A pathogenic germline BRCA1 mutation in a patient with non-Hodgkin lymphoma and rectum adenocarcinoma

A pathogenic germline BRCA1 mutation in a patient with non-Hodgkin lymphoma and rectum adenocarcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report A pathogenic germline BRCA1 mutation in a patient with non-Hodgkin lymphoma and rectum adenocarcinoma You Zhou, Yanjie Xu, Jiemin Zhao, Xuefeng Ni, Wenwei Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2622517/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Tumor suppressor gene BRCA1, known for its vital roles in regulating DNA damage, is frequently mutated in hereditary breast and ovarian cancer (HBOC), whose mutation also increases susceptibility to intestinal, prostatic and pancreatic cancers of patients. As the main subtype of lymphoma, non-Hodgkin lymphoma (NHL) is malignant disorders arising from immune cells and displays predominantly as lymphadenopathy or solid tumors, which is rarely considered hereditary. However, the relationship between BRCA1 mutation and NHL is rarely reported. Here, we present a primary NHL and recent second primary tumor rectum adenocarcinoma. Considering the hereditary factors in developing colorectal cancer, we investigated her family history and found her sister died with ovarian cancer. Meanwhile, her genetic testing identified a pathologic germline mutation in BRCA1 (c.1115G＞A). Taken into account the strong evidence between BRCA1 mutation and HBOC occurrence, we also did genetic test for her daughter and found the same BRCA1 mutation. Although strong evidence between BRCA1 mutation and HBOC exists, the patient harboring pathogenic BRCA1 mutation did not suffer from HBOC but NHL and rectum adenocarcinoma which required further investigations and modifications of current screening criteria for HBOC. And great attention should also be paid to her daughter with BRCA1 mutation carrier. BRCA1 Hereditary breast and ovarian cancer Non-Hodgkin lymphoma Rectum adenocarcinoma Gene mutation Figures Figure 1 Figure 2 Figure 3 Introduction Since identified in 1994, tumor suppressor genes breast-cancer susceptibility gene 1 (BRCA1) and BRCA2 have long been considered as key regulators of DNA repair, transcription and cell cycle in response to DNA damage, whose mutations were associated with elevated susceptibility to breast and ovarian cancers [ 1 – 3 ]. The detailed mechanism is that double-strand damage in cancer cells is increased upon inhibition of DNA repair enzyme poly ADP-ribose polymerase (PARP), subsequently by reduced repair ability of DNA double-strand damage in BRCA-mutant cells which leads to cell apoptosis [ 4 ]. As the most commonly mutated genes tested in hereditary breast and ovarian cancer (HBOC), deleterious mutations of BRCA1/2 account for 20%-40% of the familial breast cancer and confer high lifetime risks of developing breast and ovarian cancers in women [ 5 , 6 ]. In addition, accumulating evidence has also showed potential links between BRCA1/2 mutations with increased susceptibility to intestinal, prostatic and pancreatic cancers. Lymphoma is one of the most leading causes responsible for cancer mortality in the world, among which approximately 90% of the cases are non-Hodgkin lymphoma (NHL) [ 7 ]. According to the Surveillance, Epidemiology, and End Results (SEER) Program, 80,470 new cases and 20,250 deaths of NHL patients are estimated in the United States in 2022 [ 8 ]. A majority of NHL arises from mature B lymphocytes and a small number of cases derive from T lymphocytes or natural killer (NK) cells. Due to progressive acquisition of DNA alterations such as gene mutations, indels and chromosomal translocations, NHL develops and is particularly associated with specific gene abnormalities including translocations of BCL2 and MYC [ 9 ]. Meanwhile, infections of diverse viruses are also found in certain subtypes of NHL, suggesting their relationship with the occurrence of NHL [ 10 ]. Although a slightly elevated risk is observed in family members, NHL is not generally considered hereditary [ 11 ]. Herein, we report a rare case of germline BRCA1 mutation (c.1115G＞A) in a patient who presented with long-term history of NHL and recent rectum adenocarcinoma, expanding the spectrum of BRCA1 mutation to other types of cancer as well as modifying current screening criteria for HBOC. Method The family was enrolled with informed consent into the hereditary cancers study. The phenotype of an individual was longitudinally and systematically evaluated. Exome capture, sequencing and analysis of DNA extracted from peripheral blood cells of the proband and her daughter were carried out. Bioinformatics tools were employed to analyze the candidate variants including point mutation, indel, copy number variation, fusion/rearrangement and large fragment rearrangement. Results A 76-year-old Chinese female patient was admitted to the hospital in 1998 due to retroperitoneal lymphadenopathy. After diagnosed with NHL, she completed five cycles of standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen and acquired complete response (CR). The examination of computed tomography (CT) in 2001 showed retroperitoneal lymphadenopathy and suspected relapse. After six cycles of ifosfamide, cisplatin and etoposide regimen, she acquired partial response (PR). Another CT examination in 2006 demonstrated lymphadenopathy of retroperitoneum, mediastinum and bilateral supraclavicular. Based on the pathology, she was diagnosed with follicular lymphoma. After six cycles of fludarabine, mitoxantrone and dexamethasone regimen, she achieved PR. Surprising, after several years of palliative treatment, she was diagnosed with post-germinal center B cell-derived diffuse large B cell lymphoma (DLBCL) in 2021 followed by four cycles of combination of CHOP with rituximab (R-CHOP) resulting in PR. However, she quickly developed grade IV myelosuppression and was unable to tolerate systemic chemotherapy. A recent colonoscopy test in 2022 showed that she was diagnosed with rectum adenocarcinoma - a second primary tumor (Fig. 1 ). During her treatment and surveillance, genetic testing identified a pathologic germline mutation in BRCA1 (Table 1 ). This variant was noted to be heterozygous for c.1115G＞A (p.W372*), which was previously reported in Chinese patients with HBOC [ 12 ]. Furthermore, ten somatic mutations including MSH2 c.520G > T (p.G174*) and TP53 c.328C > T (p.R110C) were detected (Table 1 ). The tumor mutation burden (TMB) was 16.78 Muts/Mb which was rated as high (from the Geneplus database). Also, microsatellite analysis showed microsatellite stability (MSS). Then she started oral fluzoparib. A month later she underwent coma and passed away. Table 1 Somatic and germline mutations in white blood cells Gene cHGVS pHGVS Mutation abundance/ Copy Number DNMT3A c.1012_1014 + 2delinsA - 0.34% MSH2 c.520G > T p.G174* 0.04% CCND1 - - 6 FGF19 - - 6 FGF3 - - 6 FGF4 - - 6 TP53 c.273G > A p.W91* 0.05% c.328C > T p.R110C 0.25% c.538G > T p.E180* 0.15% c.376-1G＞A 52.89% BRCA1 c.1115G > A p.W372* Germline mutation, heterozygous We first began to investigate her family history for the reason of potential hereditary factors triggering colorectal cancer. Unexpectedly, her sister was diagnosed with ovarian cancer at age 62. Her father was diagnosed with unknown primary lesion at age 52. Her husband’s brother was diagnosed with NHL at age 69 (Fig. 2 ). Combined with her BRCA1 mutation and her sister’s ovarian cancer history, her family could be referred as HBOC. Nevertheless, the patient was diagnosed with long-term NHL not HBOC syndrome. Notably, the same mutation for BRCA1 c.1115G＞A (p.W372*) was also detected in the white blood cells of her healthy daughter whose age was 49, increasing her predisposition to developing cancer. Discussion As a caretaker tumor suppressor gene, BRCA1 is responsible for repairing DNA double-strand breaks and maintaining genomic stability [ 13 ]. Since firstly reported that BRCA1 was the cause of hereditary breast cancer through linkage analysis, BRCA1 mutation has been most frequently found among HBOC of all ethnic groups and races [ 14 ]. According to the ClinVar database, more than 2,900 variants of BRCA1 are identified as pathogenic germline mutations, approximately 80% of which generate truncated proteins and reduced expression [ 15 ]. The estimated frequency of BRCA1 pathogenic variants is 0.2%-0.25%. Meanwhile, among all patients with breast and ovarian cancers, the retention rate of BRCA1 mutation is 1.45–3.7% and 3.4%-9.9%, respectively [ 16 , 17 ]. Moreover, the risk of developing ovarian cancer with a BRCA1 mutation is 39–63%, while the risk of developing male breast cancer, prostate cancer and pancreatic cancer is 1.2%, 8.6% and 1–3%, respectively [ 18 ]. Despite strong evidence between BRCA1 mutation and HBOC occurrence persistently exists, in this case the patient harboring pathogenic BRCA1 mutation did not suffer from HBOC but NHL and rectum adenocarcinoma which required further investigations and modifications of current screening criteria for HBOC. Next we explored the mutation rate of BRCA1 in NHL patients from The Cancer Genome Atlas (TCGA) database. The results demonstrated that compared to mutant genes with high frequency, the mutation rate of BRCA1 is only 7%. And all the mutations are missense mutations (Fig. 3 ). Actually, previous studies have implicated elevated risks for leukemia or lymphoma in definite BRCA1 mutation carriers due to the association of the former with large gene rearrangements mediated by BRCA pathway [ 2 , 19 , 20 ]. Thus, it is reasonable to infer that great attention should also be paid to hematologic cancers with BRCA1-mutant patients, which needs further discussion and research. In consideration of targeting BRCA1 mutation, PARP inhibitors are licensed as maintenance treatment for primary high-grade serous ovarian cancer, fallopian tube and peritoneal cancer after response (CR/PR) to platinum-based chemotherapy. A large number of clinical trials show that PARP inhibitors such as olaparib, niraparib and fluzoparib could significantly prolong the progression free survival (PFS), most notably in patients with BRCA-mutant ovarian cancers [ 21 – 24 ]. However, a considerable number of patients will eventually develop resistance of PARP inhibitors on account of secondary somatic reversion mutations in BRCA genes in cancer cells, which could be explained by tumor heterogeneity and clonal expansion driven by chemotherapy [ 25 , 26 ]. In this case, the patient did not seem to benefit from PARP inhibitor fluzoparib probably due to two reasons. One is that efficacy of PARP inhibitor may be influenced by BRCA-independent mechanisms that restore homologous recombination, which could be inferred that mutation of mismatch repair gene MSH2 was also found in this patient. The other is the loss or reduced expression of PARP-1 in cancer cells leading to off-target of drug. Thus we should detect the expression level of PARP-1 in this patient and estimate if PARP inhibitor is beneficial for her. Traditionally, hereditary cancers are defined by loci of primary lesions. The major inherited cancer syndromes include hereditary nonpolyposis colorectal cancer, HBOC, hereditary diffuse gastric cancer and hereditary pancreatic cancer. Yet, mounting research has verified typical mutations that did not cause the corresponding hereditary cancers as shown in our case. This phenomenon triggers our deep understanding on redefining hereditary cancers based on classification of gene mutations, for instance, “hereditary BRCA1 syndromes”. Similarly, clinicians should firstly consider loci of primary lesions or typical hereditary cancers caused by gene mutations of patients upon genetic counseling, subsequently by the adjustment of the follow-up policies. This is particularly important because the knowledge of clinicians on the cancer is greatly related to the choice of treatment strategies and the prognosis of patients and their whole family. Conclusions BRCA1 mutation is commonly found in HBOC and rarely leads to NHL and rectum adenocarcinoma. The present case indicates a pathologic germline mutation in BRCA1 (c.1115G＞A) with high TMB and MSS. Given its scarcity, germline BRCA1 mutation in NHL and rectum adenocarcinoma is rarely reported and correlation between them requires further research. Also our study broadens the spectrum of BRCA1 mutation to more types of cancer and modifies current screening criteria for HBOC. Declarations Acknowledgments We owe thanks to the proband and her family for their collaboration, which was fundamental for publishing this work. Author contributions YX, JZ and XN examined and treated the patient. WH designed and supervised this study. YZ and WH wrote the manuscript. All authors contributed to the article and approved the submitted version. Funding This work was supported by grants from the National Natural Science Foundation of China (31701111), Major Science and Technology Project of Changzhou Health Commission (ZD202203) and Young Talent Development Plan of Changzhou Health Commission (CZQM2020008). Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. Ethics approval All procedures followed were approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University (No. 2022-science-158). The patient’s next of kin has read and signed the informed consent form to participate. Consent for publication The patient’s next of kin provided written informed consent for publication of case details of the patient. Competing interests The authors declare no competing interests. References Yoshida K, Miki Y (2004) Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 95(1):866–871 Friedenson B (2007) The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers .BMC Cancer, 7(1) Saleh-Gohari N et al (2005) Spontaneous Homologous Recombination Is Induced by Collapsed Replication Forks That Are Caused by Endogenous DNA Single-Strand Breaks. Mol Cell Biol 25(16):7158–7169 Rouleau M et al (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer. PubMed, Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7(12):937–948 Couch FJ, Nathanson KL, Offit K (2014) Two Decades After BRCA: Setting Paradigms in Personalized Cancer Care and Prevention. Science 343(6178):1466–1470 Shankland KR, Armitage JO, Hancock BW (2012) Non-Hodgkin lymphoma. Rev Med Suisse 380(9844):2203 Siegel RL et al (2022) Cancer statistics, 2022. CA: A Cancer Journal for Clinicians. 72:7–331 Bowzyk Al-Naeeb A et al (2018) Non-Hodgkin lymphoma. Bmj, : p. k3204 Parkin DM (2011) 11. Cancers attributable to infection in the UK in 2010. Br J Cancer 105(S2):S49–S56 Ansell SM (2015) Non-Hodgkin Lymphoma: Diagnosis and Treatment. Mayo Clinic Proceedings, 90(8): p. 1152–1163 N., et al., BRCA1 germline mutations in Chinese patients with hereditary breast and ovarian cancer .International Journal of Gynecological Cancer, Venkitaraman AR (2014) Cancer Suppression by the Chromosome Custodians, BRCA1 and BRCA2 .Science, Hall JM et al (1990) Linkage analysis of early-onset familial breast cancer to chromosome 17q12. Venkitaraman AR (2019) How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility? DNA Repair 81:102668 Momozawa Y et al (2018) Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls .Nature Communications, 9(1) Enomoto T et al (2019) The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE) .International Journal of Gynecological Cancer, ( 6) Yoshida R (2020) Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer 28(6):1167–1180 Friedenson B (2005) BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian. MedGenMed: Medscape general medicine 7(2):60 de Boer M et al (2020) Increased prevalence of BRCA1/2 mutations in women with macrotextured breast implants and anaplastic large cell lymphoma of the breast. Blood 136(11):1368–1372 Klotz DM, Wimberger P (2020) Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Arch Gynecol Obstet 302(5):1087–1102 Moore K et al (2018) Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 379(26):2495–2505 Ledermann JA et al (2016) Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 17(11):1579–1589 Li N et al (2021) An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer. Clin Cancer Res 27(9):2452–2458 Greaves M, Maley CC Clonal evolution in cancer .Nature Gross J et al (2011) Secondary Somatic Mutations Restoring BRCA1/2 Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas . 29:3008–301522 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2622517","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":178595449,"identity":"a33f1cee-30be-4426-8ea3-bc9379337e52","order_by":0,"name":"You Zhou","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"You","middleName":"","lastName":"Zhou","suffix":""},{"id":178595450,"identity":"96764cf5-9ab5-4274-b660-f41d78c52398","order_by":1,"name":"Yanjie Xu","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yanjie","middleName":"","lastName":"Xu","suffix":""},{"id":178595451,"identity":"8ef82948-f192-40e9-9ec5-426b748b492b","order_by":2,"name":"Jiemin Zhao","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jiemin","middleName":"","lastName":"Zhao","suffix":""},{"id":178595452,"identity":"f6cd4187-086e-4336-b8b1-6bfa373a5a77","order_by":3,"name":"Xuefeng Ni","email":"","orcid":"","institution":"The Third Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xuefeng","middleName":"","lastName":"Ni","suffix":""},{"id":178595453,"identity":"61cd0b78-bee2-4dc5-a068-0decaa9a033a","order_by":4,"name":"Wenwei Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYDACZgY2KIux8QGDAQMDG3v7AaK1NBuAtPDxnEkgZA8bnCEBIuUkHAzwqjc4znvsMW+bTZ7B8ea2ap6COyCNCQw/Krbh1nKYL92Yty2t2ODMwbbbPAbPGNikGw8w9py5jVOLZDOPmTTvtsOJ224ktt2cYXCYgU3mQAIzYxtBLf8Tt91/2FYI1iKRYIBXCz8zWMsBoC2MbQwfiNPClyY5919y4v4zic0SHwye8bABA/kgPr+w8Z89JvHmjF3izPbjDz8k/LkjJ9/efvDBjwrcWhgYeFB4B8DcA3jUY2rBr3gUjIJRMApGJAAAO6tVe2q2SlAAAAAASUVORK5CYII=","orcid":"","institution":"The Third Affiliated Hospital of Soochow University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wenwei","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2023-02-24 01:44:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2622517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2622517/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":33567753,"identity":"9c3dc570-dc38-4412-8109-25e1c4da5880","added_by":"auto","created_at":"2023-02-28 15:40:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":12750516,"visible":true,"origin":"","legend":"\u003cp\u003ePathology image of the patient’s rectum adenocarcinoma\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2622517/v1/a1a3cca82790548bccb7b751.png"},{"id":33567752,"identity":"31d677e2-442e-44f7-934d-99b04000db05","added_by":"auto","created_at":"2023-02-28 15:40:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60496,"visible":true,"origin":"","legend":"\u003cp\u003eFamily pedigree of the patient presented in this case\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2622517/v1/3072efa83410edf5e76ea92d.png"},{"id":33567751,"identity":"f02419bc-3488-4840-8221-749e71dae8d2","added_by":"auto","created_at":"2023-02-28 15:40:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":111030,"visible":true,"origin":"","legend":"\u003cp\u003eMutation annotations of NHL patients from TCGA database. Top 10 high frequently mutant genes and BRCA1 were shown\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2622517/v1/7a5762d801a7eb809a6b892c.png"},{"id":33568692,"identity":"0b0ba15f-bd05-4290-aac5-f2d411658ec2","added_by":"auto","created_at":"2023-02-28 15:48:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1974638,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2622517/v1/699e5954-8e2c-4be3-b623-7b237c739bf2.pdf"},{"id":33568691,"identity":"2e91c130-b2fd-4dca-97e5-394fbd04eb7c","added_by":"auto","created_at":"2023-02-28 15:48:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1974638,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2622517/v1/c3462e1d-45ec-4cf6-a538-965227692f36.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A pathogenic germline BRCA1 mutation in a patient with non-Hodgkin lymphoma and rectum adenocarcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSince identified in 1994, tumor suppressor genes breast-cancer susceptibility gene 1 (BRCA1) and BRCA2 have long been considered as key regulators of DNA repair, transcription and cell cycle in response to DNA damage, whose mutations were associated with elevated susceptibility to breast and ovarian cancers [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The detailed mechanism is that double-strand damage in cancer cells is increased upon inhibition of DNA repair enzyme poly ADP-ribose polymerase (PARP), subsequently by reduced repair ability of DNA double-strand damage in BRCA-mutant cells which leads to cell apoptosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As the most commonly mutated genes tested in hereditary breast and ovarian cancer (HBOC), deleterious mutations of BRCA1/2 account for 20%-40% of the familial breast cancer and confer high lifetime risks of developing breast and ovarian cancers in women [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In addition, accumulating evidence has also showed potential links between BRCA1/2 mutations with increased susceptibility to intestinal, prostatic and pancreatic cancers.\u003c/p\u003e \u003cp\u003eLymphoma is one of the most leading causes responsible for cancer mortality in the world, among which approximately 90% of the cases are non-Hodgkin lymphoma (NHL) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. According to the Surveillance, Epidemiology, and End Results (SEER) Program, 80,470 new cases and 20,250 deaths of NHL patients are estimated in the United States in 2022 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A majority of NHL arises from mature B lymphocytes and a small number of cases derive from T lymphocytes or natural killer (NK) cells. Due to progressive acquisition of DNA alterations such as gene mutations, indels and chromosomal translocations, NHL develops and is particularly associated with specific gene abnormalities including translocations of BCL2 and MYC [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Meanwhile, infections of diverse viruses are also found in certain subtypes of NHL, suggesting their relationship with the occurrence of NHL [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although a slightly elevated risk is observed in family members, NHL is not generally considered hereditary [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHerein, we report a rare case of germline BRCA1 mutation (c.1115G＞A) in a patient who presented with long-term history of NHL and recent rectum adenocarcinoma, expanding the spectrum of BRCA1 mutation to other types of cancer as well as modifying current screening criteria for HBOC.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e The family was enrolled with informed consent into the hereditary cancers study. The phenotype of an individual was longitudinally and systematically evaluated. Exome capture, sequencing and analysis of DNA extracted from peripheral blood cells of the proband and her daughter were carried out. Bioinformatics tools were employed to analyze the candidate variants including point mutation, indel, copy number variation, fusion/rearrangement and large fragment rearrangement.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA 76-year-old Chinese female patient was admitted to the hospital in 1998 due to retroperitoneal lymphadenopathy. After diagnosed with NHL, she completed five cycles of standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen and acquired complete response (CR). The examination of computed tomography (CT) in 2001 showed retroperitoneal lymphadenopathy and suspected relapse. After six cycles of ifosfamide, cisplatin and etoposide regimen, she acquired partial response (PR). Another CT examination in 2006 demonstrated lymphadenopathy of retroperitoneum, mediastinum and bilateral supraclavicular. Based on the pathology, she was diagnosed with follicular lymphoma. After six cycles of fludarabine, mitoxantrone and dexamethasone regimen, she achieved PR. Surprising, after several years of palliative treatment, she was diagnosed with post-germinal center B cell-derived diffuse large B cell lymphoma (DLBCL) in 2021 followed by four cycles of combination of CHOP with rituximab (R-CHOP) resulting in PR. However, she quickly developed grade IV myelosuppression and was unable to tolerate systemic chemotherapy. A recent colonoscopy test in 2022 showed that she was diagnosed with rectum adenocarcinoma - a second primary tumor (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During her treatment and surveillance, genetic testing identified a pathologic germline mutation in BRCA1 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This variant was noted to be heterozygous for c.1115G＞A (p.W372*), which was previously reported in Chinese patients with HBOC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, ten somatic mutations including MSH2 c.520G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.G174*) and TP53 c.328C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.R110C) were detected (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The tumor mutation burden (TMB) was 16.78 Muts/Mb which was rated as high (from the Geneplus database). Also, microsatellite analysis showed microsatellite stability (MSS). Then she started oral fluzoparib. A month later she underwent coma and passed away.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSomatic and germline mutations in white blood cells\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecHGVS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003epHGVS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMutation abundance/\u003c/p\u003e \u003cp\u003eCopy Number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDNMT3A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1012_1014\u0026thinsp;+\u0026thinsp;2delinsA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.34%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMSH2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.520G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.G174*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.04%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCND1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGF19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGF3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFGF4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eTP53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.273G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.W91*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.05%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.328C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.R110C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.538G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.E180*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.15%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.376-1G＞A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e52.89%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRCA1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec.1115G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep.W372*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eGermline mutation, heterozygous\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe first began to investigate her family history for the reason of potential hereditary factors triggering colorectal cancer. Unexpectedly, her sister was diagnosed with ovarian cancer at age 62. Her father was diagnosed with unknown primary lesion at age 52. Her husband\u0026rsquo;s brother was diagnosed with NHL at age 69 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Combined with her BRCA1 mutation and her sister\u0026rsquo;s ovarian cancer history, her family could be referred as HBOC. Nevertheless, the patient was diagnosed with long-term NHL not HBOC syndrome. Notably, the same mutation for BRCA1 c.1115G＞A (p.W372*) was also detected in the white blood cells of her healthy daughter whose age was 49, increasing her predisposition to developing cancer.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs a caretaker tumor suppressor gene, BRCA1 is responsible for repairing DNA double-strand breaks and maintaining genomic stability [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Since firstly reported that BRCA1 was the cause of hereditary breast cancer through linkage analysis, BRCA1 mutation has been most frequently found among HBOC of all ethnic groups and races [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. According to the ClinVar database, more than 2,900 variants of BRCA1 are identified as pathogenic germline mutations, approximately 80% of which generate truncated proteins and reduced expression [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The estimated frequency of BRCA1 pathogenic variants is 0.2%-0.25%. Meanwhile, among all patients with breast and ovarian cancers, the retention rate of BRCA1 mutation is 1.45\u0026ndash;3.7% and 3.4%-9.9%, respectively [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Moreover, the risk of developing ovarian cancer with a BRCA1 mutation is 39\u0026ndash;63%, while the risk of developing male breast cancer, prostate cancer and pancreatic cancer is 1.2%, 8.6% and 1\u0026ndash;3%, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Despite strong evidence between BRCA1 mutation and HBOC occurrence persistently exists, in this case the patient harboring pathogenic BRCA1 mutation did not suffer from HBOC but NHL and rectum adenocarcinoma which required further investigations and modifications of current screening criteria for HBOC. Next we explored the mutation rate of BRCA1 in NHL patients from The Cancer Genome Atlas (TCGA) database. The results demonstrated that compared to mutant genes with high frequency, the mutation rate of BRCA1 is only 7%. And all the mutations are missense mutations (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Actually, previous studies have implicated elevated risks for leukemia or lymphoma in definite BRCA1 mutation carriers due to the association of the former with large gene rearrangements mediated by BRCA pathway [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Thus, it is reasonable to infer that great attention should also be paid to hematologic cancers with BRCA1-mutant patients, which needs further discussion and research.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn consideration of targeting BRCA1 mutation, PARP inhibitors are licensed as maintenance treatment for primary high-grade serous ovarian cancer, fallopian tube and peritoneal cancer after response (CR/PR) to platinum-based chemotherapy. A large number of clinical trials show that PARP inhibitors such as olaparib, niraparib and fluzoparib could significantly prolong the progression free survival (PFS), most notably in patients with BRCA-mutant ovarian cancers [\u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, a considerable number of patients will eventually develop resistance of PARP inhibitors on account of secondary somatic reversion mutations in BRCA genes in cancer cells, which could be explained by tumor heterogeneity and clonal expansion driven by chemotherapy [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this case, the patient did not seem to benefit from PARP inhibitor fluzoparib probably due to two reasons. One is that efficacy of PARP inhibitor may be influenced by BRCA-independent mechanisms that restore homologous recombination, which could be inferred that mutation of mismatch repair gene MSH2 was also found in this patient. The other is the loss or reduced expression of PARP-1 in cancer cells leading to off-target of drug. Thus we should detect the expression level of PARP-1 in this patient and estimate if PARP inhibitor is beneficial for her.\u003c/p\u003e \u003cp\u003eTraditionally, hereditary cancers are defined by loci of primary lesions. The major inherited cancer syndromes include hereditary nonpolyposis colorectal cancer, HBOC, hereditary diffuse gastric cancer and hereditary pancreatic cancer. Yet, mounting research has verified typical mutations that did not cause the corresponding hereditary cancers as shown in our case. This phenomenon triggers our deep understanding on redefining hereditary cancers based on classification of gene mutations, for instance, \u0026ldquo;hereditary BRCA1 syndromes\u0026rdquo;. Similarly, clinicians should firstly consider loci of primary lesions or typical hereditary cancers caused by gene mutations of patients upon genetic counseling, subsequently by the adjustment of the follow-up policies. This is particularly important because the knowledge of clinicians on the cancer is greatly related to the choice of treatment strategies and the prognosis of patients and their whole family.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eBRCA1 mutation is commonly found in HBOC and rarely leads to NHL and rectum adenocarcinoma. The present case indicates a pathologic germline mutation in BRCA1 (c.1115G＞A) with high TMB and MSS. Given its scarcity, germline BRCA1 mutation in NHL and rectum adenocarcinoma is rarely reported and correlation between them requires further research. Also our study broadens the spectrum of BRCA1 mutation to more types of cancer and modifies current screening criteria for HBOC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe owe thanks to the proband and her family for their collaboration, which was fundamental for publishing this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYX, JZ and XN examined and treated the patient. WH designed and supervised this study. YZ and WH wrote the manuscript. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (31701111), Major Science and Technology Project of Changzhou Health Commission (ZD202203) and Young Talent Development Plan of Changzhou Health Commission (CZQM2020008).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures followed were approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University (No. 2022-science-158). The patient\u0026rsquo;s next of kin has read and signed the informed consent form to participate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient\u0026rsquo;s next of kin provided written informed consent for publication of case details of the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYoshida K, Miki Y (2004) Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci 95(1):866\u0026ndash;871\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedenson B (2007) \u003cem\u003eThe BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers\u003c/em\u003e.BMC Cancer, 7(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaleh-Gohari N et al (2005) Spontaneous Homologous Recombination Is Induced by Collapsed Replication Forks That Are Caused by Endogenous DNA Single-Strand Breaks. Mol Cell Biol 25(16):7158\u0026ndash;7169\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRouleau M et al (2010) \u003cem\u003ePARP inhibition: PARP1 and beyond. Nat Rev Cancer.\u003c/em\u003e PubMed,\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7(12):937\u0026ndash;948\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCouch FJ, Nathanson KL, Offit K (2014) Two Decades After BRCA: Setting Paradigms in Personalized Cancer Care and Prevention. Science 343(6178):1466\u0026ndash;1470\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShankland KR, Armitage JO, Hancock BW (2012) Non-Hodgkin lymphoma. Rev Med Suisse 380(9844):2203\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSiegel RL et al (2022) \u003cem\u003eCancer statistics, 2022.\u003c/em\u003e CA: A Cancer Journal for Clinicians. 72:7\u0026ndash;331\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowzyk Al-Naeeb A et al (2018) \u003cem\u003eNon-Hodgkin lymphoma.\u003c/em\u003e Bmj, : p. k3204\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParkin DM (2011) 11. Cancers attributable to infection in the UK in 2010. Br J Cancer 105(S2):S49\u0026ndash;S56\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnsell SM (2015) \u003cem\u003eNon-Hodgkin Lymphoma: Diagnosis and Treatment.\u003c/em\u003e Mayo Clinic Proceedings, 90(8): p.\u0026nbsp;1152\u0026ndash;1163\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eN., et al., \u003cem\u003eBRCA1 germline mutations in Chinese patients with hereditary breast and ovarian cancer\u003c/em\u003e.International Journal of Gynecological Cancer,\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVenkitaraman AR (2014) \u003cem\u003eCancer Suppression by the Chromosome Custodians, BRCA1 and BRCA2\u003c/em\u003e.Science,\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHall JM et al (1990) \u003cem\u003eLinkage analysis of early-onset familial breast cancer to chromosome 17q12.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVenkitaraman AR (2019) How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility? DNA Repair 81:102668\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMomozawa Y et al (2018) \u003cem\u003eGermline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls\u003c/em\u003e.Nature Communications, 9(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnomoto T et al (2019) \u003cem\u003eThe first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE)\u003c/em\u003e.International Journal of Gynecological Cancer, ( 6)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoshida R (2020) Hereditary breast and ovarian cancer (HBOC): review of its molecular characteristics, screening, treatment, and prognosis. Breast Cancer 28(6):1167\u0026ndash;1180\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedenson B (2005) BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian. MedGenMed: Medscape general medicine 7(2):60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Boer M et al (2020) Increased prevalence of BRCA1/2 mutations in women with macrotextured breast implants and anaplastic large cell lymphoma of the breast. Blood 136(11):1368\u0026ndash;1372\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlotz DM, Wimberger P (2020) Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Arch Gynecol Obstet 302(5):1087\u0026ndash;1102\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoore K et al (2018) Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 379(26):2495\u0026ndash;2505\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLedermann JA et al (2016) Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 17(11):1579\u0026ndash;1589\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi N et al (2021) An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer. Clin Cancer Res 27(9):2452\u0026ndash;2458\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreaves M, Maley CC \u003cem\u003eClonal evolution in cancer\u003c/em\u003e.Nature\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGross J et al (2011) \u003cem\u003eSecondary Somatic Mutations Restoring BRCA1/2 Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas\u003c/em\u003e. 29:3008\u0026ndash;301522\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"BRCA1, Hereditary breast and ovarian cancer, Non-Hodgkin lymphoma, Rectum adenocarcinoma, Gene mutation","lastPublishedDoi":"10.21203/rs.3.rs-2622517/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2622517/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTumor suppressor gene BRCA1, known for its vital roles in regulating DNA damage, is frequently mutated in hereditary breast and ovarian cancer (HBOC), whose mutation also increases susceptibility to intestinal, prostatic and pancreatic cancers of patients. As the main subtype of lymphoma, non-Hodgkin lymphoma (NHL) is malignant disorders arising from immune cells and displays predominantly as lymphadenopathy or solid tumors, which is rarely considered hereditary. However, the relationship between BRCA1 mutation and NHL is rarely reported. Here, we present a primary NHL and recent second primary tumor rectum adenocarcinoma. Considering the hereditary factors in developing colorectal cancer, we investigated her family history and found her sister died with ovarian cancer. Meanwhile, her genetic testing identified a pathologic germline mutation in BRCA1 (c.1115G＞A). Taken into account the strong evidence between BRCA1 mutation and HBOC occurrence, we also did genetic test for her daughter and found the same BRCA1 mutation. Although strong evidence between BRCA1 mutation and HBOC exists, the patient harboring pathogenic BRCA1 mutation did not suffer from HBOC but NHL and rectum adenocarcinoma which required further investigations and modifications of current screening criteria for HBOC. And great attention should also be paid to her daughter with BRCA1 mutation carrier.\u003c/p\u003e","manuscriptTitle":"A pathogenic germline BRCA1 mutation in a patient with non-Hodgkin lymphoma and rectum adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-28 15:40:30","doi":"10.21203/rs.3.rs-2622517/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a9f9fe4f-2780-4b9f-86c7-1ad88014f590","owner":[],"postedDate":"February 28th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-02-28T15:48:32+00:00","versionOfRecord":[],"versionCreatedAt":"2023-02-28 15:40:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2622517","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2622517","identity":"rs-2622517","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}