Histopathological features of breast tumours in <Emphasis Type="Italic">BRCA1</Emphasis>, <Emphasis Type="Italic">BRCA2</Emphasis> and mutation-negative breast cancer families

Introduction

Histopathological features of BRCA1 and BRCA2 tumours have previously been characterised and compared with unselected breast tumours; however, familial non-BRCA1/2 tumours are less well known. The aim of this study was to characterise familial non-BRCA1/2 tumours and to evaluate routine immunohistochemical and pathological markers that could help us to further distinguish families carrying BRCA1/2 mutations from other breast cancer families.

Methods

Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases.

Results

BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups.

Conclusions

BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker.

     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in a population-based study of male breast cancer

Background

The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear.

Methods

We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk.

Results

Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives.

Conclusion

These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found.

     

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

Background

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

Methods

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

Results

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

Conclusions

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

Novel mutations in the <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>genes in Iranian women with early-onset breast cancer

Background  

Breast cancer is the most common female malignancy and a major cause of death in middle-aged women. So far, germline mutations in the BRCA1 and BRCA2 genes in patients with early-onset breast and/or ovarian cancer have not been identified within the Iranian population.     

Genetic variants of <Emphasis Type="Italic">CYP3A5</Emphasis>, <Emphasis Type="Italic">CYP2D6</Emphasis>, <Emphasis Type="Italic">SULT1A1</Emphasis>, <Emphasis Type="Italic">UGT2B15</Emphasis> and tamoxifen response in postmenopausal patients with breast cancer

Introduction  

Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.     

Age at first full-term birth and breast cancer risk in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation carriers

Purpose

Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

Methods

We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6–9 months post-baseline.

Results

Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21).

Conclusions

Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

     

High prevalence of deleterious <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutations in arab breast and ovarian cancer patients

Purpose

The BRCA1 and BRCA2 (BRCA) genes are heavily involved in mammalian cell DNA repair processes. Germline pathogenic mutations in BRCA increase the lifetime risk of developing breast and/or ovarian cancer in women. In the Arabian Peninsula, most breast and ovarian cancers are diagnosed as early-onset cases, some of which may be due to germline variants in BRCA genes. To identify the BRCA germline mutation frequency and spectrum in the Arab breast and ovarian cancers, we have sequenced the protein-coding exons of these genes.

Methods

All BRCA coding exons were sequenced using genomic DNA isolated from lymphocytes in 173 Arab breast and ovarian cancer patients by a massively parallel sequencing technology and verified by Sanger sequencing.

Results

We identified a total of 17 distinct pathogenic mutations, of which four were novel, in 28 patients; nine out of 108 breast (8.3%) and 19 out of 65 ovarian cancer (29.2%) patients. Thirteen of the 17 mutations were detected in BRCA1 and four mutations were found in BRCA2 gene. Four pathogenic BRCA1 mutations (c.1140dupG, c.4136_4137delCT, c.5095C>T, and c.5530delC) accounted for 54% of all the mutations detected in our patient cohort. Additionally, we identified a likely pathogenic BRCA1 missense variant in two of 108 breast (1.9%) and a BRCA2 missense variant in one of 65 ovarian cancer (1.5%) patients.

Conclusions

The overall frequencies of the BRCA germline mutations were 10.2% in breast and 30.7% in ovarian cancer patients. These data shed new light into the prevalence of BRCA mutations in the Arab women population.

     

Young age at first pregnancy does protect against early onset breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation carriers

Purpose

Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.

Methods

Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan–Meier analyses were performed.

Results

2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30–39 years. Kaplan–Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).

Conclusions

The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

     

<Emphasis Type="Italic">PALB2</Emphasis> analysis in <Emphasis Type="Italic">BRCA2</Emphasis>-like families

BRCA2 and PALB2 function together in the Fanconi anemia (FA)–Breast Cancer (BRCA) pathway. Mono-allelic and bi-allelic BRCA2 and PALB2 mutation carriers share many clinical characteristics. Mono-allelic germline mutations of BRCA2 and PALB2 are risk alleles of female breast cancer and have also been reported in familial pancreatic cancer, and bi-allelic mutations cause a severe form of Fanconi anemia. In view of these similarities, we investigated whether the prevalence of PALB2 mutations was increased in breast cancer families with the occurrence of BRCA2 associated tumours other than female breast cancer. PALB2 mutation analysis was performed in 110 non-BRCA1/2 cancer patients: (a) 53 ovarian cancer patients from female breast-and/or ovarian cancer families; (b) 45 breast cancer patients with a first or second degree relative with pancreatic cancer; and (c) 12 male breast cancer patients from female breast cancer families. One truncating PALB2 mutation, c.509_510delGA, resulting in p.Arg170X, was found in a male breast cancer patient. We conclude that germline mutations of PALB2 do not significantly contribute to cancer risk in non-BRCA1/2 cancer families with at least one patient with ovarian cancer, male breast cancer, and/or pancreatic cancer.     

The incidence of cardiomyopathy in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation carriers after anthracycline-based adjuvant chemotherapy

Purpose

Breast cancer remains the fourth-leading cause of death in the United States. Nearly 10% of breast cancers are hereditary, with deleterious mutations in BRCA1 and BRCA2 genes being the leading cause. Anthracycline chemotherapy, used commonly for breast cancer, carries cardiotoxicity risk. Recent studies demonstrated anthracycline-induced cardiac failure in homozygous BRCA2-deficient mice and increased rates of heart failure in homozygous BRCA1-deficient mice following ischemic insult. Therefore, we conducted a retrospective matched cohort study to determine the rates of anthracycline-induced cardiomyopathy in breast cancer patients with germline mutation in BRCA1 or BRCA2 genes compared to age-matched patients without a BRCA1 or BRCA2 gene mutation.

Methods

The primary endpoint was to determine the rate of cardiomyopathy defined as either congestive heart failure or asymptomatic decline in ejection fraction to <50%. A total of 102 breast cancer patients who were BRCA gene mutation carriers (55 BRCA1, 45 BRCA2, and two with both), who received anthracycline-based chemotherapy were compared to a matched cohort of breast cancer patients with wild-type BRCA gene status.

Results

We found a 4.9% rate of cardiomyopathy in the BRCA mutation carriers and 5.2% in the matched controls (p = 0.99). Cox proportional hazards model showed that only trastuzumab and hypertension were significantly associated with the development of cardiomyopathy in both groups (p < 0.05).

Conclusions

Given the limitations of a retrospective study, we saw no increased risk of cardiotoxicity among breast cancer patients with BRCA1 and/or BRCA2 gene mutations treated with standard doses of anthracycline compared to the general population.

     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline variants in breast cancer patients from the Republic of Macedonia

Purpose

We aimed to establish the spectrum of BRCA1/2 mutations among the breast cancer (BC) patients from the Republic of Macedonia.

Methods

We used targeted next-generation sequencing (NGS), Sanger DNA sequencing, and multiplex ligation probe amplification analysis (MLPA) to search for point mutations and deletions/duplications involving BRCA1 and BRCA2-coding regions.

Results

We have analyzed a total of 313 BC patients, enriched for family history of cancer, early age of onset and bilateral and/or triple negative (TN) BC. A total of 26 pathogenic mutations were observed in 49 unrelated BC patients (49/313, 15.7%). BRCA2 mutations (27/49, 55.1%) were more common than BRCA1 mutations (22/49, 44.9%). We identified five novel point mutations, one in BRCA1 (c.4352_4356delA) and four in BRCA2 (c.151G>T, c.4707_4708delCA, c.7811_7814delTGTG, and c.9304_9305delG), as well as two novel deletions involving parts of the BRCA1 gene (c.81??_593+?del and c.5470??_5530+?del). The most common mutations were c.181T>G, c.5266dupC, and c.3700_3704del5 in BRCA1 and c.7879A>T, c.8317_8330del14 and c.5722_5723delCT in BRCA2 gene. Thus far, BRCA2 c.7879A>T and c.8317_8330del14 mutations have been described in several isolated cases; however, our study is the first one showing that they have a founder effect among Macedonian population. Nine recurrent mutations account for 65.3% of all of the detected mutations allowing for implementation of a fast first-step BRCA1/2 mutational screening strategy in our country.

Conclusion

This study provides a comprehensive view of known and novel BRCA1/2 mutations in BC patients from the Republic of Macedonia and contributes to the global spectrum of BRCA1/2 mutations in breast cancer.

     

Frequency of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> causative founder variants in ovarian cancer patients in South-East Poland

Background

Causative variants in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland.

Methods

We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C?>?T, c.181 T?>?G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C?>?T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT).

Results

A BRCA1 causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. BRCA2 causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T?>?G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age.

Conclusions

The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three BRCA1 mutations (c.5266dupC, c.181 T?>?G, c.676delT) should be considered a sensitive test panel.

     

Cancer incidence in relatives of a population-based set of cases of early-onset breast cancer with a known <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis>mutation status

Background  

Relatives of breast cancer cases have an increased risk of the disease. The risk increases with increasing numbers and decreasing age of onset of affected relatives. In families with a BRCA1 or a BRCA2 mutation, individual carrier status predicts the risk of breast cancer. In relatives of cases where both BRCA1 and BRCA2 mutations are excluded, the risk remains undetermined.     

The <Emphasis Type="Italic">CHEK2</Emphasis> 1100delC mutation is not present in Korean patients with breast cancer cases tested for <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutation

The germline CHEK2 1100delC mutation is a low penetrance breast cancer susceptibility allele, frequently observed in patient with family history of breast cancer and/or young age and the frequency varied according to race or ethnicity. In this study, we evaluated the significance of CHEK2 1100delC in predisposition to breast cancer by assessing its frequency in a material of 493 Korean breast cancer patients who had been screened for BRCA1 and BRCA2 mutations (42 patients had deleterious mutation of BRCA1/2). Mutation detection of CHEK2 1100delC was based upon analysis of primer extension products generated for previously amplified genomic DNA using a chip based MALDI-TOP mass spectrometry platform. After overall measurement automatically, assays which had bad peaks were checked again manually. None of the 493 Korean patients with breast cancer who were candidate for BRCA1 and BRCA2 test carried the 1100delC mutation observed in Caucasians with limited frequency. In the previous studies, we observed higher or comparable prevalence of BRCA1 and BRCA2 mutations in Korean patients with breast cancer compared to Caucasian breast cancer population. In the present study, we evaluated the role of a CHEK2 1100delC as a susceptibility mutation of breast cancer in the Korean population. However, our results suggest that this mutation is absent or may be very infrequent in Korean patients with breast cancer who have high risk of BRCA1 and BRCA2 mutation, making its screening irrelevant from the practical point view.     

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

Objectives

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

Summary of the results

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

Conclusions

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

     

High frequency of pathogenic non-founder germline mutations in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> in families with breast and ovarian cancer in a founder population

Background

Pathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population.

Methods

Fifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations.

Results

In 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations.

Conclusion

A relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.

     

Germline promoter hypermethylation in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> genes is not present in hereditary breast cancer patients

Purpose

Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome.

Methods

We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay.

Results

Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed.

Conclusions

Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assayfor the detection of germline hypermethylation as an effective pre-screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA.

     

Uptake of <Emphasis Type="Italic">BRCA 1</Emphasis>/<Emphasis Type="Italic">2</Emphasis> and oncotype DX testing by medical and surgical oncologists

Purpose

The diffusion of genomic testing is critical to the success of precision medicine, but there is limited information on oncologists’ uptake of genetic technology. We aimed to assess the frequency with which medical oncologists and surgeons order BRCA 1/2 and Oncotype DX testing for breast cancer patients.

Methods

We surveyed 732 oncologists and surgeons treating breast cancer patients. Physicians were from Florida, New York, New Jersey, and Pennsylvania, and were listed in the 2010 AMA Masterfile or identified by patients.

Results

80.6% of providers ordered BRCA 1/2 testing at least sometimes and 85.4% ordered Oncotype DX (p?=?0.01). More frequent ordering of BRCA 1/2 was associated with more positive attitudes toward genetic innovation (OR 1.14, p?=?0.001), a belief that testing was likely to be covered by patients’ insurance (OR 2.84, p?<?0.001), and more frequent ordering of Oncotype DX testing (OR 8.69, p?<?0.001). More frequent use of Oncotype DX was associated with a belief that testing was likely to be covered by insurance (OR 7.33, p?<?0.001), as well as with more frequent ordering of BRCA 1/2 testing (OR 9.48, p?<?0.001).

Conclusions

Nearly one in five providers never or rarely ever ordered BRCA 1/2 testing for their breast cancer patients, and nearly 15% never or rarely ever ordered Oncotype DX. Less frequent ordering of BRCA 1/2 is associated with less frequent use of Oncotype DX testing, and vice versa. Those who do not order BRCA 1/2 testing report less positive attitudes toward genetic innovation. Further education of this subset of providers regarding the benefits of precision medicine may enable more rapid diffusion of genetic technology.

     

Cancer risk management in Tasmanian women with <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations

Women carrying germline mutations in BRCA1 or BRCA2 have significantly increased lifetime risks of breast and tubo-ovarian cancer. To manage the breast cancer risk women may elect to have breast screening by MRI/mammogram from age 30, to take risk-reducing medication, or to have a prophylactic bilateral mastectomy. To manage the tubo-ovarian cancer risk, the only effective strategy is to have a bilateral salpingo-oophorectomy, recommended by age 40 (BRCA1) or ‘around’ age 40 (BRCA2). Early studies suggested that uptake of these cancer risk-reducing strategies was low. More recent studies have revealed higher rates of uptake, however it is unclear whether uptake is genuinely improving or whether the higher uptake rates reflect changes in the populations studied. In this study we surveyed 193 BRCA1/2 mutation carriers in the state of Tasmania to determine the uptake of cancer risk-reducing strategies and what factors might influence women’s decisions in relation to both gynaecological and breast surgery. We observed that uptake of risk management strategies varied depending on the strength of the recommendation in the national guidelines. Uptake rates were >?90% for strategies which are strongly recommended, such as breast screening by MRI/mammogram and bilateral salpingo-oophorectomy, and were unaffected by demographic factors such as socio-economic disadvantage and educational achievement. Uptake rates were much lower for strategies which are presented in the guidelines as options for consideration and where patient choice and shared decision making are encouraged, such as prophylactic mastectomy (29%) and chemoprevention (1%) and in the case of prophylactic mastectomy, were influenced by both socio-economic advantage and educational achievement.