Clinical significance of large rearrangements in BRCA1 and BRCA2

BACKGROUND:

Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer.

METHODS:

Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as “high‐risk” if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. “Elective” patients did not meet the high‐risk criteria, but underwent LR testing as ordered by the referring health care provider.

RESULTS:

Overall BRCA1/2 mutation prevalence among high‐risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high‐risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high‐risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients.

CONCLUSIONS:

Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. Cancer 2012. © 2012 American Cancer Society.     

Screening for common mutations in BRCA1 and BRCA2 genes: interest in genetic testing of Tunisian families with breast and/or ovarian cancer

BackgroundIn the Tunisian population, as yet a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer. These mutations are located in a few exons of BRCA1/2. The aim of the present study was to search for these mutations in 66 unrelated patients with hereditary breast and/or ovarian cancer in order to assess the interest in such a targeted approach for genetic testing in Tunisia.Materials and MethodsBlood specimens from the 66 Tunisian patients, with family history of breast and/or ovarian cancer, were collected at the Salah Azaiz Cancer Institute of Tunis. The exons 5, 20 and part of exon 11 of BRCA1 as well as part of exons 10 and 11 of BRCA2 were analyzed by Sanger sequencing.Results12 patients had deleterious mutations in the BRCA1 or BRCA2 genes (18%), including a novel frame-shift mutation of BRCA1 (c.3751dup; 3780insT). Four distinct BRCA1 mutations were detected eight patients: c.5266dup (5382insC) and c.211dup (330insA) each in three patients, c.3751dup (3870insT) and c.4041_4042del (4160delAG) each in one patient. The four remaining cases all carried the same BRCA2 mutation, c.1310_1313del (1538delAAGA). Besides these deleterious mutations, eight polymorphisms and unclassified variants were detected, one of them being never reported (BRCA1c.3030T>G, p.Pro1010Pro).ConclusionIn this study, we show that targeting relevant exons in BRCA1 and BRCA2 genes allows detection of a substantial percentage of mutations in the Tunisian population. Therefore such an approach may be of interest in genetic testing of high-risk breast and ovarian cancer families in Tunisia.     

BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening

From February 1996 to April 1998, 2967 women received screening for breast cancer in the gynecologic ambulatory practice of the Hokkaido University Hospital. In 116 Japanese women with epithelial ovarian cancer, mutation analysis of BRCA1 exon 11 in genomic DNA was performed by the stop codon (SC) assay and DNA sequence analysis. Clinicopathological factors were also investigated in these patients. The aim of this study was to examine the advantages of performing BRCA1 mutation testing for ovarian cancer patients during breast cancer screening. We achieved a high detection rate (6.0) of patients with germline mutations in BRCA1. The high frequencies of breast ovarian cancer syndrome, serous adenocarcinoma, high histological grades, advanced FIGO stages, and breast cancer as double cancer were found to be characteristic of ovarian cancer with germline mutations in BRCA1. These characteristics may assist physicians in selecting BRCA1 mutation testing for ovarian cancer patients. The mean age at diagnosis of ovarian cancer was 51.0 and 51.2 years in the groups with and without mutation, respectively, and no difference was found in age at diagnosis. All of the nine living female mutation carriers were offered the options of increased surveillance or prophylactic surgery, and all chose the former. We have performed breast cancer screening and/or ovarian cancer screening every 6 months for these carriers. This may allow another advantage in establishing a relationship of mutual trust with a patient from a series of responsible follow-ups.     

Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients

Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (< or =30 years) and was 9.0% for single cases of early-onset ovarian cancer (< or =45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan.     

Molecular analysis of the BRCA1 and BRCA2 genes in 32 breast and/or ovarian cancer Spanish families

It is estimated that about 5-10% of breast cancer cases may be due to inherited predisposition. Until now, two main susceptibility genes have been identified: BRCA1 and BRCA2. The first linkage and mutational studies suggested that mutations in these two genes would account for the majority of high-risk breast cancer families, but recent studies show how the proportion of families due to BRCA1 or BRCA2 mutations strongly depends on the population and the types of family analyzed. It is now clear that, in the context of families with a modest cancer profile, which are the most commonly found in the clinical practice, the percentage of mutations found is much lower than that suggested by the first studies. In the present study, we analyze a group of 32 Spanish families, which contained at least three cases of female breast cancer (at least one of them diagnosed before the age of 50 years), for the presence of mutations in the BRCA genes. The total proportion of mutations was low (25%), although the percentage of mutations in the BRCA1 and BRCA2 genes was higher, considering the breast and ovarian cancer families and the male breast cancer families respectively. Our results are in agreement with the idea that a great proportion of moderate-risk cancer families could be due to low penetrance susceptibility genes distinct from BRCA1 or BRCA2.     

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.     

BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients

To date, BRCA1 and BRCA2 mutations in breast and/or ovarian patients have not been characterized in the Turkish population. We investigated the presence of BRCA mutations in 53 individuals with a personal and family history of breast and/or ovarian cancer, and 52 individuals with a personal history of breast cancer diagnosed below age 50 without additional family history. We have identified 11 mutations (nine BRCA1 and two BRCA2) using combined techniques involving protein truncation test, direct sequencing and heteroduplex analysis. We found eight out of 53 patients (15.1%) with a family history to carry BRCA gene mutations (seven BRCA1 and one BRCA2). Of these, four were found in 43 families presenting only breast cancer histories, and four were found in families presenting ovarian cancer with or without breast cancer. We also demonstrated two BRCA1 and one BRCA2 mutations in three out of 52 (5.8%) early-onset breast cancer cases without additional family history. Three of nine BRCA1 and both BRCA2 mutations detected in this study were not reported previously. These mutations may be specific to the Turkish population. The BRCA1 5382insC mutation, specific to Ashkenazi and Russian populations, was found twice in our study group, representing a possible founder mutation in the Turkish population.     

HBOC syndrome with an uncharacterized variant in the BRCA1 gene in a patient diagnosed with endometrial cancer after surgery for bilateral breast cancer: A case report

The association between endometrial cancer and the BRCA1 and BRCA2 genes is not fully understood, and the risk elevation of endometrial cancer in patients with hereditary breast and ovarian cancer (HBOC) is not understood. The present report examines a rare case of HBOC syndrome and an uncharacterized variant of the BRCA1 gene in a patient diagnosed with endometrial cancer. A 46-year-old woman, gravida 1 para 1, was referred to Wakayama Medical University Hospital (Wakayama, Japan) because positron emission tomography/computed tomography (PET/CT) showed a high FDG uptake in the corpus uteri and the left ovary. PET/CT was performed just after mastectomy for left-sided breast cancer (triple negative). The patient had previously undergone partial mastectomy for right-sided breast cancer (triple negative) and was treated with radiation therapy to the right residual breast when she was 39 years old. Laparoscopic hysterectomy and bilateral adnexectomy were performed, and the histological diagnosis was endometrioid carcinoma, grade 1. Her germline BRCA status was tested by blood examination and the result was ‘{"type":"entrez-nucleotide","attrs":{"text":"NM_007294.4","term_id":"1732746264","term_text":"NM_007294.4"}}NM_007294.4(BRCA1):c.49G>C (p.Ala17Pro)’. The variant was evaluated as ‘likely pathogenic’. The patient was diagnosed with HBOC syndrome and endometrial cancer, pT1ANxM0. The patient had no recurrence of breast or endometrial cancer 16 months after gynecologic surgery.     

Improved survival in BRCA2 carriers with ovarian cancer

Objectives The objective of this study was to investigate survival of ovarian cancer patients with BRCA1 and BRCA2 mutations compared to those without mutations in a population-based sample of incident epithelial ovarian cancer cases. Methods Follow-up for vital status was performed on a population-based sample of 232 women with incident epithelial ovarian cancer recruited between December 13, 2000 and September 30, 2003 in the Tampa Bay area. Survival analysis using Cox regression was performed on (1) all 232 cases and (2) the 209 invasive epithelial ovarian cancer cases. Results of the two analyses were similar, thus data involving the 209 invasive epithelial cancer cases are presented, as this was judged to be more clinically relevant. Results In the multivariate analysis, BRCA status and stage were statistically significant, and were adjusted for in the survival analysis model. The Kaplan–Meier method estimated expected survival at 4 years of 83% of BRCA2 carriers compared to 37% of BRCA1 carriers and 12% of non-carriers. There was a statistically significant difference between BRCA2 carriers and non-carriers (p = 0.013). No statistically significant survival differences were seen for BRCA1 carriers when compared with either BRCA2 carriers or non-carriers. Conclusion These data suggest that BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers. The etiology of this possible survival advantage is currently unknown. Larger studies are needed to confirm these results and to clarify their etiology and clinical significance. Article precis Based on a population-based sample of 232 ovarian cancer patients, BRCA2 mutation carriers with ovarian cancer may have better survival than BRCA1 carriers and non-carriers.     

BRCA2 germ-line mutations in Spanish male breast cancer patients

Background:Mutations in the BRCA2 gene account for the majorityof the families with male and female breast cancer cases, and a number ofBRCA2 mutations have been reported in males with breast cancer. The aim ofthis study was to characterise BRCA2 germ-line mutations in Spanish malebreast cancer patients. Patients and methods:We screened DNA from 11 affected men and 6women with breast cancer (BC) who had an affected male relative (father orbrother). Exons 2–9 and 12–27 were screened by SSCP, and exons 10and 11 were screened by PTT. PCR products with a variant band were sequenced. Results:Three BRCA2 frameshift mutations were identified(17.6%): the 3374delA in codon 1049 (exon 11), 6857delAA in codon 2010(exon 11), and 9254delATCAT in codon 3009 (exon 23). These mutations werepresent in patients with affected first-degree relatives (3 of 9, 33%).The proportion of male patients with a family history of BC in at least onefirst-degree relative was 53%. Conclusions:There is an association between BRCA2 mutations andmale breast cancer, especially in those with a family history of BC. The highprevalence of BRCA2 mutations among males should be considered when estimatingrisk for female relatives. All new male cases of BC should be regarded asbeing possibly inherited and should be fully investigated.     

家族性乳腺癌患者及家系成员乳腺癌易感基因携带情况调查

目的 乳腺癌易感基因1(breast cancer susceptibility gene 1,BRCA1)和BRCA2基因已经证实与家族性乳腺癌密切相关.本研究旨在分析中国汉族家族性乳腺癌患者及家系成员BRCA1和BRCA2突变特征及携带情况.方法 收集2013 12-02-2015-06-08军事医学科学院附属医院确诊的中国汉族家族性乳腺癌患者55例及家系成员48名,共计103例样本.柚取外周静脉血提取DNA,应用聚合酶链反应(polymerase chain reaction,PCR) DNA直接测序方法检测BRCA1和BRCA2基因全编码外显子序列.结果 55例家族性乳腺癌患者中发现5个BRCA基因致病性突变位点,1个突变位点乳腺癌信息库中见报道(BRCA1:4730insG),4个为新发现突变位点(BRCA1:1937insC,4538insAG;BRCA2:1382delA,2820delA).家族性乳腺癌患者BRCA1/2突变率为9.09％(BRCA1,5.45％;BRCA2,3.64％),其中三阴性乳腺癌患者突变率为22.22％(x2 =1.99,P=0.20),早发性乳腺癌患者(≤35岁)突变率为20.00％,x2=0.79,P=0.39.48例家系成员检测到3个新发现突变位点(BRCA1:1370insA,3459insA;BRCA2:6502insT),总突变率为6.25％.结论 中国汉族家族性乳腺癌患者BRCA基因突变率显著低于国外,应重点关注有家族史的三阴性乳腺癌患者和早发性乳腺癌患者;家系成员中发现BRCA基因致病性突变,家系成员突变率和发病风险有待进一步研究,应引起重视.     

Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland

Summary It has been estimated that the lifetime risk of breast cancer among women who inherit a BRCA1 or BRCA2 mutation is as high as 80%, and the risk estimates for ovarian cancer range from 15 to 40%. Several environmental and lifestyle factors are believed to contribute to the development of breast cancer in the general population and it is of interest to establish if these factors operate among mutation carriers as well. To evaluate the effects of age of menarche, parity, breast-feeding, oophorectomy and oral contraceptive use, as well as smoking and coffee consumption, on the risks of breast and ovarian cancer, we conducted a matched case–control study of Polish women with BRCA1 mutations. There were 348 breast cancer patients, 150 ovarian cancer patients and similar numbers of age-matched controls. BRCA1 carriers with late age of menarche, lower parity and long-term breast-feeding were less likely to develop breast cancer. Oral contraceptives protected against ovarian cancer.     

The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers

BACKGROUND:

The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2‐associated epithelial ovarian cancer (OC).

METHODS:

From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA‐associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected. The control groups consisted of unaffected BRCA mutation carriers (n = 351) or mutation carriers who had a previous unilateral BC (n = 294), respectively. The risks of PBC and CBC were calculated using the Kaplan‐Meier survival method with death considered as a competing risk event.

RESULTS:

Women with BRCA‐associated OC had lower 2‐year, 5‐year, and 10‐year risks of PBC (3%, 6%, and 11%, respectively) compared with unaffected mutation carriers (6%, 16%, and 28%, respectively; P = .03), although they had a considerably higher mortality rate at similar time points (13%, 33%, and 61%, respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA mutation carriers with a previous unilateral BC, the 2‐year, 5‐year, and 10‐year risks of CBC were nonsignificantly lower in patients with OC than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and 34%, respectively; P = .06), whereas the mortality rate was higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%, and 21%, respectively; P < .001).

CONCLUSIONS:

Patients with BRCA‐associated OC had a lower risk of developing a subsequent PBC or CBC than mutation carriers without OC, whereas the risk of dying from OC was greater than the risk of developing BC. These data may facilitate more tailored counseling for this patient subgroup, although confirmative studies are warranted. Cancer 2013. © 2012 American Cancer Society.     

Survival of breast cancer patients in BRCA1, BRCA2, and non-BRCA1/2 breast cancer families: a relative survival analysis from Finland.

Reports on the prognosis of familial breast cancer patients have been contradictory. True differences in survival, if they exist, would have important implications for genetic counselling and in treatment of hereditary breast cancer. We assessed the survival rates of 359 familial breast cancer patients (32 patients from BRCA1-positive families, 43 patients from BRCA2-positive families and 284 patients from BRCA1/2-negative breast cancer families) and compared them with those of all other breast cancer patients diagnosed in Finland from 1953 to 1995 (n = 59,517). Cumulative relative survival rates (RSR) were calculated by dividing the observed survival rates by the expected ones. The expected survival rates were derived from the sex, age and calendar year specific life-tables of the general population in Finland. Regression model was used to calculate relative excess risk of death (RR) and to adjust for confounding factors. The overall 5-year RSR of the patients in the BRCA1 families, BRCA2 families, non-BRCA1/2 families and among sporadic cases was 67%, 77%, 86% and 78%, respectively. However, we found no significant differences in the RR adjusted for age, stage and year of diagnosis between the different familial patient groups or the general breast cancer population. In the BRCA1 families the RR tended to be higher [RR 1.30, 95% confidence interval (CI) 0.63--2.70] and in the BRCA2 families lower (RR 0.78, 95% CI 0.39--1.57) than among the general breast cancer patient population. The RR among patients in the non-BRCA1/2 families did not differ from that of the general patient population.     

Cancer risks in women with 2 breast or ovarian cancers: clues to genetic cancer susceptibility.

Women diagnosed with 2 cancers of the breast and/or ovary are at higher risk of developing subsequent cancers. Using registrations from the Thames Cancer Registry, we quantified the risks at different cancer sites. Increased risks were found for cancers that are part of the BRCA1 and BRCA2 tumour spectrum: oropharyngeal cancer, malignant melanoma of the skin (BRCA2) and colon cancer (BRCA1). We also found significantly increased risks of myeloid leukaemia (probably due to radiotherapy) and of cancer of the corpus uteri (which may be due to hormonal factors).     

Earlier age of onset of BRCA mutation-related cancers in subsequent generations

BACKGROUND:

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations.

METHODS:

Of the 132 BRCA‐positive women with breast cancer who participated in a high‐risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA‐related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families.

RESULTS:

The median age of cancer diagnosis was 42 years (range, 28‐55 years) in Gen 2 and 48 years (range, 30‐72 years) in Gen 1 (P < .001). In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years (P < .0001). Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer‐identified and ovarian cancer‐identified families.

CONCLUSIONS:

Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA‐related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages. Cancer 2011. © 2011 American Cancer Society.     

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5+3A>G, 2478-2479insG, E1221X and BRCA2 IVS6+1G>A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (P<0.001), and the presence of a relative with ovarian cancer (P<0.0001) or multiple primary breast cancers (P=0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P=0.002). Mutations in the 5'-end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast-ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families.