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.

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.

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.

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.

The association of a single-nucleotide variant in the microRNA-146a with advanced colorectal cancer prognosis.

The aim of this study was to evaluate the association of single-nucleotide variant n.60G>C (rs2910164) of microRNA (miR)-146a, related to suppressing of BRCA1/2 DNA repair protein, with the risk and survival of colorectal cancer patients, as well as miR-146a and BRCA1/2 levels and miR binding efficiency. The genotypes were identified in 125 colorectal cancer patients and 276 controls using TaqMan polymerase chain reaction assay. The miR-146a and BRCA1/2 levels were assessed by quantitative-polymerase chain reaction protocols. Primary precursor of miR-146a containing G (wild-type) and C (variant) allele were cloned into pcDNA.3.3 vector and co-transfected in HT-29 colorectal cancer cell line. Luciferase reporter assay was performed to assess miR-146a binding to BRCA2 3'-untranslated region in HT-29. The differences between groups were calculated using chi-square or Fisher's exact test, logistic regression, and Mann-Whitney test. The prognostic impact of single-nucleotide variant genotypes on overall survival was evaluated by Kaplan-Meier estimate and Cox regression. The GC or CC genotypes prevalence was similar in patients and controls (50.4% vs 50.7%, p = 0.74). However, patients with tumors in advanced stage with miR-146a GG genotype had 2.41 more chance of dying than GC or CC genotypes. In addition, tumor tissues of patients with GG genotype presented higher miR-146a (p = 0.02) and lower BRCA1 (p = 0.01) and BRCA2 (p < 0.0001) levels when compared to those with GC or CC genotypes. In fact, pcDNA.3.3-miR-146a-G presented increased binding capacity to the 3'-untranslated region of BRCA2 (p = 0.001) compared to pcDNA.3.3-miR-146a-C. In addition, the G allele altered the binding affinity between miR-146a and its BRCA2 3'-untranslated region target (p < 0.001), thus enhancing suppression of BRCA2 expression. Our results suggest that single-nucleotide variant rs2910164 does not influence the colorectal cancer risk in Brazilian patients; however, the GG genotype could act as a factor of worse prognosis in patients with advanced disease due to suppression of BRCA1/2 modulated by miR-146a.

Influence of CASP9 c.-1339A>G and CASP3 c.-1191A>G variants in outcome of patients with head and neck squamous cell carcinoma.

BACKGROUND: Abnormalities in the intrinsic apoptosis pathway, associated with single nucleotide variants (SNVs) in caspase (CASP) genes, alter head and neck squamous cell carcinoma (HNSCC) proliferation and progression. This prospective study aimed to evaluate whether CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs influence the outcome of patients with HNSCC. Two hundred sixty-two HNSCC patients were enrolled in the study. METHODS: DNA and RNA of peripheral blood samples were analyzed using real-time polymerase chain reaction (PCR) for genotyping and quantitative PCR method for gene expression, respectively. Differences in CASP3 expressions were analyzed using the Mann-Whitney test. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier curves, log-rank test, and Cox analyses. RESULTS: CASP3 c.-1191AG or GG genotype was associated with higher CASP3 expression when compared with AA genotype (0.50 arbitrary units (AUs) ± 0.29 standard deviation (SD) vs 0.28 AUs ± 0.12 SD; P = .02). Patients with CASP9 c.-1339GG genotype had 1.54 more chance of presenting disease progression or relapse than patients with CASP9 c.-1339AA or AG genotype. Patients with CASP9 c.-1339GG and CASP3 c.-1191GG combined genotype had 2.64 more chance of presenting progression or relapse of the disease and 2.84 more chance of evolving to death than those with the remaining combined genotypes. CONCLUSIONS: Our findings provide, for the first time, preliminary evidence that inherited abnormalities in the intrinsic apoptosis pathway, related to CASP9 c.-1339A>G and CASP3 c.-1191A>G SNVs, act as predictors of HNSCC patients' survival.

Associations of VEGFA and KDR single-nucleotide polymorphisms and increased risk and aggressiveness of high-grade gliomas.

Angiogenesis, induced by the vascular endothelial growth factor A through its ligation to the vascular endothelial growth receptor 2, has been described as a crucial point in high-grade glioma development. The aim of this study was to evaluate the influence of VEGFA-2578C/A, -2489C/T, -1154G/A, -634G/C, and -460C/T, and KDR-604T/C, -271G/A, +1192G/A, and +1719A/T single-nucleotide polymorphisms on risk and clinicopathological aspects of high-grade glioma. This case-control study enrolled 205 high-grade glioma patients and 205 controls. Individuals with VEGFA-2578 CC or CA, VEGFA-1154 GG, VEGFA-634 GC or CC, and VEGFA-460 CT or TT genotypes were under 2.56, 1.53, 1.54, and 1.84 increased risks of high-grade glioma, compared to others, respectively. And 1.61, 2.66, 2.52, 2.53, and 2.02 increased risks of high-grade glioma were seen in individuals with VEGFA-2578 CC plus VEGFA-1154 GG, VEGFA-2578 CC or CA plus VEGFA-634 GC or CC, VEGFA-2578 CC or CA plus VEGFA-460 CT or TT, VEGFA-1154 GG or GA plus VEGFA-634 GC or CC, and VEGFA 634 GC or CC plus VEGFA-460 CT or TT combined genotypes, respectively, when compared to others. The "CAGT" haplotype of KDR single-nucleotide polymorphisms was more common in patients with grade IV than in those with grade III tumors, and individuals carrying this haplotype were at 1.76 increased risk of developing grade IV tumors than others. We present, for the first time, preliminary evidence that VEGFA-2578C/A and VEGFA-1154G/A single-nucleotide polymorphisms increases high-grade glioma risk, and "CAGT" haplotype of the KDR gene alters high-grade glioma aggressiveness and risk of grade IV tumors in Brazil.

Influence of functional variants Asp312Asn and Lys751Gln of Xeroderma Pigmentosum Group D (XPD) and Glutathione S-transferase Mu 1 (GSTM1) and Theta 1 (GSTT1) genes on cutaneous melanoma susceptibility and prognosis.

We aimed to evaluate whether variants in repair (XPD Asp312Asn, XPD Lys751Gln) and detoxification (GSTM1, GSTT1) genes alter risk, clinicopathological aspects and survival of cutaneous melanoma (CM). Genotyping was performed in 229 CM patients and 258 controls. Individuals with XPD 312Asp/Asn or Asn/Asn plus GSTT1 null genotype were under 2.00 (95% CI: 1.06-3.79), and XPD 312Asn/Gln haplotype was under 1.44-fold (95% CI: 0.99-2.08) increased risks to CM than others. Individuals with GSTM1 plus GSTT1 null genotype had 9.61-fold (95% CI: 2.28-40.38) increased risk of metastatic CM. At 60 months of follow-up, patients with XPD 751Gln/Gln plus GSTT1 null and GSTM1 null plus GSTT1 null genotype presented 7.36 and 3.05 more chances of evolving to death in multivariate Cox analysis, respectively. In conclusion, our data indicate, for the first time, that specific variant combinations of XPD, GSTM1 and GSTT1 may increase susceptibility to CM and influence patients' clinicopathological features and survival.

CASP8 (rs3834129) and CASP3 (rs4647601) polymorphisms in oropharynx cancer risk, tumor cell differentiation, and prognosis in a cohort of the Brazilian population.

The objective of this research was to assess the association of genetic polymorphisms related to intrinsic apoptosis pathway CASP8 rs3834129 and CASP3 rs4647601 with the risk, clinical and pathological aspects, and survival of oropharynx squamous cell carcinoma (OPSCC) patients that received cisplatin and radiotherapy. The genotypes were identified in 198 patients with OPSCC and 200 controls using polymerase chain reaction methods. Chi square or Fisher's exact test and logistic regression were applied for the detection of differences between groups. Patients' genotypes were statistically evaluated considering the event-free survival and overall analysis using Kaplan-Meier estimate and Cox regression. CASP3 rs4647601 GG genotype (44.4% vs. 30.0%, p = 0.03) and G allele (63.9% vs. 55.5%, p = 0.04) were more common in patients with OPSCC than in controls. Carriers of GG genotype and G allele were under 1.78-fold and 1.40-fold increased risk of OPSCC than others, respectively. The frequency of CASP8 rs3834129 DD genotype was higher in patients with OPSCC with poorly differentiated or undifferentiated tumors when compared to others (34.5% vs. 16.1%, p = 0.02). No influence of CASP8 and CASP3 polymorphisms on OPSCC patients' survival was seen in this study. Our results indicate that inherited genetic variants in the intrinsic apoptosis pathway related to CASP3 rs4647601 and CASP8 rs3834129 polymorphisms may be an important determinant of OPSCC risk and tumor cell differentiation.

XPC (A2920C), XPF (T30028C), TP53 (Arg72Pro), and GSTP1 (Ile105Val) polymorphisms in prognosis of cutaneous melanoma.

This study aimed to evaluate whether XPC A2920C, XPF T30028C, TP53 Arg72Pro, and GSTP1 Ile105Val polymorphisms alter outcomes of cutaneous melanoma (CM) patients. DNA from 237 CM patients seen at the University of Campinas Teaching Hospital from April 2000 to February 2014 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival (PFS) and overall survival (OS) of CM patients were examined using the Kaplan-Meier probability estimates and univariate and multivariate Cox regression analyses. At 60 months of follow-up, shorter PFS and OS were seen in patients with XPF CC genotype (48.9 vs. 66.7 %, P = 0.002; 77.9 vs. 83.5 %, P = 0.006, respectively) and XPF CC + TP53 ArgArg (43.6 vs. 65.9 %, P = 0.007; 71.6 vs. 84.8 %, P = 0.006, respectively) compared with those with remaining genotypes (Kaplan-Meier estimates). Patients with XPF CC (hazard ratio (HR) 2.45, P = 0.002; HR 3.77, P = 0.005) and XPF CC + TP53 ArgArg (HR 2.67, P = 0.009; HR 4.04, P = 0.03) genotypes had more chance to present tumor progression in univariate and multivariate analyses, whereas patients with XPF CC (HR 2.78, P = 0.009) and XPF CC + TP53 ArgArg (HR 3.84, P = 0.01) genotypes were under greater risk of progressing to death in univariate analysis, compared with those with the remaining genotypes. The data suggest, for the first time, that inherited abnormalities in DNA repair pathway related to XPF 30028C and TP53 Arg72Pro polymorphisms act as prognostic factors for PFS and OS of CM patients.

Association between genetic polymorphisms in DNA mismatch repair-related genes with risk and prognosis of head and neck squamous cell carcinoma.

We examined the influence of MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p = 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p = 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p = 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p = 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p = 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P = 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.

Associations of VEGF and VEGFR2 polymorphisms with increased risk and aggressiveness of multiple myeloma.

Angiogenesis has been highlighted as a critical component in the progression of multiple myeloma (MM), and vascular endothelial growth factor (VEGF) as well as its type 2 receptor (VEGFR2) are thought to play a major role in the process. Single nucleotide polymorphisms (SNPs) have been described in VEGF and VEGFR2 genes, with quantitative or qualitative changes in encoded VEGF and VEGFR2. The roles of VEGF -2578C/A, -1154G/A, and -634G/C as well as VEGFR2 -604T/C and +1192G/A SNPs in the risk and manifestations of MM are still unknown; therefore, this study aimed to clarify this issue. DNA from 192 patients and 209 controls were analyzed by real-time polymerase chain reaction for identification of genotypes. The frequencies of VEGF -2578CC, VEGF -2578CC plus VEGF -634GG, and VEGF -2578CC plus VEGF -1154GG plus VEGF -634GG genotypes were higher in patients than in controls. Carriers of the respective genotypes had a 1.89-, a 5.52-, and a 4.91-fold increased risk for MM than others. VEGF -2578CC plus VEGFR2 +1192GG, VEGF -2578CC plus VEGF -634GG plus VEGFR2 +1192GG, and VEGF -1154GG plus VEGF -634GG plus VEGFR2 -604TT combined genotypes were more common in patients than in controls. Carriers of the respective genotypes had a 2.56-, a 10.97-, and a 14.10-fold increased risk for MM than others. An excess of VEGFR2 -604TT genotype was also seen in patients with stage II or III tumors when compared with those with stage I tumors. Our data suggest, for the first time, that inherited abnormalities in VEGF and VEGFR2 pathways influence the risk and aggressiveness of MM.

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.

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.

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.

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.

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.

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.

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.