Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers

Purpose:

The objective of this study was to estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers; and measure the extent to which host, family history, and cancer treatment-related factors modify the risk.

Patients and methods:

Patients were 810 women, with stage I or II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up.

Results:

Overall, 149 subjects (18.4%) developed a contralateral breast cancer. The 15-year actuarial risk of contralateral breast cancer was 36.1% for women with a BRCA1 mutation and was 28.5% for women with a BRCA2 mutation. Women younger than 50 years of age at the time of breast cancer diagnosis were significantly more likely to develop a contralateral breast cancer at 15 years, compared with those older than 50 years (37.6 vs 16.8% P=0.003). Women aged <50 years with two or more first-degree relatives with early-onset breast cancer were at high risk of contralateral breast cancer, compared with women with fewer, or no first-degree relatives with breast cancer (50 vs 36% P=0.005). The risk of contralateral breast cancer was reduced with oophorectomy (RR 0.47; 95% CI 0.30–0.76; P=0.002).

Conclusion:

The risk of contralateral breast cancer risk in BRCA mutation carriers declines with the age of diagnosis and increases with the number of first-degree relatives affected with breast cancer. Oophorectomy reduces the risk of contralateral breast cancer in young women with a BRCA mutation.     

BRCA1 andBRCA2 germline mutations in Japanese with hereditary breast cancer families

We examined germline mutations inBRCA1 andBRCA2 in 23 Japanese breast cancer families, using PCR-SSCP analysis. The same nonsense mutation (exon 5, Leu63ter) ofBRCA1 was detected in two different families. Three different mutations resulting in a truncatedBRCA2 protein (exon 9, 20, 24) were detected in three different families, including one male case of breast cancer. One base substitution mutation inBRCA2, A10462G, was detected in the other two families. Although the mean age of onset for breast cancer in families with theBRCA1- mutation was 50 years, the age of onset in families with theBRCA2-mutation was from 28 to 43 years. Among the 23 families examined, two families had members with ovarian cancers, three had members with prostate cancers, and one had a pancreatic cancer. However, none of these families was positive for theBRCA1 orBRCA2 mutation. Histopathologically, we observed a prevalence of histological grade 3 inBRCA2-associated familial breast cancers, because of nuclear atypia, structural atypia and mitotic activity. It is suggested thatBRCA2 may play a more important role thanBRCA1 in Japanese familial breast cancers, and these mutations are related to the aggressive nature and highly proliferative activity of the tumors.     

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers in a large cohort of unselected Chinese breast cancer patients

To estimate the cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers in a large cohort of unselected Chinese breast cancer patients. Our study comprised 9,401 unselected Chinese breast cancer patients and BRCA1/2 germline mutations were determined in all patients. After a median follow-up of 5.7 years, 181 patients developed CBC in this cohort. Compared to noncarriers, BRCA1 and BRCA2 carriers had a 4.52-fold (95% CI, 2.63–7.76) and 5.54-fold (95% CI, 3.51–8.74) increased risk of CBC, respectively. The 10-year cumulative risk of CBC was 15.5% (95% CI, 9.9–24.2) for BRCA1 carriers, 17.5% (95% CI, 10.9–28.0) for BRCA2 carriers and 3.2% (95% CI, 2.5–4.1) for noncarriers. Younger age at first breast cancer diagnosis was significantly associated with an increased 10-year risk of CBC for BRCA1 carriers (≤40 years vs. >40 years: 21.5% vs. 11.9%, unadjusted hazard ratio [HR] = 2.51, 95% CI, 1.03–6.15, p = 0.044), but not for BRCA2 carriers and noncarriers. The 10-year cumulative CBC risk was significantly higher in both BRCA1 and BRCA2 carriers who had a family history of breast cancer than in those who did not (BRCA1: 27.5% vs. 9.4%, adjusted HR = 2.64, 95% CI, 1.01–6.97, p = 0.049; BRCA2: 27.1% vs. 12.8%, adjusted HR = 2.29, 95% CI, 1.04–5.06, p = 0.040). In conclusion, the risk of CBC was a substantial high in BRCA1/2 carriers in unselected Chinese breast cancer patients, and CBC risk is much more remarkable in both BRCA1 and BRCA2 carriers who had a family history of breast cancer. Younger age at first breast cancer diagnosis also enhanced CBC risk in BRCA1 carriers.     

Prevalence of BRCA1 and BRCA2 mutations in breast cancer patients from Cuba

The contribution of BRCA1 and BRCA2 to breast cancer incidence in Cuba has not yet been explored. In order to estimate the proportion of breast cancers due to BRCA1 and BRCA2 mutations in Cuba, and to identify possible Cuban founder mutations, we conducted a study of unselected breast cancer patients from Havana, Cuba. We enrolled 336 women with breast cancer from a large public hospital in the city. A family history of cancer was obtained from each patient and a blood sample was processed for DNA analysis. Mutations in BRCA1 and BRCA2 were sought using a combination of techniques, but all mutations were confirmed by direct sequencing. We were able to successfully complete testing on samples from 307 women. Among these, eight mutations were identified (seven in BRCA2 and one in BRCA1) representing 2.6% of the total, including 10% of familial cases and 10% of cases under age forty. One BRCA2 mutation (c.3394C > T) was found in two women, but no clear example of a founder mutation was identified. In summary, BRCA1 and BRCA2 mutations are not uncommon in Cuban women with breast cancer, but the absence of founder mutations precludes the development of a rapid and inexpensive clinical screening test.     

The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers

BACKGROUND:

We assessed the efficacy of taxane chemotherapy in BRCA1‐ and BRCA2‐associated patients compared with sporadic metastatic breast cancer patients.

METHODS:

Response rates (RRs) to and progression‐free survival (PFS) after taxane chemotherapy of 35 BRCA1‐associated and 13 BRCA2‐associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third).

RESULTS:

Among BRCA1‐associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)‐negative patients, BRCA1‐associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec‐positive patients were similar in BRCA1‐associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2‐associated patients, who were mainly HRec‐positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively).

CONCLUSIONS:

BRCA1‐associated, HRec‐negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec‐negative patients. HRec‐positive BRCA1‐ and BRCA2‐associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients. Cancer 2012;. © 2011 American Cancer Society.     

Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers

Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1-3, 4-5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72-1.12), 0.75 (95% CI 0.47-1.19) and 0.31 (95% CI 0.13-0.71; p-trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk.     

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.     

Breast conservation in BRCA1 or BRCA2 mutation carriers with early stage breast cancer

The role of breast conservation therapy (limited surgery and irradiation of the breast with/without axilla) in the approximately 5% of breast cancer patients who harbour a germline mutation in BRCA1 or BRCA2, is a largely unexplored area and is seen by some as controversial. The relatively high cumulative risk of second primary cancers in such patients and concern about a possible decreased ability of mutation carriers to repair DNA damage caused by radiation has fuelled this controversy. Published studies of breast conservation therapy in carriers of a mutation in BRCA1 or BRCA2 are reviewed, with particular attention to their methodology. These studies have not demonstrated any increase in radiation sensitivity of normal tissues in mutation carriers, either in terms of increased early or late toxicity or tumourigenesis. Likewise, tumour sensitivity to radiotherapy, which might be expected based on the known functions of the BRCA1 and BRCA2 genes, has not been documented to date in mutation carriers. Further, methodologically rigorous studies of large numbers of breast cancer patients who carry a mutation in BRCA1 or BRCA2 are required to fully elucidate these issues.     

Diabetes and breast cancer among women with BRCA1 and BRCA2 mutations

BACKGROUND:

Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

METHODS:

The authors reviewed the medical histories of 6052 women with a BRCA1 or BRCA2 mutation, half of whom had been diagnosed with breast cancer. They estimated the odds ratio for breast cancer, given a self‐report of diabetes. They then estimated the hazard ratio for a new diagnosis of diabetes associated with a history of breast cancer.

RESULTS:

There was no excess of diabetes in the period before the diagnosis of breast cancer, compared with controls with no diagnosis of breast cancer. The risk of diabetes was doubled among BRCA carriers in the 15‐year period after the diagnosis of breast cancer (relative risk, 2.0; 95% confidence interval [CI], 1.4‐2.8; P = .0001), compared with carriers without cancer. The risk was particularly high for women with a body mass index (BMI) >25.0 kg/m² (odds ratio, 5.8; 95% CI, 4.0‐8.6; P = .0001).

CONCLUSIONS:

After a diagnosis of breast cancer, women with a BRCA1 or BRCA2 mutation face a 2‐fold increase in the risk of diabetes, which is exacerbated by a high BMI. Cancer 2011. © 2010 American Cancer Society.     

The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers

Tobacco smoke is an established carcinogen, but the association between tobacco smoking and cancer risk in BRCA mutation carriers is not clear. The aim of this study was to evaluate prospectively the association between tobacco smoking and cancer incidence in a cohort of BRCA1 and BRCA2 mutation carriers. The study population consisted of unaffected BRCA mutation carriers. Information on lifestyle including smoking histories, reproductive factors, and past medical histories was obtained through questionnaires. Incident cancers were updated biennially via follow‐up questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using time‐dependent Cox regression models. There were 700 incident cancers diagnosed over 26,711 person‐years of follow‐up. The most frequent cancers seen in BRCA mutation carriers were breast (n = 428; 61%) and ovarian (n = 109; 15%) cancer. Compared to nonsmokers, (ever) smoking was associated with a modest increased risk of all cancers combined (HR = 1.17; 95%CI 1.01–1.37). Women in the highest group of total pack‐years (4.3–9.8) had an increased risk of developing any cancer (HR = 1.27; 95%CI 1.04–1.56), breast cancer (HR = 1.33, 95%CI 1.02–1.75), and ovarian cancer (HR = 1.68; 95%CI 1.06–2.67) compared to never smokers. The associations between tobacco smoking and cancer did not differ by BRCA mutation type or by age at diagnosis. This prospective study suggests that tobacco smoking is associated with a modest increase in the risks of breast and ovarian cancer among women with BRCA1 or BRCA2 mutation.     

miRNA expression patterns in normal breast tissue and invasive breast cancers of BRCA1 and BRCA2 germ-line mutation carriers

miRNA deregulation has been found to promote carcinogenesis. Little is known about miRNA deregulation in hereditary breast tumors as no miRNA expression profiling studies have been performed in normal breast tissue of BRCA1 and BRCA2 mutation carriers. miRNA profiles of 17 BRCA1- and 9 BRCA2-associated breast carcinomas were analyzed using microarrays. Normal breast tissues from BRCA1 and BRCA2 mutation carriers (both n = 5) and non-mutation carriers (n = 10) were also included. Candidate miRNAs were validated by qRT-PCR. Breast carcinomas showed extensive miRNA alteration compared to normal breast tissues in BRCA1 and BRCA2 mutation carriers. Moreover, normal breast tissue from BRCA1 mutation carriers already showed miRNA alterations compared to non-mutation carriers. Chromosomal distribution analysis showed several hotspots containing down- or up-regulated miRNAs. Pathway analysis yielded many similarities between the BRCA1 and BRCA2 axes with miRNAs involved in cell cycle regulation, proliferation and apoptosis. Lesser known pathways were also affected, including cellular movement and protein trafficking. This study provides a comprehensive insight into the potential role of miRNA deregulation in BRCA1/2-associated breast carcinogenesis. The observed extensive miRNA deregulation is likely the result of genome-wide effects of chromosomal instability caused by impaired BRCA1 or BRCA2 function. This study''s results also suggest the existence of common pathways driving breast carcinogenesis in both BRCA1 and BRCA2 germ-line mutation carriers.     

BRCA1 and BRCA2 germline mutations in Sardinian breast cancer families and their implications for genetic counseling.

BACKGROUND: The Sardinian population is genetically homogeneous and could be useful in understanding better the genetics of a complex disease like breast cancer (BC). PATIENTS AND METHODS: Using a screening assay based on a combination of single-strand conformation polymorphism, denaturing high-performance liquid chromatography and sequence analysis, 47 Sardinian families with three or more BC cases were screened for germline mutations in BRCA1 and BRCA2 genes. RESULTS: Three BRCA1/2 germline sequence variants were identified. While BRCA2-Ile3412Val is a missense variant with unknown functional significance, BRCA2-8765delAG and BRCA1-Lys505ter are two deleterious mutations (due to their predicted effects on protein truncation), which were found in seven families (15%). BRCA2-8765delAG was found in six of eight (75%) BRCA1/2-positive families and seven of 501 (1.4%) unselected and consecutively collected BC patients. Prevalence of BRCA1/2 mutations in BC families was significantly correlated with the total number of female BCs (P <0.01) and increased by the presence of (i) at least one case of ovarian or male BC, or (ii) three generations affected, or (iii) bilateral BC. CONCLUSIONS: Identification of such features should address BC patients and their families to genetic counseling and BRCA1/2 mutational analysis. In addition, this is the first report of a detailed BRCA1/2 mutation screening in Sardinia, having immediate implications for the clinical management of BC families.     

Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: A national cohort study

Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as “unfavourable.” Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79‐9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60‐year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile.     

Cancer risks among BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction.     

Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80%, and following the first diagnosis the 10-year risk of contralateral breast cancer is approximately 30%. It has been shown that both tamoxifen and oophorectomy prevent contralateral breast cancer, but it is not clear whether there is a benefit in giving tamoxifen to women who have previously undergone an oophorectomy. Furthermore, the relative degree of protection in BRCA1 and BRCA2 carriers has not been well evaluated. We studied 285 women with bilateral breast cancer and a BRCA1 or BRCA2 mutation, and 751 control women with unilateral breast cancer and a BRCA1 or BRCA2 mutation in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of breast cancer and had been followed for as long as the case for a second primary breast cancer. The history of tamoxifen use for treating the first breast cancer was compared between bilateral and unilateral cases. The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 for carriers of BRCA1 mutations (95% CI, 0.30-0.85) and was 0.42 for carriers of BRCA2 mutations (95% CI, 0.17-1.02). The protective effect of tamoxifen was not seen among women who had undergone an oophorectomy (OR = 0.83; 95%CI, 0.24-2.89) but this subgroup was small. In contrast, a strong protective effect of tamoxifen was apparent among women who were premenopausal or who had undergone natural menopause (OR = 0.44; 95% CI, 0.27-0.65).     

Prevalance of BRCA1 and BRCA2 mutations in familial breast cancer patients in Lebanon

Breast cancer is the most prevalent malignancy in women in Western countries, currently accounting for one third of all female cancers. Familial aggregation is thought to account for 5–10 % of all BC cases, and germline mutations in BRCA1 and BRCA2 account for less of the half of these inherited cases. In Lebanon, breast cancer represents the principal death-causing malignancy among women, with 50 % of the cases diagnosed before the age of 50 years.In order to study BRCA1/2 mutation spectra in the Lebanese population, 72 unrelated patients with a reported family history of breast and/or ovarian cancers or with an early onset breast cancer were tested. Fluorescent direct sequencing of the entire coding region and intronic sequences flanking each exon was performed.A total of 38 BRCA1 and 40 BRCA2 sequence variants were found. Seventeen of them were novel. Seven confirmed deleterious mutations were identified in 9 subjects providing a frequency of mutations of 12.5 %. Fifteen variants were considered of unknown clinical significance according to BIC and UMD-BRCA1/BRCA2 databases.In conclusion, this study represents the first evaluation of the deleterious and unclassified genetic variants in the BRCA1/2 genes found in a Lebanese population with a relatively high risk of breast cancer.     

Identification of a founder <Emphasis Type="Italic">BRCA2</Emphasis> mutation in Sardinian breast cancer families

The population of Sardinia is characterized by a relatively low level of genetic heterogeneity: therefore ‘founder mutations’ can be expected to be found. We analysed 17 probands from families with high incidence of breast cancer or breast and ovarian cancer by sequencing the full-length coding regions of BRCA1 and BRCA2 genes. A novel BRCA2 frameshift mutation, 3951del3insAT, which produces a protein truncated at codon 1258, was observed in six patients with BC from the same village. The mutation was not found in unaffected females (matched on basis of ethnicity and age) with no family history of cancer. Haplotype analysis strongly suggests that all affected persons had a common ancestor. The identification of this clinically significant founder mutation may facilitate screening/testing for inherited risk of breast cancer.     

Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation

Genetic testing for mutations in BRCA1 and BRCA2 is available in Canada for women with a significant family history of breast cancer. For the majority of tested women, a BRCA1 or BRCA2 mutation is not found, and counselling regarding breast cancer risk is based on the review of the pedigree. In this prospective study, we estimate breast cancer risks in women with a family history of breast cancer and for whom the proband tested negative for a mutation in BRCA1 or BRCA2. Families with two or more breast cancers under the age of 50 years, or with three cases of breast cancer at any age, and who tested negative for a BRCA1 or BRCA2 mutation were identified. Follow-up information on cancer status was collected on all first-degree relatives of breast cancer cases. The standardised incidence ratios (SIRs) for breast cancer were calculated by dividing the observed numbers of breast cancer by the expected numbers of breast cancers, based on the rates in the provincial cancer registries. A total of 1492 women from 365 families were included in the analyses. The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Sixty-five women developed breast cancer, compared to 15.2 expected number (SIR=4.3). The SIR was highest for women under the age of 40 (SIR=14.9) years and decreased with increasing age. However, the absolute risk was higher for women between the age of 50 and 70 (1% per year) years than for women between 30 and 50 (0.4% per year) years of age. There was no elevated risk for ovarian, colon or any other form of cancer. Women with a significant family history of breast cancer (ie, two or more breast cancers under the age of 50 years, or three or more breast cancers at any age), but who test negative for BRCA mutations have approximately a four-fold risk of breast cancer. Women in these families may be candidates for tamoxifen chemoprevention and/or intensified breast screening with an MRI.     

Chromosome 5 imbalance mapping in breast tumors from BRCA1 and BRCA2 mutation carriers and sporadic breast tumors

Comparative genomic hybridization (CGH) analysis has shown that chromosome 5q deletions are the most frequent aberration in breast tumors from BRCA1 mutation carriers. To map the location of putative 5q tumor suppressor gene(s), 26 microsatellite markers covering chromosome 5 were used in loss of heterozygosity (LOH) analysis of breast tumors from BRCA1 (n = 42) and BRCA2 mutation carriers (n = 67), as well as in sporadic cases (n = 65). High-density array CGH was also used to map chromosome 5 imbalance in 10 BRCA1 tumors. A high LOH frequency was found in BRCA1 tumors (range 19-82%), as compared to BRCA2 and sporadic tumors (ranges 11-44% and 7-43%, respectively). In all, 11 distinct chromosome 5 regions with LOH were observed, the most frequent being 5q35.3 (82%), 5q14.2 (71%) and 5q33.1 (69%) in BRCA1 tumors; 5q35.3 (44%), 5q31.3 (43%) and 5q13.3 (43%) in BRCA2 tumors and 5q31.3 (43%) in sporadic tumors. Array CGH analysis confirmed the very high frequency of 5q deletions, including candidate tumor suppressor genes such as XRCC4, RAD50, RASA1, APC and PPP2R2B. In addition, 2 distinct homozygous deletions were identified, spanning regions of 0.7-1.5 Mbp on 5q12.1 and 5q12.3-q13.1, respectively. These regions include only a few genes, most notably BRCC3/DEPDC1B (pleckstrin/G protein interacting and RhoGAP domains) and PIK3R1 (PI3 kinase P85 regulatory subunit). Significant association (p < or = 0.05) was found between LOH at certain 5q regions and factors of poor prognosis, including negative estrogen and progesterone receptor status, high grade, large tumor size and high portion of cells in S-phase. In conclusion, our results confirm a very high prevalence of chromosome 5q alterations in BRCA1 tumors, pinpointing new regions and genes that should be further investigated.