cancer to be more skewed than middle aged controls (13.6% v 4.4%) (p = 0.02). No association between skewed X inactivation and breast cancer was found for the BRCA1/BRCA2 patients . Conclusions: Skewed X inactivation may be a risk factor for the development of breast cancer in both sporadic and familial breast cancer and may indicate an effect of X linked genes.     

Mutational analysis of BRCA1 and BRCA2 in Mediterranean Spanish women with early-onset breast cancer: identification of three novel pathogenic mutations

In Spain, the contribution of BRCA mutations to the population incidence of early-onset breast cancer was unknown. We carried out a mutational analysis of the BRCA1 and BRCA2 genes in 124 Spanish women diagnosed with breast cancer before the age 41 and who were not selected for a family history of this disease. The genetic study was performed by PCR-SSCP analysis and DNA sequencing. We identified 6 pathogenic BRCA mutations in 7 unrelated probands (5.6%; 95% CI=2.3% to 11.3%): 1 BRCA1 (c.2080delA) and 5 BRCA2 (p.Y3006X, p.Q1994X, c.9204_9217del14, c.9254_9258del5 and c.295+2T>C). Three out of 6 mutations were novel (BRCA2 p.Y3006X, c.9204_9217del14, and c.295+2T>C), and two further mutations had not been previously found in Spain (BRCA1 c.2080delA and BRCA2 p.Q1994X). The one remaining (BRCA2 c.9254_9258del5) was detected in two probands of our sample. Additionally, we identified two new missense mutations: BRCA1 p.P1812A and BRCA2 p.G2044A. Our data support the notion that Spaniards represent a heterogeneous population with its own spectrum of BRCA mutations, some of which appear as founding mutations. We categorized patients into familial or non-familial groups on the basis of her family history of breast/ovarian cancer; this analysis indicated that among Spanish women with early-onset breast cancer, an even moderate family history is a good predictor of being a BRCA mutation carrier.     

High proportion of novel mutations of<Emphasis Type="Italic"> BRCA1</Emphasis> and<Emphasis Type="Italic"> BRCA2</Emphasis> in breast/ovarian cancer patients from Castilla-León (central Spain)

A total of 264 unrelated breast/ovarian cancer patients and 45 healthy individuals with familial antecedents referred for genetic testing were scanned for germ-line mutations in BRCA1 and BRCA2 by conformation-sensitive gel electrophoresis (CSGE) and heteroduplex analysis by capillary array electrophoresis (HA-CAE). We detected 101 distinct mutations (41 in BRCA1 and 60 in BRCA2); ten of them have not been previously reported. These mutations were c.2411_2429dup19, c.2802_2805delCAAA and c.5294A>G (p.E1725E) of BRCA1; and c.667C>T (p.Q147X), c.2683C>T (p.Q819X), c.5344_5347delAATA, c.5578_5579delAA;insT, c.8260_8261insGA, c.744+14C>T and c.8099A>G (p.Y2624C) of BRCA2. Twenty-four different mutations, including seven of the new mutations (five frameshift and two nonsense), were classified as pathogenic. These 24 alterations were found in 39 families (12.6% of all families). A remarkable proportion of deleterious mutations were found in BRCA2: 25 families carried a mutation in BRCA2 (BRCA2+; 64.1%) compared with 14 families BRCA1+ (35.9%). The highest incidences of deleterious mutations were found in families with three or more cases of site-specific breast cancer (BC) (27.4%) and families with BC and ovarian cancer (22.2%). Finally, four recurrent mutations, 3036_3039delACAA, c.5374_5377delTATG of BRCA2, as well as c.5272-1G>A and c.5242C>A (p.A1708E) of BRCA1, accounted for 44% of all of the deleterious mutations.     

Genetic alterations in breast cancer

The etiology of breast cancer involves a complex interplay of various factors, including genetic alterations. Many studies have been devoted to the identification and characterization of mutations that occur frequently during breast tumorigenesis. The major types of genetic abnormalities that are frequently observed in breast tumors are amplification of protooncogenes (MYC, ERBB2) and DNA from chromosome band 11q13; mutation of TP53; and loss of heterozygosity from chromosomes and chromosome arms 1, 3p, 6q, 7q, 8p, 11, 13q, 16q, 17, 18q, and 22q. The latter may correspond to losses or inactivations of tumor suppressor genes. Recently, linkage analyses of large families with a predisposition to breast cancer have been performed in order to map breast cancer susceptibility genes (TP53, BRCA1, BRCA2). The findings have thrown light on the molecular mechanisms of breast cancer and have enabled various genetic markers to be used in clinical oncology.     

De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer

Germline mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying mutations of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease or both. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a germline mutation in the BRCA2 gene (3034del4) in a patient with early onset breast cancer and no strong family history of the disease. Subsequent molecular analysis in her parents showed that neither of them carried the mutation. Paternity was confirmed using a set of highly polymorphic markers, showing that the proband carried a de novo germline mutation in the BRCA2 gene. Interestingly, 3034del4 is a recurrent mutation occurring in a putative mutation prone region of the BRCA2 gene. Our study presents the first case in which a de novo germline mutation in the BRCA2 gene has been identified, and supports previous results of haplotype studies, confirming that the 3034del4 mutation has multiple independent origins.


Keywords: breast cancer; BRCA2 gene; de novo mutation     

Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors

Rearrangements or loss of chromosome 17 are frequent events in breast tumors. Chromosome 17 contains at least four genes implicated in breast cancer (TP53, ERBB2 (Her2/neu), BRCA1, and NM23), as well as other putative tumor suppressor genes and oncogenes implicated in loss of heterozygosity or allelic imbalance studies. Allelic imbalance represents the addition or loss of genetic material in tumor samples, providing circumstantial evidence for the location of cancer related genes. We have analyzed a panel of 85 breast tumor/normal tissue pairs with 21 PCR-based short tandem repeat (STR) markers located at 17q12-qter to more precisely define regions of allelic imbalance and to determine their relation to clinical parameters. Our analysis revealed at least four common regions of allelic imbalance: proximal to BRCA1, including D17S800 (17q12); distal to NM23 around D17S787 (17q22); near the growth hormone (GH) locus, at D17S948 (17q23-24); and between markers D17S937 and D17S802 (17q25). These data also reveal that loss (or gain) of 17q genetic material correlates with poorly differentiated (grade III) tumors (P = <0.001), high S phase fraction (P = 0.034), and positive TP53 immunohistochemical staining (P = 0.011). However, steroid receptor status, ERBB2 (Her2/neu) staining, and aneuploidy do not correlate with allelic imbalance at 17q. Genes Chromosomes Cancer 20:354–362, 1997. © 1997 Wiley-Liss, Inc.     

BRCA1‐2 diagnostic workflow from next‐generation sequencing technologies to variant identification and final report

The BRCA1‐BRCA2 genes predispose to hereditary breast and ovarian cancer, and the germline and mutational status of these genes defines a target population that can benefit from PARP inhibitor treatments. To respond to the increasing number of BRCA1‐BRCA2 tests, it is necessary to shift to high‐throughput technologies that are reliable and less time consuming. Different methodological platforms are dedicated to this purpose with different approaches and algorithms for analysis. Our aim was to set up a cost‐effective and low time‐consuming BRCA1‐BRCA2 mutation detection workflow using the Ion Torrent PGM technology. A retrospective cohort of 40 patients with familial breast/ovarian cancer previously tested by Sanger sequencing and a prospective cohort of 72 patients (validation set) were analyzed. The validation set included 64 patients affected by familial breast/ovarian cancer and eight sporadic ovarian cancer cases, who are potential candidates for PARPi treatments. A complete and standardized workflow easily usable and suitable in a certified laboratory has been proved and validated. This includes all steps from library preparation to the final report. The use of next‐generation sequencing will be of benefit for patients enrolled in the genetic counseling process and, moreover, will enhance the process of selecting patients eligible for personalized treatments. © 2016 Wiley Periodicals, Inc.     

Hereditary breast cancer: syndromes,tumour pathology and molecular testing

Hereditary factors account for a significant proportion of breast cancer risk. Approximately 20% of hereditary breast cancers are attributable to pathogenic variants in the highly penetrant BRCA1 and BRCA2 genes. A proportion of the genetic risk is also explained by pathogenic variants in other breast cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C, RAD51D and BARD1, as well as genes associated with breast cancer predisposition syndromes – TP53 (Li–Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer), STK11 (Peutz–Jeghers syndrome) and NF1 (neurofibromatosis type 1). Polygenic risk, the cumulative risk from carrying multiple low-penetrance breast cancer susceptibility alleles, is also a well-recognised contributor to risk. This review provides an overview of the established breast cancer susceptibility genes as well as breast cancer predisposition syndromes, highlights distinct genotype–phenotype correlations associated with germline mutation status and discusses molecular testing and therapeutic implications in the context of hereditary breast cancer.     

Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India

Background

A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls.

Method

Cases were selected with regard to early onset disease (≤40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants.

Results

In total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation.

Conclusion

BRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients.     

Association of hormone receptor status with grading,age of onset,and tumor size in <Emphasis Type="Italic">BRCA1</Emphasis>-associated breast cancer

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERα) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERα is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERα and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher’s exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERα and PR positive and low grade than advanced stages. M. Graeser and K. Bosse contributed equally to this paper.     

Cancer predisposing missense and protein truncating BARD1 mutations in non‐BRCA1 or BRCA2 breast cancer families

Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported.We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families. ©2010 Wiley‐Liss, Inc.     

Identification and evaluation of 55 genetic variations in the <Emphasis Type="Italic">BRCA1</Emphasis> and the <Emphasis Type="Italic">BRCA2</Emphasis> genes of patients from 50 Japanese breast cancer families

We sequenced approximately 23 kb genomic regions containing all the coding exons and their franking introns of two breast cancer susceptibility genes, BRCA1 and BRCA2, of 55 individuals from 50 unrelated Japanese breast cancer families. We identified 55 single-nucleotide polymorphisms (SNPs) (21 in BRCA1 and 34 in BRCA2) containing nine pathogenic protein-truncating mutations (four in BRCA1 and five in BRCA2 from ten patients). Among the remaining 46 SNPs, allele frequencies of 40 were examined in both the breast cancer patients and 28 healthy volunteers with no breast cancer family history by PCR-RFLP or by direct DNA sequencing. Twenty-eight SNPs were common and were also found in the healthy volunteers and/or a SNP database. The remaining 18 were rare (allele frequency <0.05) and were not found in the healthy volunteers and/or the database. The pathogenic significance of these coding SNPs (cSNPs) remains to be clarified. The SNP information from this study will be useful in the future genetic testing of both BRCA1 and BRCA2 genes in the Japanese population.The first two authors contributed equally to this study.     

Somatic genetic alterations in BRCA2‐associated and sporadic male breast cancer

The genetic changes underlying the development and progression of male breast cancer are poorly understood. Germline BRCA2 mutations account for a significant part of male breast cancer, but the majority of patients lack a known inherited predisposition. We recently demonstrated that the progression of breast cancer in female carriers of a germline BRCA1 or BRCA2 mutation follows specific genetic pathways, distinct from each other and from sporadic breast cancer. In the present study, we performed a genome‐wide survey by comparative genomic hybridization (CGH) of somatic genetic aberrations in 26 male breast cancers, including five tumors from BRCA2 mutation carriers. BRCA2 tumors exhibited a significantly higher number of chromosomal aberrations than sporadic tumors. The most common alterations in sporadic male breast cancer were +1q (38%), +8q (33%), +17q (33%), –13q (29%), and –8p (24%). In tumors from BRCA2 mutation carriers, the five most common genetic changes were +8q (100%), +20q (100%), +17q (80%), –13q (80%), and –6q (60%). The CGH results in these two groups of male breast cancers are almost identical to those identified in the corresponding sporadic and BRCA2‐associated female breast cancers. The results suggest that despite substantial hormonal differences between females and males, similar genetic changes are selected for during tumor progression. Furthermore, the presence of a highly penetrant germline BRCA2 mutation apparently leads to a characteristic somatic tumor progression pathway, again shared between affected male and female mutation carriers. Genes Chromosomes Cancer 24:56–61, 1999. © 1999 Wiley‐Liss, Inc.