The RAD51 135 G>C polymorphism modifies breast cancer and ovarian cancer risk in Polish BRCA1 mutation carriers.

Breast and ovarian cancer penetrance in BRCA1 mutation carriers is estimated to be between 15% and 80% by age 70 years. At present, it is not possible to predict with any certainty who is most likely to develop disease or which age it will develop. Previous studies have tried to correlate the sites of BRCA1 mutations with disease risk; however, the results have not yielded any definitive association. An alternative explanation that could account for differences in the penetrance of BRCA1 mutations is the action of modifier genes. In this study, we have investigated the role of the RAD51_135_G>C polymorphism in breast and ovarian cancer case-control populations of Polish women who have been matched for BRCA1 mutation and year of birth. The results reveal that women who harbor the C allele have almost twice the reduction in breast and ovarian cancer risk compared with women who harbor only the G allele. These findings suggest that the effect of the RAD51 C allele is an important risk modifier for malignancies occurring on a background of BRCA1 mutations. In addition, we were able to show that the site of the BRCA1 mutation does not influence the effect of the RAD51 C allele, indicating that this polymorphism contributes to prevention of disease in BRCA1 carriers. In conclusion, the RAD51 C allele seems to protect against both breast and ovarian cancer in women harboring BRCA1 mutations.     

Breast cancer risk among male BRCA1 and BRCA2 mutation carriers

Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).     

A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.     

Frequency of 5382insC mutation of the BRCA1 gene

The paper assesses c5266dupC (5382insC) mutation incidence among breast cancer patients, residents of the Republic of Bashkorstan and Tyumen Region. It appeared as high as 4%.     

High frequency of BRCA1 5382insC mutation in Russian breast cancer patients

BRCA1 5382insC variant was repeatedly detected in Jewish breast cancer (BC) families residing in USA and Israel as well as in non-Jewish familial BC patients from Poland, Latvia, Hungary, Russia and some other European countries. However, the distribution of BRCA1 5382insC mutation in unselected BC cases vs. controls has been systematically investigated mainly in Ashkenazi Jews. Here we applied a case-control study design in order to evaluate the impact of BRCA1 5382insC allele on BC incidence in St Petersburg, Russia. High frequency of the BRCA1 5382insC allele was detected in a group of bilateral breast cancer patients (10.4%; 15/144). Randomly selected unilateral BC cases demonstrated noticeable occurrence of BRCA1 5382insC mutation as well (3.7%; 32/857), with evident excess of the carriers in the early-onset (40 years) category (6.1%; 6/99) and in patients reporting breast and/or ovarian tumours in first-degree relatives (11.3%; 11/97). Strikingly, none of 478 middle-aged controls and 344 elderly tumour-free women carried the 5382insC variant. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Russia, that may justify an extended BRCA1 5382insC testing within this population.     

A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers

Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The RAD51 gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the BRCA1 and BRCA2 gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP), RAD51-135g-->c, in the 5' untranslated region of the gene has been found to elevate breast cancer (BC) risk among BRCA2 carriers. We genotyped 309 BRCA1/2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the RAD51-135g-->c SNP. Risk analyses were conducted using COX proportional hazard models for the BRCA1/2 carriers and simple logistic regression analysis for the noncarrier case-control population. BRCA2 carriers were also studied using logistic regression and Kaplan-Meier survival analyses. The estimated BC hazard ratio (HR) for RAD51-135c carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85-1.90, P=0.23) for BRCA1/2 carriers, and 2.09 (95% CI 1.04-4.18, P=0.04) when the analysis was restricted to BRCA2 carriers. The median BC age was younger in BCRA2-RAD51-135c carriers (45 (95% CI 36-54) vs 52 years (95% CI 48-56), P=0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5-58.8, P=0.163). In noncarrier BC cases, carrying RAD51-135c was not associated with BC risk (0.97; 95% CI 0.47-2.00). These results indicate significantly elevated risk for BC in carriers of BRCA2 mutations who also carry a RAD51-135c allele. In BRCA1 carriers and noncarriers, no effect for this SNP was found.     

Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers.

BACKGROUND: The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. METHODS: We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. RESULTS: We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. CONCLUSIONS: Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.     

Frequency of 5382insC mutation of BRCA1 gene among breast cancer patients: an experience from Eastern India

The incidence of breast cancer in India is on the rise and is rapidly becoming the number one cancer in females pushing the cervical cancer to the second position. The mutations in two breast cancer susceptibility genes, BRCA1 and BRCA2, are frequently associated with familial breast cancer. The main objective of the study was to determine the frequency of the mutation 5382insC in BRCA1 of eastern Indian breast cancer patients and also study the hormonal receptor status and histopathology of the patients. Altogether 92 patients affected with breast cancer were included in this study. ARMS-PCR based amplification was used to detect the presence of mutation. The mutations were considered only after pedigree analysis. Out of 92 patients (age range: 20–77 years) with family history (57 individuals) and without family history (35 individuals) were screened. Fifty controls have been systematically investigated. Seven patients and two family members were found to be carriers of 5382insC mutation in BRCA1 gene. We have found 42.64 % ER^?/PR^? cancer and 20.58 % triple negative cancer. Invasive ductal carcinoma is the most common histology among the investigated individuals. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Eastern India, which may justify an extended BRCA1 5382insC testing within this patient population. We found HER-2/neu negativity and BRCA1 positivity associated with familial breast cancer. From the hospital’s patient history, it was revealed that the age of menarche plays an important role in development of breast cancer.     

中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌风险的研究

背景与目的：BRCA1和BRCA2基因突变携带者终生患乳腺癌和卵巢癌的风险显著增高。通过遗传咨询,突变携带者可采取适当的措施来降低相应肿瘤的发生风险。目前,相关的报道几乎均为白种人,尚缺乏中国人群的资料。该研究旨在探索中国汉族人群中BRCA1和BRCA2基因突变携带者患乳腺癌的风险。方法：回顾20个经基因检测证实携带BRCA1或BRCA2致病性基因突变的汉族乳腺癌高风险家系。利用Kaplan-Meier生存分析法对女性BRCA1/2基因突变携带者单侧乳腺癌及对侧乳腺癌的累积发病风险进行估算。结果：BRCA1和BRCA2基因突变携带者70岁时单侧乳腺癌的累积发病风险(外显率)分别为67.2%(sx 0.100)和76.8%(sx 0.079)。与BRCA1不同的是,BRCA2基因突变携带者70岁后乳腺癌累积发病率继续增加,到80岁时达93.1%。BRCA1/2基因突变携带者对侧乳腺癌10年和20年的累积发病率分别为19.4%(sx 0.089)和50.3%(sx 0.155)。结论：中国汉族人群中BRCA1和BRCA2基因突变携带者具有很高的乳腺癌发病风险。因而对中国高风险人群进行BRCA1/2基因突变检测具有重要临床意义。     

Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers

Introduction

Increasing parity and age at first full-term pregnancy are established risk factors for breast cancer in the general population. However, their effects among BRCA1 and BRCA2 mutation carriers is still under debate. We used retrospective data on BRCA1 and BRCA2 mutation carriers from the UK to assess the effects of parity-related variables on breast cancer risk.

Methods

The data set included 457 mutation carriers who developed breast cancer (cases) and 332 healthy mutation carriers (controls), ascertained through families seen in genetic clinics. Hazard ratios were estimated by using a weighted cohort approach.

Results

Parous BRCA1 and BRCA2 mutation carriers were at a significantly lower risk of developing breast cancer (hazard ratio 0.54, 95% confidence interval 0.37 to 0.81; p = 0.002). The protective effect was observed only among carriers who were older than 40 years. Increasing age at first live birth was associated with an increased breast cancer risk among BRCA2 mutation carriers (p trend = 0.002) but not BRCA1 carriers. However, the analysis by age at first live birth was based on small numbers.

Conclusion

The results suggest that the relative risks of breast cancer associated with parity among BRCA1 and BRCA2 mutation carriers may be similar to those in the general population and that reproductive history may be used to improve risk prediction in carriers.     

BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland.

A restriction site-generating polymerase chain reaction (RG-PCR) assay was developed to detect the BRCA1 5382insC mutation that has been reported in multiple, apparently unrelated breast/ovarian carcinoma families. The assay has been used to screen tumour DNA from 250 breast cancer patients (aged 19-86 years) and from 80 ovarian cancer patients (aged 25-90 years) in a local population of patients with no known family history. Altogether, 0/80 (0%) ovarian and 1/250 (0.4%) breast tumour DNAs were found to have the 5382insC mutation. The sole positive case was a 26-year-old woman (BC185) with no known family history. One of the reasons for carrying out this analysis was that the 5382insC mutation had previously been shown to segregate with the disease in a very large Scottish ''West Lothian'' kindred having breast/ovarian carcinoma. To investigate whether this apparently isolated case and the known family might be related, haplotypes for the markers D17S855, D17S1322, D17S1323 and D17S1327 were analysed. The mutant haplotype in the large kindred was identical to that reported in all other 5382insC mutation families for all markers with the exception of D17S1327. This implies that there has been a recombination event at the telomeric end of common ancestral haplotype in this family. Since the isolated case we identified carries the ''complete'' common haplotype, it is unlikely that she is closely related to the West Lothian family.     

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.     

Breast cancer risk after age 60 among BRCA1 and BRCA2 mutation carriers

Purpose

It is not known whether the risk of breast cancer among BRCA1 and BRCA2 mutation carriers after age 60 is high enough to justify intensive screening or prophylactic surgery. Thus, we conducted a prospective analysis of breast cancer risk in BRCA1 and BRCA2 mutation carriers from age 60 until age 80.

Methods

Subjects had no history of cancer and both breasts intact at age 60 (n?=?699). Women were followed until a breast cancer diagnosis, prophylactic bilateral mastectomy or death. We calculated the annual cancer rate and cumulative incidence of breast cancer (invasive and in situ) from age 60 to age 80. We assessed the associations between hormone replacement therapy, family history of breast cancer and bilateral oophorectomy and breast cancer risk.

Results

Over a mean follow-up of 7.9 years, 61 invasive and 20 in situ breast cancers were diagnosed in the cohort. The mean annual rate of invasive breast cancer was 1.8% for BRCA1 mutation carriers and 1.7% for BRCA2 mutation carriers. The cumulative risk of invasive breast cancer from age 60 to 80 was 20.1% for women with a BRCA1 mutation and was 17.3% for women with a BRCA2 mutation. Hormone replacement therapy, family history and oophorectomy were not associated with breast cancer risk.

Conclusions

Findings from this large prospective study indicate that the risk of developing breast cancer remains high after age 60 in both BRCA1 and BRCA2 mutation carriers. These findings warrant further evaluation of the role of breast cancer screening in older mutation carriers.

     

Breast cancer risk in BRCA1 and BRCA2 mutation carriers and polyglutamine repeat length in the AIB1 gene

Marked variation in phenotypic expression among BRCA1 and BRCA2 mutation carriers may be partly explained by modifier genes that influence mutation penetrance. Variation in CAG/CAA repeat lengths coding for stretches of glutamines in the C-terminus of the AIB1 protein (amplified in breast cancer 1, a steroid receptor coactivator) has been proposed to modify the breast cancer risk in women carrying germline BRCA1 mutations. We genotyped the AIB1 repeat length polymorphism from the genomic DNA of a group of 851 BRCA1 and 324 BRCA2 female germline mutation carriers to estimate an association with breast cancer risk modification. Hazard ratios (HR) were calculated using a Cox proportional hazards model. For BRCA1 and BRCA2 mutation carriers, analyzed separately and together, we found that women who carried alleles with 28 or more polyglutamine repeats had no increased risk of breast cancer compared to those who carried alleles with fewer repeats (HR for BRCA1/2 carriers = 0.88, 95% CI [confidence interval] = 0.75-1.04). Analyzing average repeat lengths as a continuous variable showed no excess risk of breast cancer (BC) in BRCA1 or BRCA2 mutation carriers (HR for average repeat length in BRCA1/2 carriers = 1.01, 95% CI = 0.92-1.11). These results strongly suggest that contrary to previous studies, there is no significant effect of AIB1 genetic variation on BC risk in BRCA1 mutation carriers and provide an indication that there is also no strong risk modification in BRCA2 carriers.     

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.     

Breast cancer risk following bilateral oophorectomy in BRCA1 and BRCA2 mutation carriers: an international case-control study.

PURPOSE: The purpose of this study was to estimate the extent of protection offered against breast cancer by prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations and to determine to what extent risk reduction varies with age at oophorectomy, age at diagnosis, and time elapsed since surgery. PATIENTS AND METHODS: We analyzed 1,439 patients with breast cancer and 1,866 matched controls derived from a registry of BRCA1 and BRCA2 carriers. We estimated odds ratios (ORs) of breast cancer for having had a bilateral oophorectomy, using conditional logistic regression, matched for parity and for oral contraceptive use. RESULTS: A previous history of oophorectomy was associated with a significant reduction in breast cancer risk of 56% for BRCA1 carriers (OR = 0.44; 95% CI, 0.29 to 0.66) and of 46% for BRCA2 carriers (OR = 0.57; 95% CI, 0.28 to 1.15). The risk reduction was greater if the oophorectomy was performed before age 40 (OR = 0.36; 95% CI, 0.20 to 0.64 for BRCA1 carriers) than after age 40 (OR = 0.53; 95% CI, 0.30 to 0.91). The protective effect was evident for 15 years post-oophorectomy (OR = 0.39; 95% CI, 0.26 to 0.57). CONCLUSION: Oophorectomy is an effective means of reducing the risk of breast cancer in carriers of BRCA1 mutations. The data suggest oophorectomy is protective in BRCA2 carriers as well, but needs to be confirmed in other studies.     

Germ line BRCA1 & BRCA2 mutations in Greek breast/ovarian cancer families: 5382insC is the most frequent mutation observed

BRCA1 and BRCA2 genes were screened for loss-of-function mutations in a series of 85 patients having at least one first- or second-degree relative affected by breast and/or ovarian cancer. All BRCA1 exons and BRCA2 exons 10 and 11 were screened with a combination of methods including SSCP, PTT and direct sequencing. We have found disease-associated mutations in 14 families (16.5%), eleven in BRCA1 and three in BRCA2. The known founder mutation 5382insC of BRCA1 was identified in seven unrelated families. The other mutations identified include the non-sense R1751X, the splice junction variant 5586G>A of BRCA1 and three frameshifts, 2024del5, 3034del4, and 6631del5, of BRCA2. Nine out of these 14 families had a family history of three or more breast/ovarian cancer cases. A large number of polymorphic or unclassified variants is also reported. Combined with our previously published data 5382insC was found in nine out of 20 families (45%), suggesting that this mutation may represent a common founder mutation in the Greek population.