The driver landscape of sporadic chordoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma

Recurrent histone mutations in T-cell acute lymphoblastic leukaemia.

Mutations affecting key modifiable histone type 3 (H3; Supplementary Table 1) residues are frequent oncogenic events in certain solid tumours (Feinberg, et al 2016), and have also recently been implicated in a subset of acute myeloid leukaemia (AML)(Lehnertz, et al 2017). Here, we systematically reviewed the somatic mutations in >20,000 cancer specimens to identify tumours harbouring H3 mutations. In a subset of T-cell acute lymphoblastic leukaemia (T-ALL) we identified non-methionine mutations of the key modifiable H3 residues, lysine (K) 27 and 36

Mutational signatures associated with tobacco smoking in human cancer

Tobacco smoking increases the risk of at least 17 classes of human cancer. We analyzed somatic mutations and DNA methylation in 5243 cancers of types for which tobacco smoking confers an elevated risk. Smoking is associated with increased mutation burdens of multiple distinct mutational signatures, which contribute to different extents in different cancers. One of these signatures, mainly found in cancers derived from tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clocklike mutational process. Smoking is associated with limited differences in methylation. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load, although direct evidence for this mechanism is lacking in some smoking-related cancer types

Somatic mutations and clonal dynamics in healthy and cirrhotic human liver.

The most common causes of chronic liver disease are excess alcohol intake, viral hepatitis and non-alcoholic fatty liver disease, with the clinical spectrum ranging in severity from hepatic inflammation to cirrhosis, liver failure or hepatocellular carcinoma (HCC). The genome of HCC exhibits diverse mutational signatures, resulting in recurrent mutations across more than 30 cancer genes1-7. Stem cells from normal livers have a low mutational burden and limited diversity of signatures8, which suggests that the complexity of HCC arises during the progression to chronic liver disease and subsequent malignant transformation. Here, by sequencing whole genomes of 482 microdissections of 100-500 hepatocytes from 5 normal and 9 cirrhotic livers, we show that cirrhotic liver has a higher mutational burden than normal liver. Although rare in normal hepatocytes, structural variants, including chromothripsis, were prominent in cirrhosis. Driver mutations, such as point mutations and structural variants, affected 1-5% of clones. Clonal expansions of millimetres in diameter occurred in cirrhosis, with clones sequestered by the bands of fibrosis that surround regenerative nodules. Some mutational signatures were universal and equally active in both non-malignant hepatocytes and HCCs; some were substantially more active in HCCs than chronic liver disease; and others-arising from exogenous exposures-were present in a subset of patients. The activity of exogenous signatures between adjacent cirrhotic nodules varied by up to tenfold within each patient, as a result of clone-specific and microenvironmental forces. Synchronous HCCs exhibited the same mutational signatures as background cirrhotic liver, but with higher burden. Somatic mutations chronicle the exposures, toxicity, regeneration and clonal structure of liver tissue as it progresses from health to disease.This work was supported by a Wellcome Trust and Cancer Research UK (CRUK) Grand Challenge Award (C98/A24032). P.J.C. is a Wellcome Trust Senior Clinical Fellow (WT088340MA); S.F.B. was supported by the Swiss National Science Foundation (P2SKP3-171753 and P400PB-180790); M.A.S. is supported by a Rubicon fellowship from NWO (019.153LW.038); the Cambridge Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre; and M.H. is supported by a CRUK Clinician Scientist Fellowship (C52489/A19924)

Somatic Evolution in Non-neoplastic IBD-Affected Colon.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis

Biological and prognostic impact of apobec-induced mutations in the spectrum of plasma cell dyscrasias

In multiple myeloma (MM), whole exome sequencing (WES) studies have revealed four mutational signatures: two associated with aberrant activities of APOBEC cytidine deaminases (Signatures #2 and #13) and two clock-like signatures associated with "cancer age" (Signatures #1 and #5). Mutational signatures have not been investigated systematically in larger series, nor in other primary plasma cell dyscrasias such as monoclonal gammopathy of unknown significance (MGUS) or primary plasma cell leukemia (pPCL). Finally, while APOBEC activity has been correlated to increased mutational burden and poor-prognosis MAF/MAFB translocations in MM at diagnosis, this has never been confirmed in multivariate analysis in an independent series. To answer these questions, we mined 1151 MM samples from public WES datasets, including samples from the IA9 public release of the CoMMpass trial. The CoMMpass data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives. We also analyzed 6 MGUS/Smoldering MM as well as 5 previously published pPCLs. Extraction of mutational signatures was performed using the NNMF algorithm as previously described (Alexandrov et al. Nature 2013). NNMF in the whole cohort extracted the known 4 signatures pertaining to distinct mutational processes: the two clock-like processes (signatures #1 and #5) and aberrant APOBEC deaminase activity (signatures #2 and #13). While the clock-like processes were more prominent in the cohort as a whole (median 70%, range 0-100%), the APOBEC showed a heterogeneous contribution, more visible in samples with the highest mutation burden. In fact, the absolute and relative contribution of APOBEC activity to the mutational repertoire correlated with the overall number of mutations (r=0.71, p= < 0.0001). As previously described, APOBEC contribution was significantly enriched among MM patients with t(14;16) and with t(14;20) (p<0.001), but the association between relative APOBEC contribution and mutational load remained significant across all cytogenetic subgroups with the exception of t(11;14). In the MGUS/SMM series, APOBEC contribution was generally low. Conversely, APOBEC activity was preponderant in three out of five pPCL samples, all of them characterized by the t(14;16)( IGH / MAF); in the remaining two pPCL the absolute number of APOBEC mutations was similar to MM. Overall, the APOBEC contribution was characterized by a progressive increment from MGUS/SMM to MM and pPCL. We next went on to investigate the prognostic impact of APOBEC signatures at diagnosis. Patients with APOBEC contribution in the 4th quartile had shorter PFS (2-y PFS 47% vs 66%, p<0.0001) and OS (2-y OS 70% vs 85%, p=0.0033) than patients in quartiles 1-3 (Figure 1a-b). This was independent from the association of APOBEC activity with MAF translocations and higher mutational burden, as shown by multivariate analysis with Cox regression (Figure 1c-d). ISS stage III was the only other variable that retained its independent prognostic value for both PFS and OS. We therefore combined both variables and found that co-occurrence of ISS III and APOBEC 4th quartile identifies a fraction of high-risk patients with 2-y OS of 53.8% (95% CI 36.6%-79%), while their simultaneous absence identifies long term survivors with 2-y OS of 93.3% (95% CI 89.6-97.2%). In this study, we provided a global overview on the contribution of mutational processes in the largest whole exome series of plasma cell dyscrasias investigated to date by NNMF. We propose that cases with high APOBEC activity may represent a novel prognostic subgroup that is transversal to conventional cytogenetic subgroups, advocating for closer integration of next-generation sequencing studies and clinical annotation to confirm this finding in independent series

The landscape of somatic mutation in normal colorectal epithelial cells.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer