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JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n = 50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations × 100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n = 12) with these patients having a rate of 25.6 mutations × 100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p = 0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p = 0.001) with mutations in ASXL1 (p < 0.0001), TP53 (p = 0.01), SRSF2 (p < 0.0001), IDH1/2 (p < 0.0001), and RUNX1 (p < 0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p = 0.02) and IDH1/2 (p < 0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p = 0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.

Next-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform. We describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others. The panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the (28%), (16%), (10%) and (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C). Prior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting.

The persistence of fetal cells in the mother (fetal microchimerism (FMc)) has been described in maternal tissues essential to the newborn. FMc is associated with several diseases that start or worsen in pregnancy or postpartum. This exploratory study reports—for the first time—the presence of FMc in the olfactory neuroepithelium (ON) of both healthy and depressed women with male offspring. However, depressed women had fewer microchimeric cells (digital PCR). The existence of FMc in the ON could facilitate mother–child bonding. These findings open new pathways to study FMc in the ON, female depression, and mother–child bonding.

Background Matrix metalloproteinase 7 (MMP-7) is involved in invasion, metastasis, growth, and angiogenesis. The aim of this study is to assess the prognostic role of serum MMP-7 in curatively resected colorectal cancer (CRC). Materials and Methods Patients undergoing resection for CRC ( n = 175) were recruited from July 2003 to December 2004. MMP-7 was determined using a quantitative solid phase sandwich ELISA. Cox analysis was used to assess the role of MMP-7 in predicting overall survival (OS) and disease-free survival (DFS). Results The median length of follow-up was 45 months (range 1 to 59). Levels of MMP-7 are predictors of DFS (hazard ratio [HR] 1.119, 95% confidence interval [95% CI] 1.038–1.207) and of OS (HR 1.113, 95% CI 1.025–1.209). Patients with MMP-7 higher than the median (4.3 ng/ml) are more likely to relapse (29.5% vs 18.4%, P = .084); median time to progression in relapsed patients is 8 months if MMP-7 is ≥4.3 ng/ml and 18 months if MMP-7 is <4.3 ng/ml. Node-negative patients with low MMP-7 have a predicted probability of relapse-free survival at 4 years of 88% (95% CI 83–92%); if the MMP-7 is higher than the median value; this probability is 77% (95% CI 73–81%). Conclusion MMP-7 predicts recurrence in curatively resected CRC patients.

The acquisition of driver mutations in non-tumoral cells appears to be very important during the carcinogenesis of adenocarcinoma (ADC). Recent studies suggest that cancer-related mutations may not necessarily be present only in malignant cells, but also in histologically “healthy cells”. Objective: to demonstrate the presence of EGFR or KRAS mutations in non-tumoral lung cells in subjects with ADC and negative mutational status. Results: mutations in EGFR or KRAS oncogenes were identified in the normal lung in 9.7% of the subjects. Exon 21 substitution L858R in EGFR was detected in two cases while the exon 19 deletion E746-A750 in the EGFR , the G12C and G12D substitutions in the KRAS were detected once. One patient presented three different mutations in the normal lung parenchyma ( EGFR _L858R, KRAS _G12C and KRAS _G12D). The negative-mutation status of the tumor and the mutations detected in the “normal lung” were confirmed using highly sensitive and specific TaqMan PCR (CAST-PCR). No differences were found in terms of progression, progression-free survival or overall survival during the 18 months follow-up. Conclusions: These results confirm the presence of driver mutations in the histologically normal lung parenchyma cells in the absence of mutations coexisting with the primary tumor.

Tumor recurrence is frequent and survival rates remain extremely low in lung adenocarcinoma (ADC). We hypothesize that carcinogenic factors will promote loco-regional modifications not only in the future tumor, but throughout the exposed lung. Objective: To analyze whether the most prevalent mutations observed in ADC can also be observed in the non-neoplastic lung tissue, as well as the short-term prognosis implications of this finding. Methods: Non-tumoral lung parenchyma specimens obtained during surgery from 47 patients with EGFR and/or KRAS abnormalities in their ADC tumors underwent similar genomic testing. Short-term outcomes were also recorded. Results: The same mutations were present in the tumor and the histologically normal tissue in 21.3% of patients (SM group). Although local recurrences were similar in both groups, distant metastases were more frequent in the former (60 vs. 5.4%, p < 0.001). Moreover, SM patients showed lower time-to-progression (8.5 vs. 11.7 months, p < 0.001) and disease-free survival (8.5 vs. 11.2 months, p < 0.001). COX regression showed a higher risk of progression or death (DFS) in the SM group (HR 5.94, p < 0.01]. Similar results were observed when adjusting for potential confounding variables. Conclusions: These results confirm that genetic changes are present in the apparently normal lung in many ADC patients, and this finding has prognostic implications.

JAK2 V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL , TET2 , and ASXL1 genes and human androgen receptor ( HUMARA ) assay was performed in 73 JAK2V617F-negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL , TET2 , and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46 %) female patients. With a median follow-up of 8 years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10 years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL , TET2 , or ASXL1 (64 versus 2 % in patients without mutations, p  < 0.001) and in those with HUMARA clonality (35 versus 0 % in patients with polyclonal hematopoiesis, p  < 0.004). In conclusion, disease transformation is associated with evidence of clonality in JAK2V617F-negative ET.

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm(MPN) characterised by megakaryocyte hyperplasia and thrombo-cytosis. From the genetic perspective, ET patients harbourmutations inJAK2(50–60%),CALR(15–30%) andMPL(1–5%) genes. This study was supported in part by grants from ISCIII and Spanish Ministry of Health, PI13/00557, PI13/00393, RD12/0036/0010, PT13/0010/0005, 2014SGR567 and the Xarxa de Banc de Tumors de Catalunya.

The biological basis of essential thrombocythemia (ET) patients lacking known mutations is still unknown. MicroRNAs (miRNA) regulate hematopoietic differentiation and are deregulated in several hematopoietic malignancies. However, miRNA expression in ET patients has been poorly explored. We performed miRNA profiling in platelets from 19 ET patients and 10 healthy controls. Hierarchical cluster analysis showed two well-separated clusters between patients and controls, indicating that ET platelets had a characteristic 70-miRNA signature ( P <0.0001), 68 of which were downregulated. According to the mutational status, three differentially expressed miRNAs, miR-15a ( P =0.045), miR-150 ( P =0.001) and miR-519a ( P =0.036), were identified. A 40-miRNA signature was identified characterizing JAK2V617F-positive ET patients. Eight genes, whose interaction with the miRNAs could activate the JAK/STAT pathway were identified. An inverse correlation was observed between miRNAs expression and their target genes for SOCS1 and miR-221, SOCS3 and miR-221, SOCS3 and miR-203, and PTPN11 and miR-23a. All three miRNAs were upregulated in JAK2V617F-negative ET patients. SOCS1 and SOCS3 were validated as targets of miR-221 and miR-203, respectively. In summary, our study shows that platelets from JAK2V617F-negative ET patients harbor a specific miRNA signature that can participate in the modulation of the JAK/STAT pathway through regulation of key genes as SOCS1 and SOCS3 .