Purpose
Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract with increasing incidence rates. Etiologically, HPV-dependent and HPV-independent VSCC are ...distinguished. Surgical treatment and/or radiotherapy represent the therapeutic mainstay for localized disease. For recurrent or metastatic VSCC, treatment options are limited. Research has identified trophoblast cell surface antigen 2 (TROP-2) to be broadly expressed across different tumor entities. The aim of the present study was to systematically investigate the expression of TROP-2 in VSCC.
Methods
TROP-2 protein expression was investigated by immunohistochemistry in a cohort comprising
n
= 103 patients with primary VSCC. A four-tier scoring system (0: no staining, 1 + : low staining, 2 + : moderate staining, 3 + : high staining) was applied for quantification of protein expression. For further analyses, two groups (low TROP-2 expression: 0/1 + ; high TROP-2 expression: 2 + /3 +) were generated. The entire study cohort, as well as HPV-dependent and HPV-independent VSCC were considered separately.
Results
In the entire VSCC study cohort, TROP-2 expression was present in 97.1% of all cases (
n
= 100) with 74.8% displaying high TROP-2 expression (2 + /3 +). Only 2.9% of tumors showed absent TROP-2 expression. Of note, all HPV-dependent VSCC (
n
= 18) demonstrated high TROP-2 expression (2 + /3 +). In the subgroup of HPV-independent VSCC (
n
= 70), high TROP-2 expression was associated with favorable clinical outcomes based on log rank test and univariate cox analysis.
Conclusion
TROP-2 protein expression is of prognostic value in HPV-independent VSCC. The broad expression of TROP-2 in VSCC indicates the TROP-2 directed ADC Sacituzumab govitecan as a potential new therapeutic strategy for VSCC patients.
BackgroundLymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the ...epigenetic regulation of LAG3 in KIRC by methylation.MethodsWe correlated quantitative LAG3 methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzed LAG3 methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.ResultsWe found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore, LAG3 methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+ immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.ConclusionOur data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testing LAG3 DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.
There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. ...N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ (METTL3, METTL4, METTL14, WTAP, KIAA1429), ‘erasers’ (FTO, ALKBH5), and ‘readers’ (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC.
Background/Aim: MicroRNA (miR) is implicated in the development of ovarian cancer (OC), the emergence of therapy resistance, and metastatic spread. In the past decade, a variety of relevant miRs have ...been identified in the context of OC, including miR-1 and miR-21. miR-21 plays a crucial role in OC carcinogenesis via activation of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling and development of platinum resistance, and has prognostic value. miR-1 has been identified as a tumor suppressor across various cancer entities, with reduced expression in malignant tissue compared to benign. This evidence highlights the potential of miR-1 and miR-21 to serve as diagnostic and prognostic biomarkers in OC. Patients and Methods: We studied the diagnostic potential of serum expression of miR-1 and miR-21 in a cohort comprising patients with malignant and benign ovarian tumors. Furthermore, levels of miR expression were analyzed with regard to clinical outcomes in patients with malignant ovarian tumors to evaluate their prognostic value. Results: We identified significant differential expression of miR-1 (p=0.0397) and miR-21 (p=0.0154) in malignant and benign ovarian tumors: Higher expression of miR-1 was found in patients with benign ovarian tumors, whereas expression of miR-21 was higher in patients with malignant ovarian tumors. In receiver operating characteristic analyses, the diagnostic potential of both miRs was confirmed, however, diagnostic significance was inferior to that of cancer antigen 125. No further value, in particular no prognostic value, was obtained for miR-1 and miR-21 in patients with malignant ovarian tumors. Conclusion: Serum levels of miR-1 and miR-21 might serve as promising biomarkers in the diagnosis of ovarian cancer
Dowling-Degos disease (DDD) is a rare autosomal-dominant hyperpigmentation disorder caused by mutations in KRT5, POFUT1, POGLUT1 and PSENEN. Our results suggest that dysfunctional Notch signalling in ...melanocytes plays a key role in DDD pathogenesis, and that altered biogenesis and intracellular trafficking of melanosomes, receptor tyrosine kinase signalling and oestrogen signalling receptor-mediated signalling may represent downstream molecular mechanisms through which decreased Notch signalling leads to hyperpigmentation in DDD. Furthermore, a common downstream pathomechanism for both POGLUT1 and PSENEN mutation carriers can be assumed.
•The on-treatment mGPS is a cost-effective and widely available biomarker.•The on-treatment mGPS provided superior prognostic information compared to imaging.•Particularly in the subgroup of patients ...with SD in the first staging, the mGPS provides additional prognostic insights.•The findings are based on two independent trial cohorts (OAK and BIRCH), comprising 1310 patients.
A large number of patients with non-small cell lung cancer (NSCLC) on immune checkpoint inhibition (ICI) achieve stable disease (SD) as the best overall response, which is associated with heterogeneous outcomes. In this context, complementary biomarkers that improve outcome prediction are needed. We have recently demonstrated that measuring the on-treatment modified Glasgow prognostic score (mGPS), which is based on the two serum markers C-reactive protein (CRP) and albumin, can improve outcome prediction complementary to radiological staging in metastatic renal cell carcinoma. However, this concept has not been assessed for patients with NSCLC on ICI.
We assessed the prognostic and predictive value of on-treatment mGPS at week six in patients with NSCLC treated with atezolizumab or docetaxel in the phase 3 OAK trial (NCT02008227) comprising n = 750 patients and validated the findings in the phase 2 BIRCH (NCT02031458, n = 560).
On-treatment mGPS assessed at week six demonstrated valuable prognostic information (Hazard Ratio (HR) for mGPS low-risk vs intermediate risk 2.34 (95 % CI 1.76–3.11, p < 0.001) and vs high risk 3.56, (95 % CI 2.57–4.91, p < 0.001) in the atezolizumab-treated subgroup. On-treatment mGPS predicted overall survival more accurately than imaging using RECIST criteria (concordance index: on-treatment mGPS 0.646 (95 % CI 0.615–0.677) vs RECIST 0.606 (95 % CI 0.575–0.637)). On-treatment mGPS provides additional prognostic information to imaging-assessed treatment response at first staging, especially for the patient subgroup with SD. These findings were validated in the BIRCH trial.
We highlight the novel concept of integrating on-treatment mGPS for improved outcome prediction in conjunction with radiological imaging for patients with NSCLC on ICI.
Background Vulvar squamous cell carcinoma (VSCC) is an uncommon gynecologic malignancy but with an increasing incidence in recent years. Etiologically, VSCC is classified into two subtypes: ...HPV-dependent and HPV-independent. Localized VSCC is treated surgically and/or with radiation therapy, but for advanced, metastatic or recurrent disease, therapeutic options are still limited. N6-methyladenosine (m6A) is the most prevalent post-transcriptional messenger RNA (mRNA) modification and involved in many physiological processes. The group of m6A proteins can be further divided into: ,writers' (METTL3, METTL4, METTL14, WTAP, KIAA1429), ,erasers' (FTO, ALKBH5), and ,readers' (HNRNPA2B1, HNRNPC, YTHDC1, YTHDF1-3). Dysregulated m6A modification is implicated in carcinogenesis, progression, metastatic spread, and drug resistance across various cancer entities. Up to date, however, only little is known regarding the role of m6A in VSCC. Methods Here, we comprehensively investigated protein expression levels of a diverse set of m6A writers, readers and erasers by applying immunohistochemical staining in 126 patients with primary VSCC. Results In the entire study cohort, dominated by HPV-independent tumors, m6A protein expression was not associated with clinical outcome. However, we identified enhanced protein expression levels of the ,writers' METTL3, METTL14 and the ,reader' YTHDC1 as poor prognostic markers in the 23 patients with HPV-dependent VSCC. Conclusion Our study suggests dysregulated m6A modification in HPV-associated VSCC. Keywords: m6A, N6-methyladenosine RNA modification, Vulvar squamous cell carcinoma, HPV, Biomarker
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein ...O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.
Purpose
N6-methyladenosine (m6A) is the most frequent type of messenger RNA (mRNA) modification and is implicated in diverse physiological processes. The procedure of m6A RNA modification is ...regulated by a dynamic interaction of writers (METTL3, METTL4, METTL14, WTAP, KIAA1429), erasers (FTO, ALKBH5), and readers (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In the oncological context, alterations in m6A were identified to be critically involved in tumorigenesis, proliferation, angiogenesis, and drug resistance across diverse cancer entities including endometrial cancer (EC).
Methods
In this study, we comprehensively examined the protein expression of m6A writers, readers and erasers by immunohistochemical staining in a cohort of
N
= 65 EC patients. Protein expression data were analyzed with regard to clinical outcomes.
Results
We identified enhanced protein expression levels of METTL3, METTL14, FTO, HNRNPA2B1, and HNRNPC, respectively to be of prognostic value and linked to a shortened overall survival in EC.
Conclusion
Overall, our study points toward dysregulated m6A modification in EC and its possibility to serve as a promising prognostic biomarker.
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