According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87–159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3–70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

Recently, Chen et al (J Biol Chem.2005;280:5361–9) showed SHP-1 (PTPN6) gene supression by FLT3/ITD in TF-1 cell lines and in primary cells from AML patients. To address the prognostic impact that both together FLT3/ITD and SHP-1 gene suppression may have in myeloid malignancies patients, we have studied 85 patients diagnosed with de novo AML and MDS. SHP-1 gene expression was quantified by real time PCR and compared with normal CD34+ cells from healthy donors. FLT3/ITD was detected by conventional agarose gel electrophoresis after PCR. FLT3/D835 was detected by melting curve methodology. FLT3 mutations were correlated with higher WBC and blasts count at diagnosis (p=0.001). FLT3/ITD had a negative impact on DFS compared with wt or D835 mutations (log-rank p=0.054). Median levels for SHP-1 were lower in leukemic blasts than in normal peripheral blood CD34+ cells (p=0.001). SHP-1 lowest expression was found in those patients where FLT3 mutations were present (p=0.001). SHP-1 lowest expression was associated with higher blasts count in BM at diagnosis (p=0.017). Having both Flt3 mutations and lowest expression for SHP-1 were strongly associated with higher WBC (> 20 x109/L) (p=0.005). OS univariate analysis yielded a worse prognosis for patients having both lower SHP-1 expression and harboring an Flt3 mutation (p=0.021). Figure Figure In summary, SHP-1 (PTPN6) gene supression by FLT3 constitutively activating mutations confers a bad prognosis for myeloid malignancies patients and is associated with hyperleukocytosis at diagnosis.

The SOGUG-IMANOL trial was a phase 2, uncontrolled, Spanish multicenter study to assess the effect of maintenance treatment with olaparib on radiographic progression-free survival (PFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who achieved partial or complete response or disease stabilization on docetaxel treatment and had a documented germline/somatic mutation in any of the homologous recombination repair (HRR) genes. Patients received olaparib 300 mg orally twice daily. From the screened population (n = 134), 26 (19.4%) somatic mutations were found, and 14 patients were included in the study. The median radiographic PFS was 11.1 (95%CI, 5.7 to 16.5) months. The median PSA-PFS was 3.5 (95%CI, 1.0 to 6.0) months, and the median clinical PFS was 14.7 (95%CI, 1.8 to 27.5 months). Clinical benefit was observed in 12 patients (85.7%, 95%CI 67.4% to 100%), including two patients with partial response and 10 with stable disease. Six patients reported grade 3–5 adverse events: asthenia (n = 3), anemia (n = 2) and neutropenia (n = 1). In this setting, olaparib has been shown to be an efficacious maintenance treatment in terms of radiographic PFS and clinical benefit, becoming a therapeutic option for some patients harboring an HRR gene mutation and in scenarios where further investigation is needed.