Epigenomic evolution in diffuse large B-cell lymphomas

The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis–relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse

Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas

OBJECTIVES: The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. METHODS: A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramér's V-test. RESULTS: The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers (P = 0.001), underwent segmentectomy or limited resections (P = 0.004) and were not submitted to adjuvant therapy (P = 0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramér's V: 0.25, P < 0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P < 0.001. No correlation between skip N2 and KRAS mutations was observed (Cramér's V: 0.05, P = 0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P = 0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P = 0.446; 95% CI: 0.427-1.454). CONCLUSIONS: In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours

Beyond NPM-anaplastic lymphoma kinase driven lymphomagenesis

PURPOSE OF REVIEW: Anaplastic large cell lymphomas (ALCLs) are rare entities whose somatic genetic lesions have been identified only in a subset of patients. Thus, an integrated and massive discovery programme is required to define their tumourigenic alterations and to design more successful tailored therapies. RECENT FINDINGS: The discovery of anaplastic lymphoma kinase (ALK) fusions has provided the basis for the characterization of distinct subsets among ALCL patients. Although the oncogenic addiction of ALK signalling is proven, the tumorigenic contribution of coactivating lesions is still missing. As ALK- and ALK+ share common signatures, it is plausible that analogous mechanisms of transformation may be operating in both subsets, as confirmed by the dysregulated activation of c-MYC, RAS and NF\u3baB, and the loss of Blimp-1 and p53/p63 axis. Nonetheless, recurrent genetic alterations for ALK- ALCL or refractory leukaemic ALK+ ALCL are lacking. Moreover, although conventional chemotherapies (anthracycline-based) are most successful, that is in ALK+ ALCL patients, the implementation of ALK inhibitors or of anti-CD30 based treatments provides innovative solutions, particularly in paediatric ALK+ ALCL and in chemorefractory/relapsed patients. SUMMARY: The complete portrayal of the landscape of genetic alterations in ALCL will dictate the development of innovative chemotherapeutic and targeted therapies that will fit most with the molecular and clinical profiling of individual patients