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An inherited single nucleotide variant (SNV) in the 5′UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation. Keyword BRCA1 · Methylation · Breast cancer Introduction . A recent estimation is that germline mutations in high- risk genes linked to breast cancer, including BRCA1, BRCA2, Breast cancer is the most common type of cancer in women PALB2, PTEN, TP53, CDH1, and STK11, combined explain . In some cancer patients, genetic predisposition plays a approximately 20% of the genetic predisposition [3, 4]. Parts role, and in families with many breast cancer diagnoses, the of the missing predisposition have been attributed to poly- possibility of an underlying genetic predisposition increases genic variants and genes with moderate penetrance, includ- substantially. Pathogenic germline variants in the BRCA1 ing CHEK2, and ATM [3–6]. Next to pathogenic germline and BRCA2 genes are present in 3% of all breast cancer cases variants in genes, germline epigenetic silencing may also increase the risk of cancer. For instance, Lynch syndrome is known for its increased risk of cancer due to germline Prior presentation: This work has not been presented. epigenetic silencing; a mechanism that might also be asso- ciated with other types of cancer . In breast cancer, new * Sabine C. linn strategies are being developed to detect heritable hypermeth- email@example.com ylation in families, however, so far without success [8, 9]. Department of Molecular Pathology, Netherlands Of all sporadic breast tumors, it is estimated that 5–20% Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, harbor hypermethylation of the BRCA1 promoter, depend- Netherlands ing on the case mix studied [10–14]. BRCA1 promoter Department of Pathology, The Netherlands Cancer Institute, hypermethylation is especially known to be associated Amsterdam, Netherlands with the triple-negative subtype, defined by its absence of Department of Medical Oncology, The Netherlands Cancer expression of the estrogen, progesterone, and HER2 recep- Institute, Amsterdam, Netherlands tor [10, 15]. In 2018, Evans et al. identified an inherited Department of Clinical Genetics, The Netherlands Cancer 5′UTR single nucleotide variant (SNV) c.-107A > T linked Institute, Amsterdam, Netherlands to epigenetic silencing of the BRCA1 gene. The epige- Department of Pathology, University Medical Center Utrecht, netic silencing of BRCA1 was present in both germline Utrecht, Netherlands Vol.:(0123456789) 1 3 V. M. T. de Jong et al. and tumor DNA. Forty-nine patients from families with a gene expression was found, pointing towards almost com- high risk of developing breast or ovarian cancer (Manches- plete promotor hypermethylation [15, 20]. ter score of > 34) without a known germline pathogenic BRCA1 mutation were examined. The Manchester score is PCR and sanger‑sequencing based on family history and pathological characteristics of the tumor and indicative of the risk of a germline BRCA1 Tumor DNA was amplified and sequenced using BigDye™ or BRCA2 mutation for patients with breast or ovarian can- Terminator v1.1 Cycle Sequencing Kit (Thermofisher, USA, cer . Two families were identified to carry the BRCA1 Waltham), according to manufacturer’s protocol. To detect c.-107A > T SNV and in these two families this variant the NM_007294.4:c.-107A > T SNV (hg19) we used the was associated with an increased risk of breast and ovar-following primers: Forward TTC TGA GAG GCT GCT GCT ian cancer . T A, R e v erse AAA CCC C A C A GC CT G T CC . Seq uences w ere In 2020, a study from South-East Germany failed to analyzed using Mutation Surveyor (Softgenetics, Pennsyl- identify the germline presence of BRCA1 c.-107A > T SNV vania, USA). in a large population, including 3297 patients with a high familial risk to develop breast and ovarian cancer, without a germline BRCA1 or BRCA2 mutation. These results indi- Results cated that the incidence of the BRCA1 c.-107A > T SNV may be low . For the Dutch population, the prevalence We identified 193 tumor samples with BRCA1 promoter of the BRCA1 c.-107A > T SNV is unknown. Information hypermethylation in 178 unique patients (Table 1). For on the prevalence of this SNV could have implications for most patients the tumor promoter methylation status was genetic counseling, screening, and prophylactic surgeries tested in the context of a clinical trial: n = 50 Neo-TN . Therefore, we selected patients with a proven hyper- (NCT01057069), n = 17 Triple-B (NCT01898117), OLIGO methylated BRCA1 promoter in their tumor to increase the n = 5 (NCT01646034), and SUBITO n = 24 (NCT02810743). chance of finding the SNV. In this study, we investigated All other patients were tested during regular diagnostics or the occurrence of the BRCA1 c.-107A > T SNV in 178 in a research setting. Of the identified patients, none (0%) patients, most of them with triple-negative breast cancer, had the BRCA1 c.-107A > T SNV. For 51 patients familial who tested positive for BRCA1 promoter hypermethylation information was available for review in our institute, all had by MLPA in their breast or ovarian tumor. tested negative for a germline pathogenic BRCA1 or BRCA2 variant. They had a median Manchester score of 9 (range 2–30). Subjects and methods Discussion Patient selection In this study, we aimed to identify the prevalence of the We selected all patients with breast or ovarian cancer BRCA1 c.-107A > T SNV in breast or ovarian cancer with promoter hypermethylation of BRCA1 in their tumor patients with tumor BRCA1 promoter hypermethylation. In tested between 01-08-2007 and 01-09-2019 at the Nether- lands Cancer Institute. Clinical information was obtained from the electronic health record of the institute. For the Table 1. Patient and tumor characteristics patients known in our clinical genetics department, the N (%) Manchester score was calculated by a clinical geneticist Median age, year (range) 40 (24–76) (FB) . Gender, no. (%) Female 178 (100%) Median manchester score, (range) 9 (2–30) Methylation assay Missing no. (%) 127 (72%) Tumor origin, no. (%) Methylation of the BRCA1 promoter was previously deter- Breast 183 (95%) mined by MS-MLPA (kit ME001 or kit ME005-custom) Ovarian 10 (5%) (MRC-Holland, Amsterdam). Analyzes and the cutoff were done according to manufacturer’s protocol. We used a ratio 134 tumors were triple-negative, 2 estrogen receptor-positive HER2 of 0.2 to define hypermethylation . Earlier research negative, and of 47 tumors information on receptor status was miss- showed that with the cutoff used here (0.2) very low BRCA1 ing 1 3 Identifying the BRCA1 c.‑107A > T variant in Dutch patients with a tumor BRCA1 promoter… our cohort of 178 patients with a tumor BRCA1 promoter In case we had identified the SNV in any of the tumor sam- hypermethylation, we did not find any sample harboring ples, our next step would have been to test the germline the specific BRCA1 c.-107A > T SNV. Our study design DNA for this SNV. was based on the presence of BRCA1 hypermethylation, To conclude, the BRCA1 c.-107A > T SNV is not preva- rather than based on familial risk, in contrast to previous lent in a large cohort of patients with tumor BRCA1 pro- research [17, 18]. moter hypermethylation. Given these results and those from In the original study of Evans et al., the specific BRCA1 previous studies, this germline variant does not seem to have c.-107A > T variant was identified in 2/49 high-risk fami- a high prevalence in the Western-European population. lies, all patients (n = 7) with BRCA1 promoter hypermeth- Acknowledgements The authors would like to thank the Data Desk ylation harbored the same germline variant . Notably, of the Netherlands Cancer Institute for their help with gathering the their selection included patients from families affected by clinical information. breast and ovarian cancer without a germline BRCA1 or BRCA2 mutation, while our selection was focused on the Author contributions SL, PN, FH, FB, and VJ conceived the study. The data were contributed by PN, VJ, RP, and TS. The data was analyzed presence of tumor BRCA1 promoter hypermethylation. by VJ and interpreted by all authors. VJ wrote the first version of the With the used methylation assay, tumor BRCA1 promoter manuscript. All authors listed critically reviewed, and approved the hypermethylation and a germline BRCA1 mutation seem manuscript before submission. mutually exclusive [11, 21, 22]. In general it seems that co-occurrence of BRCA1 promoter hypermethylation and Data availability All data generated or analyzed during this study are a germline BRCA1 mutation is extremely rare. Of the 51 included in this published article. patients known at our genetics department, not a single patient had a germline BRCA1 or BRCA2 mutation and Declarations none had the same familial risk as patients in the study by Conflict of interest SCL reports grants from ZonMw, the Dutch Can- Evans and colleagues. Of note, for the majority of patients cer Society, and A Sister’s Hope during the conduct of the study. SCL included in this study the familial risk is unknown. In is an advisory board member for Cergentis, and IBM, and received contrast, the study of Laner et al. included all patients institutional research support from Agendia, AstraZeneca, Eurocept- pharmaceuticals, Genentech, Novartis, Pfizer, Roche, Tesaro, and who had wild-type germline BRCA1/2 and fulfilled the Immunomedics. In addition, SCL received institutional non-financial criteria necessary for genetic testing in Germany, which is support from AstraZeneca, Genentech, Novartis, Roche, Tesaro, and less strict than the criteria used by Evans and colleagues Immunomedics and institutional educational financial support from . Similar to our findings, Laner and colleagues did not Bayer and Daiichi-Sankyo outside of this study. All other authors de- clare no competing interest. detect the SNV in any of the 3297 patients tested. Further- more, the two presumed unrelated families identified by Ethical approval The study was approved by the institutional research Evans et al. shared a common ancestral haplotype, very board of the Netherlands Cancer Institute (IRBdm19-106). All (retro- indicative of a common ancestor . spective) medical data/biospecimen studies at the Netherlands Cancer Institute have been executed pursuant to Dutch legislation and interna- Our study has a clear strength since it focused on a cohort tional standards. Prior to 25 May 2018, national legislation on data pro- of patients with a proven tumor BRCA1 promoter hyper- tection applied, as well as the International Guideline on Good Clinical methylation. However, our study also has some limitations. Practice. From 25 May 2019 we also adhere to the GDPR. Within this Firstly, we did not have the Manchester Score for all patients framework, patients are informed and have always had the opportunity to object or actively consent to the (continued) use of their personal limiting our ability to establish their familial risk. Nonethe- data & biospecimens in research. Hence, the procedures comply both less, the study from Laner et al. did not identify any patients with (inter-) national legislative and ethical standards. Patients included with the SNV either even though they were selected for in clinical trials have given written informed consent. hereditary predisposition. Secondly, although the studied population is relatively large, this is not a representative Open Access This article is licensed under a Creative Commons selection of all breast cancer patients in The Netherlands. Attribution 4.0 International License, which permits use, sharing, Therefore, we cannot definitively reject the hypothesis that adaptation, distribution and reproduction in any medium or format, the SNV plays a role in the familial breast or ovarian cancer as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate risk for some Dutch patients. However, if the SNV was prev- if changes were made. The images or other third party material in this alent in the population, we would expect it to be included article are included in the article's Creative Commons licence, unless in the gnomAD database, which it is not . Thirdly, we indicated otherwise in a credit line to the material. If material is not investigated tumor DNA for the SNV instead of germline included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted DNA. We do not think investigating tumor DNA is an issue use, you will need to obtain permission directly from the copyright since all samples were identified as wild-type and a somatic holder. To view a copy of this licence, visit http:// creat iveco mmons. reverse mutation in the tumor would be extremely unlikely. org/ licen ses/ by/4. 0/. 1 3 V. M. T. de Jong et al. 14. 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Familial Cancer – Springer Journals
Published: Apr 1, 2023
Keywords: BRCA1; Methylation; Breast cancer
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