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1.
Clin Cancer Res ; 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33737308

RESUMO

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals. EXPERIMENTAL DESIGN: We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I-IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models. RESULTS: Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89-0.96] in the discovery cohort and 0.92 (95% CI, 0.87-0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95-0.98) in the discovery cohort and 0.93 (95% CI, 0.90-0.96) in the replication cohort. All nine serum proteins of index I were found in index II. CONCLUSIONS: This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.

3.
Cancers (Basel) ; 12(11)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198174

RESUMO

Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

4.
Nat Commun ; 11(1): 5660, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168830

RESUMO

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.


Assuntos
Retrovirus Endógenos/genética , Neoplasias Hematológicas/virologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Linfócitos T CD8-Positivos , Epigênese Genética , Epitopos de Linfócito T , Perfilação da Expressão Gênica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia , Monitorização Imunológica , Células Mieloides , Neoplasias
5.
Clin Cancer Res ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208343

RESUMO

PURPOSE: Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2 mutant cases. EXPERIMENTAL DESIGN: We use a series of NER proficient and NER deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anti-cancer agent. In addition, we use available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity. RESULTS: We identify a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the transcription-coupled NER (TC-NER) pathway and leads to robust responses in vitro and in vivo, including in models with acquired cisplatin resistance, while having minimal effect on cells with intact NER. We also find that a composite mutational signature of ERCC2 deficiency is strongly associated with cisplatin response in patients and is also associated with cisplatin and irofulven sensitivity in preclinical models. CONCLUSIONS: Tumor NER deficiency confers sensitivity to irofulven, a previously abandoned anti-cancer agent with minimal activity in NER proficient cells. A composite mutational signature of NER deficiency may be useful in identifying patients likely to respond to NER-targeting agents including cisplatin and irofulven.

6.
Prz Gastroenterol ; 15(3): 215-219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005266

RESUMO

Introduction: Several reports have stated that thrombocytosis is associated with worse survival and higher rate of metastasis in solid tumours. A study in ovarian tumours implicated IL-6 produced by tumour cells as a key mechanistic factor. Aim: To evaluate the relevance of this paraneoplastic pathway in gastrointestinal cancer. Material and methods: After excluding thromboembolic and inflammatory disorders, 161 patients were enrolled who had been operated due to various gastrointestinal cancer at the 1st Department of Surgery at the Semmelweis University between 2015 and 2017. Platelet counts and serum IL-6 levels were determined from preoperative blood samples. Thrombocytosis was defined as the upper limit of normal platelet count, e.g. 400 × 103/µl. Results: A weak but significantly positive correlation was found between elevated platelet counts and serum IL-6 (correlation coefficient: R = 0.214, p = 0.006), which became more pronounced in colon and oesophageal cancer if evaluated in the different tumour types (R = 0.292 and R = 0.419, respectively). However, using a multivariant linear regression model (R 2 = 0.47) corrected with haemoglobin, white blood cell count, and advanced disease stage, the analysis showed no significant correlation between serum IL-6 and platelet counts. Conclusions: In gastrointestinal cancer our study did not support the paracrine-mediated paraneoplastic pathway described in ovarian tumors. Thrombocytosis showed significant correlation with white blood cells instead of serum IL-6, which implies that the inflammatory process may influence both parameters. Further studies are needed on larger patient cohorts.

7.
Cancer Discov ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046534

RESUMO

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor-1 (FPR1) on the surface of dendritic cells (DCs). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3 (TLR3), polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or that of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC and T lymphocyte-mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared to wild type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.

8.
Thorac Cancer ; 11(11): 3193-3204, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32941706

RESUMO

BACKGROUND: Metastatic lung cancer is a debilitating disease, but with the advances in immunotherapy, therapeutic options have vastly increased. Numerous complete blood count parameters (CBC) have been described as easily accessible biomarkers that might predict response to immunotherapy. However, to date, no comprehensive study has been performed on the longitudinal changes of these parameters during cancer progression. METHODS: The clinicopathological variables and CBC parameters of 986 advanced stage lung cancer patients were retrospectively analyzed. Blood tests were performed as part of the routine checkup and the results were recorded at the time of the diagnosis of the primary tumor, the diagnosis of brain or bone metastases, and also during the last available follow-up. RESULTS: In the experimental subcohort, 352 and 466 patients were diagnosed with brain and bone metastases, respectively. The control group consisted of 168 patients without clinically detectable or other distant organ metastases. In our longitudinal analyses, we found significantly decreasing absolute lymphocyte count (ALC: P < 0.001), and significantly increasing absolute neutrophil count (ANC: P < 0.001) levels in all patient subgroups, irrespective of histopathological type and metastatic site. Interestingly, patients with brain metastases had significantly descending-ascending platelet count (PLT) trendlines (P < 0.001), while the bone metastatic subgroup exhibited significantly ascending-descending trendlines (P = 0.043). CONCLUSIONS: Significantly decreasing ALC, significantly increasing ANC and fluctuating PLT levels may be found in brain and bone metastatic lung cancer patients during disease progression. Our findings might contribute to improve personalized healthcare in this devastating malignancy. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Significantly decreasing ALC, and significantly increasing ANC levels can be found in advanced-stage lung cancer patients during disease progression Patients with brain metastases have descending-ascending PLT trendlines, while patients with bone metastases exhibit ascending-descending trendlines during disease progression WHAT THIS STUDY ADDS: The descending values for ALC, and the ascending mean values for PLT and ANC, might be suggestive of poor response to second- or third-line immunotherapy in advanced-stage lung cancer patients. The current study might help to improve patient selection and treatment strategies for brain and/or bone metastatic lung cancer patients.

9.
Nature ; 587(7832): 126-132, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32879494

RESUMO

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.

10.
Cancers (Basel) ; 12(8)2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32824649

RESUMO

Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue "niche", cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.

11.
Science ; 369(6506): 936-942, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820119

RESUMO

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.


Assuntos
Antígenos de Neoplasias/imunologia , Bacteriófagos/imunologia , Streptococcus faecium ATCC 9790/virologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas da Cauda Viral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , Ciclofosfamida/uso terapêutico , Epitopos/imunologia , Fezes/virologia , Antígenos H-2/imunologia , Humanos , Camundongos , Neoplasias/dietoterapia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteínas da Cauda Viral/uso terapêutico
13.
J Cell Biol ; 219(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391871

RESUMO

BRCA1/2 help maintain genomic integrity by stabilizing stalled forks. Here, we identify the E3 ligase RFWD3 as an essential modulator of stalled fork stability in BRCA2-deficient cells and show that codepletion of RFWD3 rescues fork degradation, collapse, and cell sensitivity upon replication stress. Stalled forks in BRCA2-deficient cells accumulate phosphorylated and ubiquitinated replication protein A (ubq-pRPA), the latter of which is mediated by RFWD3. Generation of this intermediate requires SMARCAL1, suggesting that it depends on stalled fork reversal. We show that in BRCA2-deficient cells, rescuing fork degradation might not be sufficient to ensure fork repair. Depleting MRE11 in BRCA2-deficient cells does block fork degradation, but it does not prevent fork collapse and cell sensitivity in the presence of replication stress. No such ubq-pRPA intermediate is formed in BRCA1-deficient cells, and our results suggest that BRCA1 may function upstream of BRCA2 in the stalled fork repair pathway. Collectively, our data uncover a novel mechanism by which RFWD3 destabilizes forks in BRCA2-deficient cells.

14.
Front Immunol ; 11: 373, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226429

RESUMO

Mutation-derived neoantigens are important targets for T cell-mediated reactivity toward tumors and, due to their unique tumor expression, an attractive target for immunotherapy. Neoepitope-specific T cells have been detected across a number of solid cancers with high mutational burden tumors, but neoepitopes have been mostly selected from single nucleotide variations (SNVs), and little focus has been given to neoepitopes derived from in-frame and frameshift indels, which might be equally important and potentially highly immunogenic. Clear cell renal cell carcinomas (ccRCCs) are medium-range mutational burden tumors with a high pan-cancer proportion of frameshift mutations. In this study, the mutational landscape of tumors from six RCC patients was analyzed by whole-exome sequencing (WES) of DNA from tumor fragments (TFs), autologous tumor cell lines (TCLs), and tumor-infiltrating lymphocytes (TILs, germline reference). Neopeptides were predicted using MuPeXI, and patient-specific peptide-MHC (pMHC) libraries were created for all neopeptides with a rank score < 2 for binding to the patient's HLAs. T cell recognition toward neoepitopes in TILs was evaluated using the high-throughput technology of DNA barcode-labeled pMHC multimers. The patient-specific libraries consisted of, on average, 258 putative neopeptides (range, 103-397, n = 6). In four patients, WES was performed on two different sources (TF and TCL), whereas in two patients, WES was performed only on TF. Most of the peptides were predicted from both sources. However, a fraction was predicted from one source only. Among the total predicted neopeptides, 16% were derived from frameshift indels. T cell recognition of 52 neoepitopes was detected across all patients (range, 4-18, n = 6) and spanning two to five HLA restrictions per patient. On average, 21% of the recognized neoepitopes were derived from frameshift indels (range, 0-43%, n = 6). Thus, frameshift indels are equally represented in the pool of immunogenic neoepitopes as SNV-derived neoepitopes. This suggests the importance of a broad neopeptide prediction strategy covering multiple sources of tumor material, and including different genetic alterations. This study, for the first time, describes the T cell recognition of frameshift-derived neoepitopes in RCC and determines their immunogenic profile.

15.
Clin Cancer Res ; 26(11): 2673-2680, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32071115

RESUMO

PURPOSE: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. EXPERIMENTAL DESIGN: Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. RESULTS: Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. CONCLUSIONS: These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

16.
Oncotarget ; 11(4): 362-377, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32064040

RESUMO

Prostate cancer is a disease with heterogeneity of multiple gene transcriptomes and biological signaling pathways involved in tumor development. The prostate transmembrane protein, androgen induced 1 (PMEPA1), a multifunctional protein played critical roles in prostate tumorigenesis. The pleiotropic nature of PMEPA1 in modulating androgen and TGF-ß signaling as well as splice variants mechanisms for functional regulations of cancer-associated genes prompted us to investigate the biological roles of PMEPA1 isoforms in prostate cancer. In addition to 4 reported PMEPA1 isoforms (a, b, c and d), one novel isoform PMEPA1-e was identified with RNA Seq analysis of hormone responsive VCaP, LNCaP cells and human prostate cancer samples from The Cancer Genome Atlas (TCGA) dataset. We analyzed the structures, expressions, biological functions and clinical relevance of PMEPA1-e isoform and less characterized isoforms c and d in the context of prostate cancer and AR/TGF-ß signaling. The expression of PMEPA1-e was induced by androgen and AR. In contrast, PMEPA1-d was responsive to TGF-ß and inhibited TGF-ß signaling. Both PMEPA1-d and PMPEA1-e promoted the growth of androgen independent prostate cancer cells. Although PMEPA1-c was responsive to TGF-ß, it was found to have no impacts on cell growth and androgen/TGF-ß signaling. The TCGA data analysis from 499 patients showed higher expression ratios of PMEAP1-b versus -d or -e strongly associated with enhanced Gleason score. Taken together, our findings first time defined the prostate tumorigenesis mediated by PMEPA1-d and -e isoforms, providing novel insights into the new strategies for prognostic evaluation and therapeutics of prostate tumor.

17.
Cancers (Basel) ; 11(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842254

RESUMO

Dysfunctions of androgen/TGF-ß signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-ß signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-ß responsive PC3 cells. TGF-ß signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-ß-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-ß signaling.

18.
Genome Biol ; 20(1): 240, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727117

RESUMO

BACKGROUND: Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. RESULTS: Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. CONCLUSION: Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.


Assuntos
Genes cdc , Mutagênese , Variantes Farmacogenômicos , Inibidores de Poli(ADP-Ribose) Polimerases , Reparo de DNA por Recombinação/genética , Animais , Linhagem Celular , Galinhas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mutação Puntual
19.
Nat Med ; 25(10): 1540-1548, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591602

RESUMO

An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2-6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.


Assuntos
Evolução Clonal/genética , Neoplasias Pulmonares/genética , Prognóstico , Transcriptoma/genética , Idoso , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Intervalo Livre de Doença , Exoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Fatores de Risco , Sequenciamento Completo do Exoma
20.
Magy Onkol ; 63(3): 233-238, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533144

RESUMO

Survival of patients with lung cancer is unfavorable. Distant metastasis is detected in more than half of the patients at diagnosis. In advanced stages, platinum-based chemotherapy has been the main therapeutic approach for a long time, however, in 2004 targeted therapies emerged. Recently, PDL1/ PD-1 inhibitors have been introduced in the treatment of metastatic lung cancers, for which the therapeutic criteria are increasingly outlined. Based on international and Hungarian data, it is likely that determination of PD-L1 expression in the primary tumor samples may be sufficient for the establishment of therapeutic indication, if PD-L1 expression of tumor cells remains the sole criterion. However, if the combined positive score, which takes into account PD-L1 expression of both tumor and immune cells, will be introduced as a therapeutic criterion, testing of all the actual tumor samples may be required to initiate treatment, as conventional oncotherapies may affect the PD-L1 expression of immune cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo
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