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.
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.
What is new?
Not all smokers get cancer: the disease results from a combination of environmental and genetic factors. Mutations that hamper DNA repair could contribute, and in this paper the authors investigated four such variants. These polymorphisms, they found, could triple the risk of head and neck cancer. Among smokers, the effect was even more pronounced. Thus, these DNA mismatch repair alleles could be useful for predicting patient outcomes.
Background
Single nucleotide polymorphisms (SNPs) in genes that act in intrinsic apoptosis pathway may modulate cancer susceptibility. This study investigated the roles of CASP9 c.‐1339A>G ...(rs4645978) and CASP3 c.‐1191A>G (rs12108497) SNPs on risk and behavior of head and neck (HN) squamous cell carcinoma (SCC).
Methods
DNA of 350 patients with HNSCC and 350 controls was analyzed by polymerase chain reaction method for genotyping.
Results
CASP3 c.‐1191AG or GG genotype was more common in patients with HNSCC and oral cavity or oropharynx SCC than in controls; carriers of this genotype were under 2.15 and 2.81‐fold increased risks of the respective tumors. CASP9 c.‐1339AG or GG plus CASP3 c.‐1191AG or GG genotypes were associated with oral cavity or oropharynx SCC early onset.
Conclusion
These findings present, for the first time, preliminary evidence that inherited abnormalities related to CASP9 c.‐1339A>G and CASP3 c.‐1191A>G SNPs are determinants of HNSCC risk and clinical aspects.
Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The ...study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele "A" were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients' clinicopathological features.
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.
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-1β (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.
We conducted a two-stage association study on patients with oropharynx (OP) squamous cell carcinoma (SCC) and healthy controls to identify single nucleotide variants (SNVs) located at the microRNA ...(miR)-binding sites of carcinogenesis genes associated with risk and prognosis of the disease. In stage 1, 49 patients and 49 controls were analyzed using Genome-Wide Human SNV Arrays to identify variants in the 3'-untranslated region (3'-UTR) of carcinogenesis-related genes, and one SNV was selected for data validation in stage 2 by TaqMan assays in 250 OPSCC patients and 250 controls. The ERP29 c.*293A > G (rs7114) SNV located at miR-4421 binding site was selected for data validation among 46 SNVs. The ERp29 and miR-4421 levels were evaluated by quantitative-PCR and Western blotting. Interaction between miR-4421 with 3'-UTR of ERP29 was evaluated by luciferase reporter assay. Event-free survival (EFS) was calculated by Kaplan-Meier and Cox methods. ERP29 GG variant genotype was more common in OPSCC patients than in controls (6.4% vs 3.6%, p = 0.02; odds ratio: 5.67; 95% confidence interval (CI) 1.27-25.26). Shorter EFS were seen in the base of tongue (BT) SCC patients with GG genotype (0.0% vs 36.2%, p = 0.01; hazard ratio: 2.31; 95% CI: 1.03-5.15). Individuals with ERP29 AG or GG genotypes featured lower levels of ERP29 mRNA (p = 0.005), ERp29 protein (p < 0.001) and higher levels of miR-4421 (p = 0.02). The miR-4421 showed more efficient binding with 3'-UTR of the variant G allele when compared with wild-type allele A (p = 0.001). Our data suggest that ERP29 rs7114 SNV may alter the risk and prognosis of OPSCC due to variation in the ERp29 production possibly modulated by miR-4421.
Purpose
The outcome of RCC has improved considerably in the last few years, and the treatment options have increased. LACOG-GU and LARCG held a consensus meeting to develop guidelines to support the ...clinical decisions of physicians and other health professionals involved in the care of RCC patients.
Methods
Eighty questions addressing relevant advanced RCC treatments were previously formulated by a panel of experts. The voting panel comprised 26 specialists from the LACOG-GU/LARCG. Consensus was determined as 75% agreement. For questions with less than 75% agreement, a new discussion was held, and consensus was determined by the majority of votes after the second voting session.
Results
The recommendations were based on the highest level of scientific evidence or by the opinion of the RCC experts when no relevant research data were available.
Conclusion
This manuscript provides guidance for advanced RCC treatment according to the LACOG-GU/LARCG expert recommendations.
Abstract Aims To compare the efficacy and tolerability of taxane and nontaxane therapy in senior adults with chemonaïve metastatic castration-resistant prostate cancer (mCRPC), and examine the effect ...of patient health status on outcomes. Patients and methods Between 2009 and 2011, 333 patients aged≥70 years with mCRPC were enrolled in a prospective international registry. Patients were categorized as having received taxane-based or nontaxane therapy, and classified as fit, vulnerable, frail, or terminal, according to investigator judgement or International Society of Geriatric Oncology guidelines. Efficacy measures included overall survival (OS) and progression-free survival. Grade 3/4 toxicities were recorded. Predictors of OS were identified using multivariate Cox regression. Results The proportions of fit/vulnerable/frail patients were 65%/14%/17% (International Society of Geriatric Oncology), and 39%/43%/17% (investigator). In single-factor analyses, taxane therapy improved OS (hazard ratio 95%CI = 0.53 0.30–0.93; P = 0.027) and progression-free survival (hazard ratio 95% CI = 0.55 0.40–0.76; P <0.001) vs. nontaxane therapy. Patients with frailty also benefited from taxane therapy (adapted regimen in 52%). In multivariate analysis, taxanes improved OS even with poor prognostic factors present ( P = 0.017); age was unrelated to prognosis. Taxane therapy was well tolerated; most common grade 3/4 toxicities (taxane vs. nontaxane) were fatigue (17% vs. 4%), nausea/vomiting (14% vs. 5%) and neutropenia (10% vs. 1%). Conclusions The results of this nonrandomized, observational study suggest that first-line taxane therapy may benefit senior adults with mCRPC more than alternative therapies. Treatment decisions should not be based on chronological age.
To present a summary of the recommendations for the treatment and follow-up for metastatic castration-resistant prostate cancer (mCRPC) as acquired through a questionnaire administered to 99 ...physicians working in the field of prostate cancer in developing countries who attended the Prostate Cancer Consensus Conference for Developing Countries.
A total of 106 questions out of more than 300 questions addressed the use of imaging in staging mCRPC, treatment recommendations across availability and response to prior drug treatments, appropriate drug treatments, and follow-up, and those same scenarios when limited resources needed to be considered. Responses were compiled and the percentages were presented by clinicians to support each response. Most questions had five to seven relevant options for response including abstain and/or unqualified to answer, or in the case of yes or no questions, the option to abstain was offered.
Most of the recommendations from this panel were in line with prior consensus, including the preference of a new antiandrogen for first-line therapy of mCRPC. Important aspects highlighted in the scenario of limited resources included the option of docetaxel as treatment preference as first-line treatment in several scenarios, docetaxel retreatment, consideration for reduced doses of abiraterone, and alternative schedules of an osteoclast-targeted therapy.
There was wide-ranging consensus in the treatment for men with mCRPC in both optimal and limited resource settings.
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