TNFRSF1B Gene Variants in Clinicopathological Aspects and Prognosis of Patients with Cutaneous Melanoma.

Regulatory T lymphocytes play a critical role in immune regulation and are involved in the aberrant cell elimination by facilitating tumor necrosis factor connection to the TNFR2 receptor, encoded by the TNFRSF1B polymorphic gene. We aimed to examine the effects of single nucleotide variants TNFRSF1B c.587T>G, c.*188A>G, c.*215C>T, and c.*922C>T on the clinicopathological characteristics and survival of cutaneous melanoma (CM) patients. Patients were genotyped using RT-PCR. TNFRSF1B levels were measured using qPCR. Luciferase reporter assay evaluated the interaction of miR-96 and miR-1271 with the 3'-UTR of TNFRSF1B. The c.587TT genotype was more common in patients younger than 54 years old than in older patients. Patients with c.*922CT or TT, c.587TG or GG + c.*922CT or TT genotypes, as well as those with the haplotype TATT, presented a higher risk of tumor progression and death due to the disease effects. Individuals with the c.*922TT genotype had a higher TNFRSF1B expression than those with the CC genotype. miR-1271 had less efficient binding with the 3'-UTR of the T allele when compared with the C allele of the SNV c.*922C>T. Our findings, for the first time, demonstrate that TNFRSF1B c.587T>G and c.*922C>T variants can serve as independent prognostic factors in CM patients.

Clinicopathological Aspects and Inflammation-Immune Markers in Alcohol and/or Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients Treated With Sorafenib.

Background: Tyrosine kinase inhibitors have been used to treat hepatocellular carcinoma (HCC), but the outcomes of patients under treatment vary. Since the roles of clinicopathological aspects and markers of chronic inflammation/immune homeostasis in the outcome of HCC patients treated with sorafenib are still unclear, these were the aims of this study. Methods: Patients with alcohol-induced and/or hepatitis C virus (HCV)-induced HCC (n = 182) uniformly treated with sorafenib were included in the study. Baseline clinicopathological aspects of patients were computed from the medical records. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), and systemic immune-inflammation index (SII) were obtained from the hematological exam performed before the administration of sorafenib. Overall survival (OS) was analyzed using Kaplan-Meier probabilities, log-rank test, and univariate and multivariate Cox proportional hazard ratio (HR) analyses. Results: In multivariate analysis, alpha-foetoprotein (AFP) level and Child-Pugh score were predictors of OS. Patients with AFP levels higher than 157 ng/mL and Child-Pugh B or C had 1.40 (95% confidence interval (CI): 1.03 - 1.91, P = 0.03) and 1.64 (95% CI: 1.07 - 2.52, P = 0.02) more chances of evolving to death than the remaining patients, respectively. NLR, PLR, LMR, SIRI, and SII did not alter the OS of HCC patients. Conclusions: AFP level and Child-Pugh score act as independent prognostic factors in patients with alcohol and/or HCV-induced HCC treated with sorafenib, but markers of chronic inflammation/immune homeostasis seem not to alter the outcome of patients with HCC induced by alcohol and/or HCV.

Genetic variability in cisplatin metabolic pathways and outcome of locally advanced head and neck squamous cell carcinoma patients.

Advanced head and neck squamous cell carcinoma (HNSCC) patients have been treated with cisplatin (CDDP) chemoradiation, and the variability of treatment effects has been attributed to single nucleotide variants (SNVs) in genes of metabolic pathways. This study investigated the roles of GSTM1, GSTT1, GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.93G>A, MSH2 c.211+9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-182-247G>T, FAS c.-1378G>A and c.-671A>G and FASL c.-844C>T SNVs in outcome of 109 patients treated with CDDP chemoradiation. Genotypes were identified in genomic DNA by PCR-based methods. Conventional criteria and tests analyzed response and survival. Patients with XPC c.2815AC or CC had 3.43 times more chances of presenting partial response or stable disease. Patients with FAS c.-671GG, GSTM1 present plus XPC c.2815AA, or plus XPD c.934GG, or plus XPD c.2251AA, or plus TP53 c.215GC or CC, and XPD c.2251AA plus XPF c.2505TT had up to 2.70 and 2.37 times more chances of presenting tumor progression and evolving to death, respectively. Our data indicate, for the first time, preliminary evidence that combined SNVs of CDDP metabolism act as independent prognostic factors and can be used to select patients for distinct treatments.

Influence of variants in serotonin modulating genes on the risk, aggressiveness, and prognosis of oropharynx cancer.

BACKGROUND: Serotonin (5-HT) is involved in regulating tumor growth, as well as psychiatric disorders. It is synthesized by tryptophan hydroxylase (TPH) and acts through 5-HT receptors (HTRs). Single-nucleotide variations (SNVs) in TPH1 rs623580 (T>A), TPH2 rs4570625 (G>T), and HTR1D rs674386 (G>A) may affect 5-HT levels. However, the effect of these SNVs on oropharynx carcinoma (OPC) is unknown. METHODS: DNA from 251 patients with OPC and 254 controls was analyzed by RT-PCR. Transcriptional activity of TPH1 rs623580 and HTR1D rs674386 was studied by luciferase assays. Multivariate statistical tests were utilized to evaluate group differences and survival outcomes. RESULTS: TPH1 TT was more frequent in patients than in controls (OR: 1.56, p = 0.03). Patients with HTR1D GG/GA showed invasive tumors (p = 0.01) and shorter survival (HR: 1.66, p = 0.04). TPH1 TT (0.79-fold, p = 0.03) and HTR1D GG (0.64-fold, p = 0.008) presented lower transcriptional activity. CONCLUSION: Our data suggest that SNVs in 5-HT modulating genes can influence OPC.

Association of Clinical Aspects and Genetic Variants with the Severity of Cisplatin-Induced Ototoxicity in Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study.

BACKGROUND: Cisplatin (CDDP) is a major ototoxic chemotherapy agent for head and neck squamous cell carcinoma (HNSCC) treatment. Clinicopathological features and genotypes encode different stages of CDDP metabolism, as their coexistence may influence the prevalence and severity of hearing loss. METHODS: HNSCC patients under CDDP chemoradiation were prospectively provided with baseline and post-treatment audiometry. Clinicopathological features and genetic variants encoding glutathione S-transferases (GSTT1, GSTM1, GSTP1), nucleotide excision repair (XPC, XPD, XPF, ERCC1), mismatch repair (MLH1, MSH2, MSH3, EXO1), and apoptosis (P53, CASP8, CASP9, CASP3, FAS, FASL)-related proteins were analyzed regarding ototoxicity. RESULTS: Eighty-nine patients were included, with a cumulative CDDP dose of 260 mg/m2. Moderate/severe ototoxicity occurred in 26 (29%) patients, particularly related to hearing loss at frequencies over 3000 Hertz. Race, body-mass index, and cumulative CDDP were independent risk factors. Patients with specific isolated and combined genotypes of GSTM1, GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A, EXO1 c.1762G>A, MSH3 c.3133A>G, FASL c.-844A>T, and P53 c.215G>C SNVs had up to 32.22 higher odds of presenting moderate/severe ototoxicity. CONCLUSIONS: Our data present, for the first time, the association of combined inherited nucleotide variants involved in CDDP efflux, DNA repair, and apoptosis with ototoxicity, which could be potential predictors in future clinical and genomic models.

Evaluating Single-Nucleotide Variants in MicroRNA Targeting Sites and Mature MicroRNA In Vitro Cell Culture by Luciferase Reporter Gene Assays.

MicroRNAs (miRs) are small non-coding RNAs of 21-24 nucleotides in length that modulate gene expression by targeting the untranslated region (UTR) of mRNA. Single-nucleotide variants (SNVs) in primary miRs (pri-miRs), precursor miRs (pre-miRs), promoters of pri-miRs, and seed regions can affect miR stability or processing, may influence mature miR expression, and can affect target gene identification, respectively. The present protocol tests the binding and activity of miRs on 3'-UTR target sequences based on the expression of luciferase as a reporter gene fused to the UTR sequence in the presence of plasmids containing pre-miR of interest to test in vitro cell culture assay.

Association of Inherited Copy Number Variation in ADAM3A and ADAM5 Pseudogenes with Oropharynx Cancer Risk and Outcome.

Inherited copy number variations (CNVs) can provide valuable information for cancer susceptibility and prognosis. However, their association with oropharynx squamous cell carcinoma (OPSCC) is still poorly studied. Using microarrays analysis, we identified three inherited CNVs associated with OPSCC risk, of which one was validated in 152 OPSCC patients and 155 controls and related to pseudogene-microRNA-mRNA interaction. Individuals with three or more copies of ADAM3A and ADAM5 pseudogenes (8p11.22 chromosome region) were under 6.49-fold increased risk of OPSCC. ADAM5 shared a highly homologous sequence with the ADAM9 3'-UTR, predicted to be a binding site for miR-122b-5p. Individuals carrying more than three copies of ADAM3A and ADAM5 presented higher ADAM9 expression levels. Moreover, patients with total deletion or one copy of pseudogenes and with higher expression of miR-122b-5p presented worse prognoses. Our data suggest, for the first time, that ADAM3A and ADAM5 pseudogene-inherited CNV could modulate OPSCC occurrence and prognosis, possibly through the interaction of ADAM5 pseudogene transcript, miR-122b-5p, and ADAM9.

Quality of life of family caregivers and survival of head and neck cancer patients in palliative care.

OBJECTIVE: The aim of this study is to assess the effect of sociodemographic and genetic features on the quality of life (QoL) of family caregivers (FCGs) of patients with head and neck cancer (HNC) in palliative care (PC) and the effect of QoL of FCGs on patients' survival. METHODS: A questionnaire was applied to obtain sociodemographic information of 100 FCGs of patients with HNC in PC. The WHOQoL-bref questionnaire was used to measure QoL. Genotypes were identified using real-time PCR. Differences between groups were assessed by linear regression. Event-free survival (EFS) and overall survival (OS) were calculated by the Cox proportional hazard ratio (HR) regression. RESULTS: Worse QoL in the overall QoL (p = 0.04), physical health (p = 0.04), psychological (p = 0.005), and environment (p = 0.02) domains was associated to employed caregivers. Collective transport was related to worse QoL of the FCGs in the general health (p = 0.02) and psychological (p = 0.01) domains. Lower levels of QoL of FCGs in the social relationships domain were predictive of a decrease in EFS (HR: 1.98, p = 0.01) and OS (HR: 2.01, p = 0.01) of the patients. CONCLUSION: The results suggest that employment status and means of transportation may impair the QoL of FCGs. Lower levels of QoL of FCGs in the social relationships domain could decrease patients' survival.

PD1.5 variant on PDCD1 gene, regulator of T lymphocyte activity, influences non-muscle-invasive bladder cancer risk.

BACKGROUND: Since failure in recognition of abnormal cells by the immune system has an important role in bladder cancer development and progression, this study aimed to evaluate whether PD1 (c.627+252C>T) and PD1.5 (c.804C>T) single-nucleotide variants (SNVs) in PDCD1 gene, enrolled in modulation of T lymphocyte activity, influence risk, clinicopathological aspects, and outcome of non-muscle-invasive bladder cancer (NMIBC) patients. MATERIAL AND METHODS: DNA genotyping by real-time polymerase chain reaction was offered to 160 non muscle invasive bladder cancer (NMIBC) patients and 250 controls. One hundred and twenty-seven patients treated with bladder transurethral resection and intravesical bacillus Calmette-Guérin were enrolled in survival analyses. RESULTS: Individuals with PD1.5 CC genotype had 2.3-fold increased risk of developing NMIBC. Similar genotype and haplotype frequencies were seen in patients stratified by clinicopathological aspects. Patients with T allele, CT or TT plus CT or TT genotype and TT haplotype of PD1 and PD1.5 SNVs had up to 4.0-times greater chances of presenting NMIBC relapse and death by any cause than the remaining patients, but analysis of NMIBC specific survival was not possible in study due to the small number of patients evolving to death during follow up. CONCLUSIONS: Our data presented for the first time, preliminary evidence that inherited abnormality in regulation of T lymphocyte activity alters NMIBC risk.

Association of JAK/STAT genetic variants with cutaneous melanoma.

Background: The Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway regulates cutaneous melanoma (CM) development and progression. The JAK1, JAK2, and STAT3 proteins are encoded by polymorphic genes. This study aimed to verify whether single-nucleotide variants (SNVs) in JAK1 (c.1648+1272G>A, c.991-27C>T), JAK2 (c.-1132G>T, c.-139G>A), and STAT3 (c.*1671T>C, c.-1937C>G) altered the risk, clinicopathological aspects, and survival of CM patients as well as protein activity. Methods: CM patients (N = 248) and controls (N = 274) were enrolled in this study. Genotyping was performed by real-time polymerase chain reaction (PCR), and JAK1, JAK2, and STAT3 expression was assessed by quantitative PCR (qPCR). STAT3 c.-1937C>G SNV was investigated by luciferase, qPCR, western blot, apoptosis, and cell cycle assays in SKMEL-28 cells with CC or GG genotype. Results: Individuals with STAT3 c.*1671TT and c.-1937CC genotypes and TC haplotype of both SNVs were under about 2.0-fold increased risk of CM. Specific JAK1, JAK2, and STAT3 combined genotypes were associated with up to 4.0-fold increased risk of CM. Higher luciferase activity [4,013.34 vs. 2,463.32 arbitrary units (AU); p = 0.004], STAT3 expression by qPCR (649.20 vs. 0.03 AU; p = 0.003) and western blot (1.69 vs. 1.16 AU; p = 0.01), and percentage of cells in the S phase of the cell cycle (57.54 vs. 30.73%; p = 0.04) were more frequent in SKMEL-28 with STAT3 c.-1937CC than with GG genotype. CM cell line with CC genotype presented higher STAT3 protein levels than the one with GG genotype (1.93 versus 1.27 AU, p = 0.0027). Conclusion: Our data present preliminary evidence that inherited abnormalities in the JAK/STAT pathway can be used to identify individuals at a high risk of CM, who deserve additional attention for tumor prevention and early detection.

Demographic history differences between Hispanics and Brazilians imprint haplotype features.

Admixture is known to greatly impact the genetic landscape of a population and, while genetic variation underlying human phenotypes has been shown to differ among populations, studies on admixed subjects are still scarce. Latin American populations are the result of complex demographic history, such as 2 or 3-way admixing events, bottlenecks and/or expansions, and adaptive events unique to the American continent. To explore the impact of these events on the genetic structure of Latino populations, we evaluated the following haplotype features: linkage disequilibrium, shared identity by descent segments, runs of homozygosity, and extended haplotype homozygosity (integrated haplotype score) in Latinos represented in the 1000 Genome Project along with array data from 171 Brazilians sampled in the South and Southeast regions of Brazil. We found that linkage disequilibrium decay relates to the amount of American and African ancestry. The extent of identity by descent sharing positively correlates with historical effective population sizes, which we found to be steady or growing, except for Puerto Ricans and Colombians. Long runs of homozygosity, a particular instance of autozygosity, was only enriched in Peruvians and Native Americans. We used simulations to account for random sampling and linkage disequilibrium to filter positive selection indexes and found 244 unique markers under selection, 26 of which are common to 2 or more populations. Some markers exhibiting positive selection signals had estimated time to the most recent common ancestor consistent with human adaptation to the American continent. In conclusion, Latino populations present highly divergent haplotype characteristics that impact genetic architecture and underlie complex phenotypes.

Addressing psychiatric disorders and genetics: the meaningful use of comics for health information.

In the fields of healthcare and education, comics have shown considerable academic and teaching importance, with their combination of text and images. As a well-known character in comics, Batman allows us to discuss several relevant topics, from the outcomes in adulthood of experiencing parental death in childhood to genetic and epigenetic changes that may be factors of vulnerability to psychiatric disorders in adulthood. In this text, a narrative of Batman is developed, demonstrating the possibility of using it in an academic context and intending at paying greater attention to patients' history and the relationship between genetics and behaviour.

Influence of Sociodemographic Characteristics and Inflammation-Related Gene Variants on the Comfort Level of Caregivers of Patients With Head and Neck Cancer.

Background: Sociodemographic characteristics and inflammatory cytokines, such as interleukin (IL)-1ß, IL-1 cytokine receptor type 2 (IL1R2), IL-6, and triggering receptor expressed on myeloid cells like 2 (TREML2), may influence psychological disorders, including discomfort. Single-nucleotide variants (SNVs) determine individual differences for the modulation of cytokines and indicate that genetics may also influence the comfort levels. However, the relationship between sociodemographic characteristics, holistic comfort, and the roles played by IL1B rs16944, IL1R2 rs4141134, IL6 rs1800795, and TREML2 rs3747742 SNVs on the comfort levels of family caregivers (FCGs) of head and neck cancer (HNC) patients in palliative care (PC) is unknown. Thus, its investigation consisted in the aim of the present study. Methods: A questionnaire was applied to obtain sociodemographic information on 95 FCGs. The genotypes were identified using TaqMan assays. The Holistic Comfort Questionnaire for the Caregiver, which consists of 49 questions, was used to measure comfort levels. Differences between groups were assessed by the t test and linear regression. Results: Employed FCGs (p = .04), those youngest (p = .04), smokers (p = .04), and those with IL1R2 GA or AA genotypes (p = .03) presented lower comfort regarding the overall, environmental, sociocultural, and psychospiritual domains, respectively. Conclusions: Employment status, smoking habit, young age, and SNV IL1R2 rs4141134 could influence the comfort levels of FCGs of patients with HNC in PC.

Intronic variants of MITF (rs7623610) and CREB1 (rs10932201) genes may enhance splicing efficiency in human melanoma cell line.

We previously reported that intronic single nucleotide variations (SNVs) in MITF (c.938-325G>A, rs7623610) and CREB1 (c.303+373G>A, rs10932201) genes were associated with risk, aggressiveness, and prognosis of cutaneous melanoma (CM). In this study, we investigated the influence of the above SNVs in splicing patterns and efficiency. We constructed minigenes with wild type and variant alleles from MITF and CREB1 to assess the effect of the SNVs on splicing. The minigenes were transfected in the human melanoma cell line (SK-MEL-28). RT-PCR and DNA sequencing investigated the constructs' splicing patterns. Minigenes constructs' splicing efficiency and HNRNPA1 and SF1 splicing genes' expression were investigated by qPCR. We found that MITF and CREB1 SNVs did not alter the splicing pattern, but they influenced the splicing efficiency. MITF-A (p= 0.03) and CREB1-A (p= 0.005) variant minigenes yielded an increase of mRNA generated from the constructions. Additionally, lower mRNA levels of HNRNPA1 and SF1 were seen in the variant minigenes MITF-A (p= 0.04) and CREB1-A (p= 0.005). We described for the first time the potential importance of MITF rs7623610 and CREB1 rs10932201 SNVs in splicing efficiency and its relationship with CM.

Pseudogene Transcripts in Head and Neck Cancer: Literature Review and In Silico Analysis.

Once considered nonfunctional, pseudogene transcripts are now known to provide valuable information for cancer susceptibility, including head and neck cancer (HNC), a serious health problem worldwide, with about 50% unimproved overall survival over the last decades. The present review focuses on the role of pseudogene transcripts involved in HNC risk and prognosis. We combined current literature and in silico analyses from The Cancer Genome Atlas (TCGA) database to identify the most deregulated pseudogene transcripts in HNC and their genetic variations. We then built a co-expression network and performed gene ontology enrichment analysis to better understand the pseudogenes' interactions and pathways in HNC. In the literature, few pseudogenes have been studied in HNC. Our in silico analysis identified 370 pseudogene transcripts associated with HNC, where SPATA31D5P, HERC2P3, SPATA31C2, MAGEB6P1, SLC25A51P1, BAGE2, DNM1P47, SPATA31C1, ZNF733P and OR2W5 were found to be the most deregulated and presented several genetic alterations. NBPF25P, HSP90AB2P, ZNF658B and DPY19L2P3 pseudogenes were predicted to interact with 12 genes known to participate in HNC, DNM1P47 was predicted to interact with the TP53 gene, and HLA-H pseudogene was predicted to interact with HLA-A and HLA-B genes. The identified pseudogenes were associated with cancer biology pathways involving cell communication, response to stress, cell death, regulation of the immune system, regulation of gene expression, and Wnt signaling. Finally, we assessed the prognostic values of the pseudogenes with the Kaplan-Meier Plotter database, and found that expression of SPATA31D5P, SPATA31C2, BAGE2, SPATA31C1, ZNF733P and OR2W5 pseudogenes were associated with patients' survival. Due to pseudogene transcripts' potential for cancer diagnosis, progression, and as therapeutic targets, our study can guide new research to HNC understanding and development of new target therapies.

Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma.

Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1ß (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients' survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher's exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan-Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III-V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10-8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.

Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma.

BACKGROUND: There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL. METHODS: We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models. RESULTS: High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFß levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.

GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel-Based Chemotherapy in Ovarian Cancer.

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014-2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion of GSTM1 and GSTT1 genes. GSTP1 (c.313A>G/rs1695) and ABCB1 (c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real-time PCR. Subjects with the GSTP1 c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04-0.69, P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12-0.64, P < 0.01; OR 0.18, 95% CI 0.03-0.85, P = 0.03, either dominant or recessive model), respectively. The GSTP1 c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13-0.90, P = 0.03). The ABCB1 c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03-0.82, P = 0.03), whereas ABCB1 c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08-121.01, P = 0.03) in recessive model (CC + CT vs. TT). This study suggests that GSTP1 c.313A>G, ABCB1 c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.