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.

     

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> 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.

     

The yield of targeted genotyping for the recurring mutations in <Emphasis Type="Italic">BRCA1</Emphasis>/<Emphasis Type="Italic">2</Emphasis> in Israel

Background

Hereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations—first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing.

Methods

Clinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other.

Results

Overall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained.

Conclusions

The currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.

     

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.

     

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.

     

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> 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.

     

Contribution of <Emphasis Type="Italic">BRCA1</Emphasis> large genomic rearrangements to early-onset and familial breast/ovarian cancer in Pakistan

Background

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers. Pakistan has one of the highest rates of breast cancer incidence in Asia, where BRCA1/2 small-range mutations account for 17% of early-onset and familial breast/ovarian cancer patients. We report the first study from Pakistan evaluating the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in breast and/or ovarian cancer patients who do not harbor small-range BRCA1/2 mutations.

Materials and methods

Both BRCA1/2 genes were comprehensively screened for LGRs using multiplex ligation-dependent probe amplification in 120 BRCA1/2 small-range mutations negative early-onset or familial breast/ovarian cancer patients from Pakistan (Group 1). The breakpoints were characterized by long-range PCR- and DNA-sequencing analyses. An additional cohort of 445 BRCA1/2 negative high-risk patients (Group 2) was analyzed for the presence of LGRs identified in Group 1.

Results

Three different BRCA1 LGRs were identified in Group 1 (4/120; 3.3%), two of these were novel. Exon 1–2 deletion was observed in two unrelated patients: an early-onset breast cancer patient and another bilateral breast cancer patient from a hereditary breast cancer (HBC) family. Novel exon 20–21 deletion was detected in a 29-year-old breast cancer patient from a HBC family. Another novel exon 21–24 deletion was identified in a breast-ovarian cancer patient from a hereditary breast and ovarian cancer family. The breakpoints of all deletions were characterized. Screening of the 445 patients in Group 2 for the three LGRs revealed ten additional patients harboring exon 1–2 deletion or exon 21–24 deletion (10/445; 2.2%). No BRCA2 LGRs were identified.

Conclusions

LGRs in BRCA1 are found with a considerable frequency in Pakistani breast/ovarian cancer cases. Our findings suggest that BRCA1 exons 1–2 deletion and exons 21–24 deletion should be included in the recurrent BRCA1/2 mutations panel for genetic testing of high-risk Pakistani breast/ovarian cancer patients.

     

OLA1 gene sequencing in patients with <Emphasis Type="Italic">BRCA1/2</Emphasis> mutation-negative suspected hereditary breast and ovarian cancer

Background

Of individuals with suspected hereditary breast and ovarian cancer (HBOC), approximately 30–70 % do not harbor mutations in either BRCA1 or BRCA2 gene, which suggests that these individuals have other genetic or epigenetic alterations that could lead to the onset of this hereditary disease. We have recently identified OLA1 as a novel BRCA1/BARD1-interacting protein. In the present study, we aimed to elucidate whether any genetic mutations in OLA1 are detected among patients with suspected HBOC without BRCA1 or BRCA2 mutations.

Methods

Among 53 patients with suspected HBOC enrolled at Hoshi General Hospital, 23 patients without any BRCA1 or BRCA2 mutations were analyzed for OLA1 mutations. Genomic DNA was extracted from the peripheral blood samples. PCR and Sanger sequencing were performed to elucidate whether there were any mutations in any of the ten exons and flanking introns of the OLA1 gene.

Results

No germline sequence variation was detected in the OLA1 gene among the 23 patients enrolled in this study.

Conclusions

No germline mutations were found in the OLA1 gene among the cohort of patients with suspected HBOC without BRCA1 or BRCA2 mutations. Further studies are needed to clarify whether other mutations/epigenetic alterations are involved in the pathogenesis of BRCA1 or BRCA2 mutation-negative inherited disease with breast or ovarian cancer.

     

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.

     

Revisiting breast cancer patients who previously tested negative for <Emphasis Type="Italic">BRCA</Emphasis> mutations using a 12-gene panel

Purpose

BRCA mutations contribute to about 20% of all hereditary breast cancers. With full-genome sequencing as the emerging standard for genetic testing, other breast cancer susceptibility genes have been identified and may collectively contribute to up to 30% of all hereditary breast cancers. We re-assessed women who had previously tested negative for a BRCA mutation when outdated techniques were used, and discuss the implications of identifying a mutation several years after initial genetic testing.

Methods

We evaluated the prevalence of mutations in 12 breast cancer susceptibility genes (including BRCA1 and BRCA2) in 190 breast cancer patients with a strong family history of breast cancer. These women had previously tested negative for mutations in the large coding exons of BRCA1 and BRCA2 using the protein truncation test (PTT) between the years of 1996 and 2013.

Results

We identified pathogenic mutations in 17 of 190 (9%) women. Six mutations were detected in BRCA1 (n = 2) and BRCA2 (n = 4). Eleven mutations were found in other breast cancer susceptibility genes including CHEK2 (n = 5), PALB2 (n = 2), BLM (n = 2), ATM (n = 1) and TP53 (n = 1).

Conclusion

Among 190 breast cancer patients with a family history of the disease, and who previously received a negative result for BRCA mutations using the PTT, 17 (9%) women were found to carry a high-risk pathogenic mutation in a breast cancer susceptibility gene. Six of these women were BRCA mutation carriers who were missed previously. These findings support the rationale for updated genetic testing in patients who tested BRCA mutation negative using outdated techniques.

     

Cost-effectiveness of surveillance and prevention strategies in <Emphasis Type="Italic">BRCA1/2</Emphasis> mutation carriers

Background

Cost-effectiveness analysis is an important aspect of healthcare, including in Japan, where preventive measures for BRCA1/2 mutation carriers are not covered by health insurance.

Methods

We developed Markov models in a simulated cohort of women aged 35–70 years, and compared outcomes of surveillance with risk-reducing mastectomy (RRM) at age 35, risk-reducing salpingo-oophorectomy (RRSO) at age 45, and both (RRM&RRSO). We used breast and ovarian cancer incidences and adverse event rates from the previous studies, adjuvant chemotherapy, and hormonal therapy rates from the Hereditary Breast and Ovarian Cancer Registration 2015 in Japan, mortality rates from the National Cancer Center Hospital, Japan Society of Clinical Oncology, and Ministry of Health, Labour and Welfare, and direct costs from St. Luke’s International Hospital and Keio University Hospital. We used previously published preference ratings of women without known high risk to adjust survival for quality of life. The discount rate was 2%.

Results

Compared with surveillance, RRSO and RRM&RRSO were dominant (both cost-saving and more effective), and RRM was cost-effective in BRCA1 mutation carriers, while RRM and RRM&RRSO were dominant and RRSO was cost-effective in BRCA2. Among the four strategies including surveillance, RRM&RRSO and RRM were the most cost-effective in BRCA1 and BRCA2 mutation carriers, respectively.

Conclusions

With quality adjustment, RRM, RRSO, and RRM&RRSO were all cost-effective preventive strategies in BRCA1/2 mutation carriers, with RRM&RRSO being the most cost-effective in BRCA1 and RRM in BRCA2. This result supports the inclusion of insurance coverage for BRCA mutation carriers in Japan.

     

Analysis of <Emphasis Type="Italic">PALB2</Emphasis> mutations in 155 Japanese patients with breast and/or ovarian cancer

Background

PALB2 (Partner and Localizer of BRCA2) was identified as a moderate-risk gene in breast and pancreatic cancers. Recently, it was reported that PALB2 carriers have a high risk of developing breast cancer, with the cumulative risk of 34 % by the age of 70.

Patients and methods

Peripheral blood samples from 155 patients at risk for hereditary breast and/or ovarian cancer were tested for BRCA1/2 and PALB2 by targeted sequencing using a next-generation sequencer. Of these 155, 146 met NCCN criteria and the remaining 9 did not.

Results

BRCA1/2 analysis was performed on 155 patients, for whom the results were reported previously (Hirotsu Y et al. Mol Genet Genomic Med, doi:10.1002/mgg3.157, 2015). Eleven patients were identified to have deleterious BRCA mutations (Hirotsu Y et al. Mol Genet Genomic Med, doi:10.1002/mgg3.157, 2015). However, none of the 155 patients were found to have deleterious PALB2 germline mutations. Missense mutations [variants of uncertain significance (VUS)] of PALB2 were found in 12 cases. In silico analyses by SIFT (Sorting Intolerant Form Tolerant) and PolyPhen2 (Polymorphism Phenotyping version 2) indicated that 2 of 12 VUS were deleterious and probably damaging.

Conclusions

This is the first report on PALB2 mutations in Japan, revealing two missense mutations as “deleterious and probably damaging” by in silico analyses, but no PALB2 premature truncation mutations were identified. The sample size is relatively small and a larger cohort study is needed in Japan.

     

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.

     

Feasibility study of contralateral risk-reducing mastectomy with breast reconstruction for breast cancer patients with <Emphasis Type="Italic">BRCA</Emphasis> mutations in Japan

Background

Contralateral risk-reducing mastectomy (CRRM) for breast cancer patients with BRCA mutations has been reported to not only reduce breast cancer incidence but also to improve survival. The National Comprehensive Cancer Network guidelines recommend providing CRRM to women with BRCA mutations who desire CRRM after risk-reduction counseling. However, in Japan, CRRM cannot be performed generally because it is not covered by health insurance. Thus, we conducted a feasibility study to confirm the safety of CRRM.

Methods

CRRM with bilateral breast reconstructions were performed for breast cancer patients with BRCA mutations. The primary endpoint was early adverse events within 3 months, and secondary endpoints were late adverse events.

Results

Between August 2014 and November 2016, ten patients were enrolled. The median age was 37.5 years, and five of the patients had the BRCA1 mutation while five had the BRCA2 mutation. Six patients received neoadjuvant chemotherapy. Eight patients selected silicone breast implants, and two patients selected transverse rectus abdominis myocutaneous flap reconstruction. Pathological findings showed no evidence of occult breast cancers in any of the patients. At a median of 25.5 months follow-up time, CRRM-related early adverse events were hematoma (subsequently removed by re-operation; grade 2, n?=?1), wound infection (grade 2, n?=?1), skin ulceration (grade 1, n?=?2) and wound pain (grade 1, n?=?1). Overall, there were no grade 3 or more severe adverse events.

Conclusion

Our results confirm that CRRM with reconstruction could be performed safely.

     

Managing Patient with Mutations in <Emphasis Type="Italic">PALB2</Emphasis>, <Emphasis Type="Italic">CHEK2</Emphasis>, or <Emphasis Type="Italic">ATM</Emphasis>

Purpose of Review

The use of panel testing of multiple cancer-causing genes has allowed to find a subset of patients with harmful mutations in moderate penetrance genes. While extensive information is available regarding patients with BRCA1 and BRCA2 pathogenic variants, information regarding these less common genes and their management remains scarce. The aim of this review is to discuss penetrance, incidence, and management recommendations for PALB2, ATM, and CHEK2.

Recent Findings

NCCN guidelines now provide management recommendation for patients with pathogenic variants in these genes. In addition, more widespread testing has provided more information on penetrance and incidence. Although this is a huge step toward improving quality of care, prospective studies are still needed. We summarize the NCCN and other guidelines/suggestions for these genes and deliver our insight on the matter based on the best information we could find.

Summary

PALB2, ATM, and CHEK2 are less penetrant than BRCA1–2 and have a different spectrum, suggesting differing management. Data about incidence and penetrance along with management recommendations for these genes are provided.

     

RETRACTED ARTICLE: The <Emphasis Type="Italic">BRCA2</Emphasis> variant c.68-7 T&gt;A is associated with breast cancer

Background

BRCA2 c.68-7T>A has been demonstrated to cause aberrant splicing and is possibly pathogenic. The population prevalence of the variant is 0.2%, which higher than usual for pathogenic BRCA2 variants. The pathogenicity of the variant is discussed.

Methods

The outpatient genetic clinic at The Norwegian Radium Hospital, part of Oslo University Hospital, has invited breast cancer kindreds for genetic examinations and prospective follow-up of high risk patients since 1988. We have complete files of all activities and results, and we examined the files for association between BRCA2 c.68-7T>A and breast cancer.

Results

Seventeen out of 714 (2.4%) breast cancer kindreds sequenced for BRCA2 carried the variant BRCA2 c.68-7T>A (p?<?0.0001 compared to population controls). Segregation analysis was inconclusive (likelihood ratio 0.36) for pathogenicity. Two breast cancers were prospectively observed during 134 observation years (annual incidence rate 1.5% (95% CI 0.15% to 5.4%) and one additional breast cancer was diagnosed at first (prevalence) round.

Conclusion

BRCA2 c.68-7T>A is associated with breast cancer. In the families selected due to aggregation of breast cancer, carriers of the BRCA2 c.68-7T>A variant have increased risk for breast cancer. It is, however, possible that the variant has lower penetrance than the average pathogenic BRCA2 variants, and that in the families selected for having known aggregation of breast cancer other (modifying) factors contributed to the observed results.

     

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.