دورية أكاديمية
PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer.
| العنوان: | PTEN Loss and BRCA1 Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer. |
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| المؤلفون: | Kraya AA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Maxwell KN; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Eiva MA; Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Wubbenhorst B; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Pluta J; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Feldman M; Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Nayak A; Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Powell DJ Jr; Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Domchek SM; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.; Basser Center for BRCA and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Vonderheide RH; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.; Basser Center for BRCA and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA., Nathanson KL; Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.; Basser Center for BRCA and Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. |
| المصدر: | JCO precision oncology [JCO Precis Oncol] 2022 Feb; Vol. 6, pp. e2100159. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society of Clinical Oncology Country of Publication: United States NLM ID: 101705370 Publication Model: Print Cited Medium: Internet ISSN: 2473-4284 (Electronic) Linking ISSN: 24734284 NLM ISO Abbreviation: JCO Precis Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Alexandria, VA : American Society of Clinical Oncology, [2017]- |
| مواضيع طبية MeSH: | Germ-Line Mutation* , Ovarian Neoplasms*/genetics, BRCA1 Protein/genetics ; Carcinoma, Ovarian Epithelial/genetics ; DNA Methylation/genetics ; Humans ; PTEN Phosphohydrolase/genetics ; Promoter Regions, Genetic/genetics |
| مستخلص: | Purpose: Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in BRCA1/2 mutation-associated cancers. Materials and Methods: Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of BRCA1/2 and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline BRCA1/2 pathogenic variants from Penn. Results: We found two groups of BRCA1/2 ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for PTEN loss (11, 30%) and BRCA1 promoter-hypermethylated (10, 27%; P = .0016) and (2) PTEN wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; P = .0186, median OS not reached v median OS = 66.1 months). BRCA1/2 -mutant PTEN loss and BRCA1 promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression ( P = .0030), cytolytic index ( P = .034), and cytokine expression but higher homologous recombination deficiency scores ( P = .00013). Large-scale state transitions were the primary discriminating feature ( P = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, PTEN loss and high homologous recombination deficiency cancers exhibited fewer CD3+ ( P = .05), CD8+ ( P = .012), and FOXP3+ ( P = .0087) T cells; decreased PRF1 expression ( P = .041); and lower immune costimulatory and inhibitory molecule expression. Conclusion: Our study suggests that within ovarian cancers with genetic loss of BRCA1/2 are two subsets exhibiting differential immunogenicity, with lower levels associated with PTEN loss and BRCA hypermethylation. These genomic features of BRCA1/2 -associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic. Competing Interests: Michael FeldmanResearch Funding: Scopio Inc (Inst) Daniel J. PowellStock and Other Ownership Interests: Atara Biotherapeutics, InsTIL Bio IncConsulting or Advisory Role: Neon Therapeutics, Iovance Biotherapeutics, Tmunity Therapeutics Inc, InsTIL Bio Inc, Bellicum PharmaceuticalsResearch Funding: Lilly, Tmunity Therapeutics Inc, Incyte, Monojul, AstraZeneca/MedImmune, InsTIL BioPatents, Royalties, Other Intellectual Property: I hold patents in the field of CAR T-cell therapy in oncology and have received royalties related to their licensing to Novartis, I hold patents in the field of CAR T-cell therapy in oncology and have received royalties related to their licensing to Tmunity, and I hold patents in the field of universal immune receptor T-cell therapy in oncology and have received payments related to their licensing to Prescient TherapeuticsTravel, Accommodations, Expenses: Iovance Biotherapeutics Susan M. DomchekHonoraria: AstraZeneca, GlaxoSmithKlineResearch Funding: AstraZeneca (Inst), Clovis Oncology (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Robert H. VonderheidePatents, Royalties, Other Intellectual Property: Receives royalties from Children's Hospital Boston for a licensed research-only monoclonal antibody, Inventor on a licensed patient regarding cancer vaccine antigensNo other potential conflicts of interest were reported. |
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| معلومات مُعتمدة: | K12 CA076931 United States CA NCI NIH HHS; P30 CA016520 United States CA NCI NIH HHS; T32 HG009495 United States HG NHGRI NIH HHS; TL1 TR001880 United States TR NCATS NIH HHS |
| المشرفين على المادة: | 0 (BRCA1 Protein) 0 (BRCA1 protein, human) EC 3.1.3.67 (PTEN Phosphohydrolase) EC 3.1.3.67 (PTEN protein, human) |
| تواريخ الأحداث: | Date Created: 20220224 Date Completed: 20220404 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC8982238 |
| DOI: | 10.1200/PO.21.00159 |
| PMID: | 35201851 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2473-4284 |
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| DOI: | 10.1200/PO.21.00159 |