The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy. © 2014 Nature America, Inc.This study was predominantly funded by Cancer Research UK through the Genomic Initiative and Programme grant (15968) to J.F. and was also supported by Leukemia and Lymphoma Research (grant to J.F.) and Hungarian Scientific Research Fund (Országos Tudományos Kutatási Alapprogramok, OTKA) grant K-76204 (to A.M.). Y.F. is a recipient of the Georgia Cancer Coalition Distinguished Scholar Award, and C.P. and Y.F. are, in part, supported by US National Institutes of Health grant GM085261 (to Y.F.). C.B. is a recipient of the European Hematology Association (EHA) Partner fellowship (2009/1) and was supported by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of TÁMOP 4.2.4. A/1-11-1-2012-0001 National Excellence Program. J.O. is a recipient of the Kay Kendall Leukaemia Fund (KKLF) Junior Clinical Research Fellowship (KKL 557)