An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

Ewa Przybytkowski, Thomas Davis, Abdelrahman Hosny, Julia Eismann, Ursula A Matulonis, Gerburg M Wulf, Sheida Nabavi, Ewa Przybytkowski, Thomas Davis, Abdelrahman Hosny, Julia Eismann, Ursula A Matulonis, Gerburg M Wulf, Sheida Nabavi

Abstract

Background: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies.

Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas.

Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD.

Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.

Trial registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.

Keywords: BRCA1; BRCA2; BRCAness; Biomarkers; Breast cancer; Homologous recombination deficiency; Immunotherapy; Ovarian cancer; PARP; Platinum resistance; Tumor mutation burden.

Conflict of interest statement

GMW reports grants from SU2C-AACR-DT0209, grants from Mary Kay Ash Foundation, grants from Ovarian Cancer Research Foundation, grants from Breast Cancer Alliance, grants from Breast Cancer Research Foundation, grants from NIH RO1 1R01CA226776–01, grants from Merck&Co, during the conduct of the study; In addition, Dr. Wulf has a patent Application 14/348810, Compositions and Methods for the Treatment of proliferative diseases pending, and a patent US 20090258352 A1, Pin1 as a marker for abnormal cell growth licensed to Cell Signaling; R&D Systems.

UAM reports personal fees from Astrazeneca, personal fees from Myriad Genetics, personal fees from Clovis, personal fees from Merck, personal fees from Eli Lilly, personal fees from Mersana, personal fees from Geneos, personal fees from Fuji Film, from 2X Oncology, personal fees from Cerulean, personal fees from Immunogen, personal fees from Novartis, outside the submitted work .

Figures

Fig. 1
Fig. 1
Biological processes enriched in breast and ovarian non-carriers from the clinical trial. The list of 813 genes was analyzed with Panther classification system (http://www.pantherdb.org). The table shows the top most significantly enriched biological process. The complete list of enriched processes is shown in Additional file 2: Table S2
Fig. 2
Fig. 2
The common genes upregulated in breast and ovarian non-carriers from the clinical trial are involved in immune functions. 60 genes overexpressed in breast non-carriers overlapped with those overexpressed in ovarian non-carriers. The list of 60 genes was analyzed with Panther classification system (http://www.pantherdb.org). The table shows the top most significantly enriched biological process. The complete list of processes is shown in Additional file 7: Table S7
Fig. 3
Fig. 3
Patterns of expression of 782 genes representing 28 immune cell types, in samples from the clinical trial. Heat-maps represent expression of 782 genes in breast (a) and ovarian (b) samples from our cohort. The 782 gene list is shown in Additional file 8: Table S8. Breast carriers (BC), breast non-carriers (BN), ovarian carriers (OC), ovarian non-carriers (ON). The numbers correspond to the patient number (Fig. 4a)
Fig. 4
Fig. 4
Subtypes of hereditary and sporadic breast and ovarian cancers in the clinical trial and in TCGA database. a) List of clinical trial samples. Subtyping of tumors from this cohort was obtained using TNBCtype tool (http://cbc.mc.vanderbilt.edu/tnbc) for breast cancers and CLOVAR scheme [14] for ovarian cancers. b) List of hereditary breast tumors from TCGA. Subtyping of these tumors was acquired from Lehmann at al [16]. c) Distribution of TNBC subtypes within TCGA breast cancers (sporadic TNBC and hereditary BRCA1 and BRCA2 related breast tumors). d) Distribution of HGSOC subtypes within TCGA ovarian cancers (sporadic HGSOC and hereditary BRCA1 and BRCA2 related ovarian tumors). The list of breast germline mutation carriers was established according the information acquired from CBioPortal (http://www.cbioportal.org) and iAtlas https://www.cri-iatlas.org/about/. The list of ovarian germline mutation carriers was established from CBioPortal (http://www.cbioportal.org) and it is shown in Additional file 9: Table S9. Immune Subtypes for our cohort were identified using tool available in iAtlas interactive platform and for TCGA samples were download from the site
Fig. 5
Fig. 5
Hereditary breast and ovarian cancers from the clinical trial and from TCGA database show high TMB and low overall immune activity relative to the sporadic tumors. Data obtained for our cohort (a, b), data acquired for TCGA breast (c-e) and ovarian (f-h) cancers. c and f) Somatic mutation count acquired from CBioPortal (http://www.cbioportal.org), d and g) Global immune gene expression representing averaged expression of genes from 28 meta-gene sets. Expression data was downloaded from FireBrowse data version 2016_01_28 (this link http://firebrowse.org/) e and h) Leukocyte fraction acquired from Cancer Research Institute iAtlas https://www.cri-iatlas.org/about/. The dotted lines indicate the average value for all the samples in each panel
Fig. 6
Fig. 6
Pattern of genomic instability vary widely within hereditary and sporadic breast and ovarian cancers and it is different in BRCA1 versus BRCA2 germline related tumors. Heat-maps represent genomic instability measures in breast (a) and ovarian (b) cancers from TCGA. The data was acquired from Cancer Research Institute iAtlas (https://www.cri-iatlas.org/about/)
Fig. 7
Fig. 7
High HR deficiency score characterize most of TNBC and predicts platinum sensitivity in HGSOC. a) Distribution of HR deficiency score across 33 TCGA cancer types, b) across the breast cancer subtypes and c) across the HGSOC subtypes. The data was acquired from Cancer Research Institute iAtlas (https://www.cri-iatlas.org/about/). d) HR deficiency score in HGSOC, which are resistant or sensitive to platinum-based therapy. The sensitivity/resistance criteria were established according to Integrated genomic analysis of ovarian carcinoma [27] and applied to TCGA data (Additional file 10: Table S10). The dotted lines indicate mean HR deficiency score for all HGSOC (top line) and all breast cancers (bottom line)
Fig. 8
Fig. 8
The immune response pattern in hereditary and sporadic breast and ovarian cancers from the clinical trial and from TCGA database. Expression of PD-L1 (CD274) in carriers and non-carriers from our cohort (a) in breast tumors from TCGA (b) and in HGSOC from TCGA (c). Heat-map showing relative contribution (percentage) of six universal intratumor immune states (C1-C6) within microenvironments of tumors from our cohort and from hereditary and sporadic breast and ovarian cancers form TCGA (d). PD-L1 for TCGA samples was downloaded from The Cancer Immunome Atlas (TCIA) (https://tcia.at/home). Immune Subtyping on the clinical trial samples was performed using the Immune Subtype Classifier available from The Cancer Research Institutes iAtlas (https://www.cri-iatlas.org/about/) and is also shown in Fig. 4a. Immune Subtypes for TCGA data were download from iAtlas

References

    1. Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J. 1957;1:841–847. doi: 10.1136/bmj.1.5023.841.
    1. Thomas L. Cellular and Humoral aspects of the hypersensitive states. New York: Hoeber-Harper; 1959.
    1. Mouw KW, Goldberg MS, Konstantinopoulos PA, D’Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017;7:675–693. doi: 10.1158/-17-0226.
    1. Ohmoto A, Yachida S. Current status of poly (ADP-ribose) polymerase inhibitors and future directions. OTT. 2017;10:5195–5208. doi: 10.2147/OTT.S139336.
    1. Turner N, Tutt A, Ashworth A. Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer. 2004;4:814–819. doi: 10.1038/nrc1457.
    1. Wang Y, Ung MH, Cantor S, Cheng C. Computational investigation of homologous recombination DNA repair deficiency in sporadic breast Cancer. Sci Rep. 2017;7:15742. doi: 10.1038/s41598-017-16138-2.
    1. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110–120. doi: 10.1038/nrc.2015.21.
    1. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16:2598–2608. doi: 10.1158/1535-7163.MCT-17-0386.
    1. Sedic M, Kuperwasser C. BRCA1-hapoinsufficiency: unraveling the molecular and cellular basis for tissue-specific cancer. Cell Cycle. 2016;15:621–627. doi: 10.1080/15384101.2016.1141841.
    1. Joosse SA. BRCA1 and BRCA2: a common pathway of genome protection but different breast cancer subtypes. Nat Rev Cancer. 2012;12:372. doi: 10.1038/nrc3181-c2.
    1. Hyman DM, Solit DB, Arcila ME, Cheng DT, Sabbatini P, Baselga J, et al. Precision medicine at memorial Sloan Kettering Cancer center: clinical next-generation sequencing enabling next-generation targeted therapy trials. Drug Discov Today. 2015;20:1422–1428. doi: 10.1016/j.drudis.2015.08.005.
    1. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–2767. doi: 10.1172/JCI45014.
    1. Chen X, Li J, Gray WH, Lehmann BD, Bauer JA, Shyr Y, et al. TNBCtype: a subtyping tool for triple-negative breast Cancer. Cancer Informat. 2012;11:147–156. doi: 10.4137/CIN.S9983.
    1. Verhaak RGW, Tamayo P, Yang J-Y, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123:517–525.
    1. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009;462:108–112. doi: 10.1038/nature08460.
    1. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast Cancer molecular subtypes: implications for Neoadjuvant chemotherapy selection. PLoS One. 2016;11:e0157368. doi: 10.1371/journal.pone.0157368.
    1. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61. doi: 10.1016/j.cell.2014.12.033.
    1. Iglesia MD, Parker JS, Hoadley KA, Serody JS, Perou CM, Vincent BG. Genomic analysis of immune cell infiltrates across 11 tumor types. J Natl Cancer Inst. 2016;108:1. doi: 10.1093/jnci/djw144.
    1. Iglesia MD, Vincent BG, Parker JS, Hoadley KA, Carey LA, Perou CM, et al. Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin Cancer Res. 2014;20:3818–3829. doi: 10.1158/1078-0432.CCR-13-3368.
    1. Hackl H, Charoentong P, Finotello F, Trajanoski Z. Computational genomics tools for dissecting tumour-immune cell interactions. Nat Rev Genet. 2016;17:441–458. doi: 10.1038/nrg.2016.67.
    1. Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. Pan-cancer Immunogenomic analyses reveal genotype-Immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18:248–262. doi: 10.1016/j.celrep.2016.12.019.
    1. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–795. doi: 10.1016/j.immuni.2013.10.003.
    1. Hubalek M, Czech T, Müller H. Biological subtypes of triple-negative breast Cancer. Breast Care (Basel) 2017;12:8–14. doi: 10.1159/000455820.
    1. Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SAW, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 2015;21:1688–1698. doi: 10.1158/1078-0432.CCR-14-0432.
    1. Murakami R, Matsumura N, Mandai M, Yoshihara K, Tanabe H, Nakai H, et al. Establishment of a novel Histopathological classification of high-grade serous ovarian carcinoma correlated with Prognostically distinct gene expression subtypes. Am J Pathol. 2016;186:1103–1113. doi: 10.1016/j.ajpath.2015.12.029.
    1. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14:5198–5208. doi: 10.1158/1078-0432.CCR-08-0196.
    1. Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–615. doi: 10.1038/nature10166.
    1. Omarini C, Guaitoli G, Pipitone S, Moscetti L, Cortesi L, Cascinu S, et al. Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going. Cancer Manag Res. 2018;10:91–103. doi: 10.2147/CMAR.S146658.
    1. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K, et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149:979–993. doi: 10.1016/j.cell.2012.04.024.
    1. Severson TM, Peeters J, Majewski I, Michaut M, Bosma A, Schouten PC, et al. BRCA1-like signature in triple negative breast cancer: molecular and clinical characterization reveals subgroups with therapeutic potential. Mol Oncol. 2015;9:1528–1538. doi: 10.1016/j.molonc.2015.04.011.
    1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. doi: 10.1126/science.aaa4971.
    1. Daud AI, Wolchok JD, Robert C, Hwu W-J, Weber JS, Ribas A, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody Pembrolizumab in melanoma. J Clin Oncol. 2016;34:4102–4109. doi: 10.1200/JCO.2016.67.2477.
    1. Spigel DR, Schrock AB, Fabrizio D, Frampton GM, Sun J, He J, et al. Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies. J Clin Oncol. 2016;34:9017. doi: 10.1200/JCO.2016.34.15_suppl.9017.
    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–2520. doi: 10.1056/NEJMoa1500596.
    1. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang T-H, et al. The Immune Landscape of Cancer. Immunity. 2018;48:812–830.e14. doi: 10.1016/j.immuni.2018.03.023.
    1. Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. Cell Rep. 2018;23:239–254.e6. doi: 10.1016/j.celrep.2018.03.076.
    1. van Beers EH, van Welsem T, Wessels LFA, Li Y, Oldenburg RA, Devilee P, et al. Comparative genomic hybridization profiles in human BRCA1 and BRCA2 breast tumors highlight differential sets of genomic aberrations. Cancer Res. 2005;65:822–827.
    1. Wang C, Zhang J, Wang Y, Ouyang T, Li J, Wang T, et al. Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer. Ann Oncol. 2015;26:523–528. doi: 10.1093/annonc/mdu559.
    1. Wunderle M, Gass P, Häberle L, Flesch VM, Rauh C, Bani MR, et al. BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients. Breast Cancer Res Treat. 2018;171:85–94. doi: 10.1007/s10549-018-4797-8.
    1. Nicolas E, Bertucci F, Sabatier R, Gonçalves A. Targeting BRCA Deficiency in Breast Cancer: What are the Clinical Evidences and the Next Perspectives? Cancers (Basel) 2018;10:1. doi: 10.3390/cancers10120506.
    1. Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res. 2013;19:5533–5540. doi: 10.1158/1078-0432.CCR-13-0799.
    1. Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain K, et al. Abstract GS3–08: Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL. General Session Abstracts. Am Assoc Cancer Res. 2018:GS3–08 [Cited 2019 May 22]. Available from: .
    1. Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7:13587–13598. doi: 10.18632/oncotarget.7277.
    1. Nolan E, Savas P, Policheni AN, Darcy PK, Vaillant F, Mintoff CP, et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci Transl Med. 2017;9:eaal4922. doi: 10.1126/scitranslmed.aal4922.
    1. Sobral-Leite M, Van de Vijver K, Michaut M, van der Linden R, Hooijer GKJ, Horlings HM, et al. Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival. Oncoimmunology. 2018;7:e1509820. doi: 10.1080/2162402X.2018.1509820.
    1. Wang X, Li M. Correlate tumor mutation burden with immune signatures in human cancers. BMC Immunol. 2019;20:4. doi: 10.1186/s12865-018-0285-5.
    1. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30:44–56. doi: 10.1093/annonc/mdy495.
    1. Burgess M, Puhalla S. BRCA 1/2-mutation related and sporadic breast and ovarian cancers: more alike than different. Front Oncol. 2014;4:19.
    1. Joosse SA, van Beers EH, Tielen IHG, Horlings H, Peterse JL, Hoogerbrugge N, et al. Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat. 2009;116:479–489. doi: 10.1007/s10549-008-0117-z.
    1. Schouten PC, Grigoriadis A, Kuilman T, Mirza H, Watkins JA, Cooke SA, et al. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms. Mol Oncol. 2015;9:1274–1286. doi: 10.1016/j.molonc.2015.03.002.
    1. Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing Neoadjuvant chemotherapy in patients with triple-negative breast Cancer. Clin Cancer Res. 2016;22:3764–3773. doi: 10.1158/1078-0432.CCR-15-2477.
    1. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006;6:836–848. doi: 10.1038/nri1961.
    1. Safonov A, Jiang T, Bianchini G, Győrffy B, Karn T, Hatzis C, et al. Immune gene expression is associated with genomic aberrations in breast Cancer. Cancer Res. 2017;77:3317–3324. doi: 10.1158/0008-5472.CAN-16-3478.
    1. Senovilla L, Vitale I, Martins I, Kepp O, Galluzzi L, Zitvogel L, et al. An anticancer therapy-elicited immunosurveillance system that eliminates tetraploid cells. Oncoimmunology. 2013;2:e22409. doi: 10.4161/onci.22409.
    1. Senovilla L, Galluzzi L, Marino G, Vitale I, Castedo M, Kroemer G. Immunosurveillance against cancer-associated hyperploidy. Oncotarget. 2012;3:1270–1271. doi: 10.18632/oncotarget.753.
    1. Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science. 2017;355:eaaf8399. doi: 10.1126/science.aaf8399.
    1. Pusztai L, Karn T, Safonov A, Abu-Khalaf MM, Bianchini G. New strategies in breast Cancer: immunotherapy. Clin Cancer Res. 2016;22:2105–2110. doi: 10.1158/1078-0432.CCR-15-1315.
    1. Sherman MH, Kuraishy AI, Deshpande C, Hong JS, Cacalano NA, Gatti RA, et al. AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol Cell. 2010;39:873–885. doi: 10.1016/j.molcel.2010.08.019.
    1. Björkman A, Qvist P, Du L, Bartish M, Zaravinos A, Georgiou K, et al. Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells. Proc Natl Acad Sci U S A. 2015;112:2157–2162. doi: 10.1073/pnas.1418947112.
    1. Friedenson B. The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers. BMC Cancer. 2007;7:152. doi: 10.1186/1471-2407-7-152.
    1. Kim HS, Lee SW, Choi YJ, Shin SW, Kim YH, Cho MS, et al. Novel Germline mutation of BRCA1 gene in a 56-year-old woman with breast Cancer, ovarian Cancer, and diffuse large B-cell lymphoma. Cancer Res Treat. 2015;47:534–538. doi: 10.4143/crt.2013.151.
    1. Levin B, Lech D, Friedenson B. Evidence that BRCA1- or BRCA2-associated cancers are not inevitable. Mol Med. 2012;18:1327–1337. doi: 10.2119/molmed.2012.00280.
    1. Friedenson B. A theory that explains the tissue specificity of BRCA1/2 related and other hereditary cancers. J Med Med Sci. 2010;1:372–384.
    1. Finn OJ. A Believer’s overview of Cancer Immunosurveillance and immunotherapy. J Immunol. 2018;200:385–391. doi: 10.4049/jimmunol.1701302.
    1. Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, et al. Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell. 2017;168:487–502.e15. doi: 10.1016/j.cell.2016.12.022.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться