No abstract

Background: Oropharyngeal squamous cell carcinomas (OpSCCs) are commonly associated with high rates of treatment failure. Objectives: To evaluate methylation-based markers in plasma from OpSCC patients as emerging tools for accurate/noninvasive follow-up. Methods: Pretreatment formalin-fixed paraffin-embedded (FFPE) biopsies (n = 52) and paired plasma (n = 15) were tested for the methylation of CCNA1, DAPK, CDH8, and TIMP3 by droplet digital PCR (ddPCR). Results: Seventy-one percent (37/52) of the biopsies showed methylation of at least one of the evaluated genes and tumor CCNA1 methylation was associated with recurrence-free survival. Methylated circulating tumor DNA (meth-ctDNA) was detected in 11/15 (73.3%) plasma samples; conversely, plasma samples from healthy controls were all negative for DNA methylation (area under the curve = 0.867; 95% confidence interval = 0.720-1.000). Additionally, preliminary results on the detection of meth-ctDNA in plasma collected during follow-up closely matched patient outcome.

Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient’s recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11–14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.

Background: Testicular germ cell tumors (TGCTs), a group of heterogeneous neoplasms, are the most frequent tumors of teenagers and young men, with the incidence rising worldwide. High cure rates can be achieved through cisplatin (CDDP)-based treatment, but approximately 10% of patients present refractory disease and virtually no treatment alternatives. Here, we explored new strategies to treat CDDP-resistant. Methods: In vitro TGCT CDDP-resistance model was established and differential mRNA expression profiles were evaluated using NanoString technology. Then, TGCT cell lines were treated with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance. Results: We found several differentially expressed genes related to DNA repair and cell cycle regulation on CDDP-resistant cell line (NTERA-2R) compared to parental cell line (NTERA-2P), and the proteasome inhibitor MG-132 demonstrated cytotoxic activity in all cell lines evaluated, even at a nanomolar range. MG-132 also enhanced cell lines' sensitivity to CDDP, increasing apoptosis in both NTERA-2P and NTERA-2R. Conclusions: MG-132 emerges as a potential new drug to treat CDDP-resistant TGCT. Targeted therapy based on molecular mechanism insights may contribute to overcome acquired chemotherapy CDDP-resistance.

Background: HPV infection represents an important etiologic factor for Oropharyngeal Squamous Cell Carcinoma (OPSCC). The different ethnic backgrounds could be related to different susceptibility to Human Papillomavirus (HPV). The aim of our study was to assess the whole of genetic ancestry in HPV status in OPSCC patients. Methods: We conducted a cross-sectional study on patients with OPSCC admitted to the Barretos Cancer Hospital, Brazil from 2014 to 2019. Of these, DNA extraction was performed on 40 patients and genetic ancestry was assessed using a specific panel of 46 informative ancestry markers. Results: We observed a predominance of European ancestry (63%), followed by African (18%), Amerindian (9%) and Asian (8%) both in the OPSCC HPV-positive and HPV-negative group. We did not find any statistically significant differences between the HPV-positive and HPV-negative OPSCC groups in relation to European (p = 0.499), African (p = 0.448), Asian (p = 0.275) or Amerindian (p = 0.836) ancestry. Conclusions: We found a predominance of European ancestry, both in the HPV-positive and HPV-negative groups. In our study, we did not find statistically significant differences between HPV-positive or HPV-negative groups in relation to ancestry.