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Effects of BRAF V600E and NRAS mutational status on the progression-free survival and clinicopathological characteristics of patients with melanoma

Funding Information: The study was supported by the project ‘Strengthening of the capacity of doctoral studies at the University of Latvia within the framework of the new doctoral model’ (grant no. 8.2.2.0/20/I/006). Publisher Copyright: © 2023 Spandidos Publications. All rights reserved.Hotspot mutations of the BRAF and NRAS genes are the most common genetic alterations in invasive cutaneous melanoma; however, the prognostic significance of BRAF and NRAS co-mutations remains controversial. The present study aimed to determine the association between NRAS and BRAF mutation status and the clinicopathological characteristics of patients with stage IA-IIC melanoma. A total of 118 patients who underwent surgical treatment for stage IA-IIC melanoma at the Riga East University Hospital between 2012 and 2018 were retrospectively enrolled in the present study. BRAF and NRAS mutation status was assessed by digital droplet PCR using the BRAFV600, NRAS Q61 and NRAS G12/G13 Screening Assays. The association between mutation status and clinicopathological features and progression-free survival (PFS) was then analyzed. The BRAF V600 mutation was detected in 67 out of 118 patients (56.8%). The PFS did not differ between patients with BRAF wild-type and BRAF-mutant melanoma. NRAS mutations were detected in 35 out of 118 patients (29.6%). The NRAS mutational status was associated with Breslow thickness (P=0.035), tumor type (P=0.020; χ2=0.20), mitotic rate (P=0.025) and lymphovascular invasion (P=0.02; χ2=0.20). Patients with NRAS-mutant melanoma had significantly worse PFS compared with NRAS wild-type melanoma (HR=12.30; 95% CI=5.78-26.21, P<0.0001). Furthermore, BRAF and NRAS co-mutant melanoma was associated with a significantly worse PFS compared with BRAF-mutant melanoma (HR=6.30; 95% CI=3.10-12.70, P<0.0001). In conclusion, NRAS-mutant and NRAS/BRAF co-mutant stage IA-IIC melanoma was associated with worse PFS compared with NRAS wild-type and BRAF-mutant melanoma. The assessment of NRAS mutation status in melanoma in routine clinical practice may be beneficial for the risk stratification of disease progression for primary non-metastatic malignant melanoma.publishersversionPeer reviewe

Features associated with melanoma metastasis in Latvia

Funding Information: This work was supported by The European Regional Development Fund (project no. 1.1.1.1/18/A/099). Publisher Copyright: © This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Cutaneous melanoma (CM) is the most aggressive form of skin cancer, exhibits an increasing incidence worldwide and has a high potential to develop metastasis. The current study aimed to identify a set of parameters that may aid in predicting the probability and timing of the onset of CM metastasis. A retrospective analysis was performed using the archive data of 2,026 patients with CM that were treated at the Riga East University Hospital Latvian Oncology Centre, which is the largest oncological hospital in the country, between 1998 and 2015. A case-control study design was employed, where patients with metastasis (n=278) were used as the cases and patients without metastasis were used as the controls. The present study examined the associations between metastasis and potential risk factors and constructed multivariate models of features that predicted metastasis using stepwise regression. Time until metastasis was analyzed using negative binomial regression models. The results of the present study indicated an increase in the number of melanomas that developed metastases during 1998-2015. Tumor Breslow thickness was demonstrated to be significantly larger in patients with metastasis compared with those without (P=0.012). The presence of ulceration significantly increased the risk of metastases [odds ratio (OR), 1.66; 95% CI, 1.07-2.59; P=0.033]. The absence of pigment in melanoma tissues was indicated to lead to a greater likelihood of metastasis (OR, 2.14; 95% CI, 1.10-4.19; P=0.035). Shorter times from diagnosis until the onset of metastases were observed in older patients (incident rate ratio (IRR), 6.85; 95% CI, 2.43-19.30; P=2.78×10 -4), and a borderline significant association was observed in those with ulcerated tumors (IRR, 1.33; 95% CI, 0.98-1.80; P=0.064). Therefore, the main features associated with the development of melanoma metastasis in Latvia were indicated to be tumor ulceration, absence of pigment and Breslow thickness.publishersversionPeer reviewe

Addressing the importance of melanoma tumor-infiltrating lymphocytes in disease progression and clinicopathological characteristics

Funding Information: The present study was supported by a PhD student grant from the Faculty of Medicine of the University of Latvia (grant no. 1.1.1.1/20/A/146) and a grant from the European Regional Development Fund (grant no. 1.1.1.1/18/A/099). Publisher Copyright: © 2021, Spandidos Publications. All rights reserved.Tumor-infiltrating lymphocytes (TILs) in primary cutaneous melanoma are considered to represent the host's antitumor immunological response; however, whether there are associations between TIL grade and histopathological characteristics and disease survival remains controversial. BRAF mutational status has been established as a routine screening method in advanced malignant melanoma, and worse prognosis rates have been demonstrated in patients harboring BRAF mutations. However, the general impact of BRAF mutational status on survival and histopathological characteristics is still debated. The aim of the present study was to compare the value of the assessment of TIL grade in stages I-II nodular and superficial spreading melanoma and BRAF mutational status, and its influence on clinicopathological characteristics. Altogether, 85 patients at stage IA-IIC who underwent melanoma surgical treatment at the Riga East University Hospital between 2012 and 2017 were retrospectively enrolled in the study. The histopathological characteristics were assessed according to the current World Health Organization and The American Joint Committee on Cancer 8th edition guidelines. The current study showed that patients with melanoma with high TIL grade had significantly better progression-free survival than patients with low TIL grade (hazard ratio, 4.9; 95% CI, 2.3-11.2; P<0.0001). BRAF mutations were observed in 52 patients (61.2%). BRAF mutational status in melanoma was associated with Clark invasion level (P=0.045), patient age (P=0.02) and TIL (P=0.04). The assessment of TIL grade in stage I-II melanoma demonstrated prognostic significance value and may help improve risk assessment in the future.Peer reviewe

The Role of the Meiotic Component in Reproduction of B-RAF-Mutated Melanoma: A Review and “Brainstorming” Session

The ectopic expression of cancer testis (CT) antigens and classic meiotic genes is characteristic and a hallmark of poor prognosis of melanoma disease. Here the potential mechanisms of meiotic influence on the cell and life cycle of malignant melanoma are reviewed in the genetic, epigenetic, and evolutionary aspects. The involved mutant B-RAF and N-RAS-induced senescence may be reversed by reprogramming, with stemness linked to meiotic landscape, possibly induced by DNA double-strand breaks at the mutual telomere hot spots. The induced by senescence mitotic slippage (reset of interphase from arrested metaphase) and resulting polyploidy trigger the meiotic ploidy cycle to function for effective DNA recombination repair, genome reduction, and escape of survivors, which enter the mitotic cycle again. The aberrant meiotic pathway in cancer is reviewed in the ancestral asexual variants; inverted meiosis is possible. The conundrum of cancer aneuploidy paradox, selection of fit clones, and the Muller’s Ratchet of inevitable accumulation of harmful mutations is discussed. The bioinformatic study of the densely connected protein interaction network of CT antigen expressed genes revealed the melanomagenesis attractor composed of PRAME and small MAGEA group in primary tumors as compared with B-RAF-mutant nevi, restructured stemness network; invasive melanoma further displays the leading role of SPANX CT antigen group; meiotic genes are expressed in all three tissue cohorts

Toluidine Blue Test for Sperm DNA Integrity and Elaboration of Image Cytometry Algorithm

Background: Sperm DNA integrity is of paramount importance in the prognosis of fertility. We applied image cytometry to a toluidine blue (TB) test we recently proposed. Methods: Sperm samples from 33 men were assayed for standard sperm parameters and classified as normal or abnormal. Sperm smears were subjected to the TB test, DNA denaturation testing with acridine orange (AO), and terminal deoxyuridine triphosphate biotin nick end labeling (TUNEL). In CCD image analysis, TB-stained sperm cell heads were microscopically assigned to one of four color groups (dark, blue, light violet, and light blue). The optical densities of 6,600 cells in green and red CCD images were used to elaborate an algorithm for discrimination of these groups. Results: The proportions of sperm in TB color groups, as estimated with the developed image cytometry algorithm, correlated with microscopic features. The number of TB dark cells correlated with the number of AO-red and TUNEL+ cells. The proportion of TB dark cells in normal samples did not exceed 35%. Light-blue sperm cell heads prevailed in normal samples, whereas dark and blue sperm cell heads dominated in abnormal samples. Conclusions: The TB test was suitable for the assessment of sperm cell DNA integrity. The elaborated image cytometry algorithm can be used for this purpose and for finer determination of sperm nucleus status.publishersversionPeer reviewe

Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance

Funding Information: Funding: This research was funded by the University of Latvia Foundation’s PhD Student Scholarship in the Natural and Life Sciences (awarded to N.M.V.), a grant from the European Regional Development Fund (ERDF) projects No. 1.1.1.2/VIAA/3/19/463 for K.S. and ERDF 099 project No. 1.1.1.1/18/A/099) for D.P. and J.E. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p < 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.publishersversionPeer reviewe

The Price of Human Evolution : Cancer-Testis Antigens, the Decline in Male Fertility and the Increase in Cancer

Publisher Copyright: © 2023 by the authors.The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default.Peer reviewe

Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination

Objective: To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma. Design: A cross-sectional, web-based survey. Setting: Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL). Participants: A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%). Main outcome measures: Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE). Results: After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE. Conclusions: Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P &lt; .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling