MIR-376A-2-5P as a potential prognostic marker for advanced penile squamous cell carcinomas trough HPV-dependent pathways.

Penile cancer (PeCa) is a rare tumor, generally associated with socioeconomic conditions in low-income countries. Hence, a delay in diagnosis and treatment leads in more advanced tumors, to higher comorbidity, and mortality. Human papillomavirus (HPV) infection has been identified as one of the major risk factors for PeCa. In addition, viral integration sites have been related to copy number alterations, impacting miRNAs/mRNA interactions and, consequently, the molecular pathways related to them. Nonetheless, studies on differentially expressed miRNAs (miRDEs) in PeCa are still scarce, especially in PeCa associated with high-risk HPV (hrHPV). To investigate the role of these gene regulators in PeCa progression, 827 miRNAs (Nanostring Technologies™, Seattle, WA, USA) were evaluated in 22 hrHPV-associated penile squamous cell carcinomas and five non-tumor penile tissues. For functions of miRNAs/target genes and relationship with HPV we conducted an integrated analysis by Diana Tools, KEGG, HPVbase, and InterSPPI-HVPPI platforms. We found that 25 miRNAs of the most differentially expressed impact 43 top molecular pathways, of which the fatty acid biosynthesis pathway, prions, miRNAs in cancer and hippo signaling (P<1.0-325, for each) were the most statistically significant. Notably, 23 out of 25 are located at HPV integration sites (HPVis). MiR-1206, miR-376b-3p and miR-495-3p were downregulated and associated with perineural invasion. In addition, a comparison between advanced and early diseases revealed 143 miRDEs. ROC analysis of a single (miR-376a-2-5p), paired (miR-376a-2-5p, miR-551b-3p) or combination of five miRDEs (miR-99a-5p, miR-150-5p, miR-155-5p, let-7c-5p, miR-342-3p) showed robust discriminatory power (AUC = 0.9; P = 0.0114, for each). Strikingly, miR-376a-2-5p exhibited the highest values of sensitivity and specificity, with 100% and 83.3%, respectively, indicating this miRNA as a potential prognostic marker in hrHPV-penile carcinogenesis.

Karyotype/phenotype correlation in partial trisomies of the long arm of chromosome 16: case report and review of literature.

Trisomy 16q is a clinically recognizable entity presenting with a wide spectrum of abnormalities. Only five infants with a diagnosis of partial trisomy 16q13 → qter have been previously reported, and all died during the first year of life. We report the clinical and molecular cytogenetic findings in a patient with trisomy 16q13 → qter due to the presence of a supernumerary marker chromosome (SMC). The child presented with microcephaly, ambiguous genitalia, cardiac malformations and dysmorphic features. Cytogenetic investigation using GTG-banding, spectral karyotyping (SKY) and fluorescence in situ hybridization analyses revealed an SMC of maternal origin with karyotype der(15)t(15;16)(q13;q13). Specific genotype-phenotype correlations among different segments of the 16q region cannot yet be defined. We suggest that the involvement of the entire region spanning from 16q11 to 16q22 is necessary for the characteristic phenotype of the trisomy 16q.

EGF+61 A>G polymorphism does not predict response to first-generation EGFR tyrosine kinase inhibitors in lung cancer patients.

Epidermal growth factor (EGF) and its receptor (EGFR) play a paramount role in lung carcinogenesis. The polymorphism in the EGF promoter region EGF+61A>G (rs4444903) has been associated with cancer susceptibility, but its role in lung cancer patients treated with tyrosine kinase inhibitors (TKIs) remains unknown. Here, we aimed to evaluate the predictive and prognostic role of EGF+61A>G SNP in lung cancer from Brazilian EGFR-mutated TKI-treated patients. Herein, patients carrying EGFR-sensitizing mutations submitted to TKI treatment (gefitinib/erlotinib) were analyzed (n = 111) for EGF+61A>G genotype by TaqMan genotyping assay. TKI treatment was classified as partial response (PR), stable disease (SD), and disease progression (DP), according to RECIST1.1. Association analysis was assessed by chi-square and Fisher's test (univariate) and multinomial model (multivariate) and survival analysis by Kaplan-Meier method and log-rank test. The EGF+61A>G genotype frequencies observed were: AA = 31.5% (n = 35), AG = 49.6% (n = 55) and GG = 18.9% (n = 21). The allelic frequencies were 56.3% for A, and 43.7% for G and the population was in Hardy-Weinberg equilibrium (P = 0.94). EGF+61A>G codominant model (AA vs. AG vs. GG) was associated with a response to TKIs (P = 0.046), as well as a recessive model (AA vs. AG + GG; P = 0.023). The multinomial regression showed an association between the codominant model (AG) and recessive model (AG + GG) with SD compared with DP (P = 0.01;OR = 0.08; 95% CI = 0.01-0.60 and P = 0.02;OR = 0.12; 95% CI = 0.20-0.72, respectively). No association between genotypes and progression-free or overall survival was observed. In conclusion, the EGF+61 polymorphism (AG and AG + GG) was independently associated with stable disease in lung cancer patients although it was not associated with the overall response rate to first-generation TKIs or patient outcome.

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer.

BACKGROUND: Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy. METHODS: 59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed. RESULTS: The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons. CONCLUSIONS: This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.