Signatures of mutational processes in human cancer

Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Aparicio, Samuel; Behjati, Sam; Biankin, Andrew V.; Bignell, Graham R.; Bolli, Niccolò; Borg, Åke; Børresen‐Dale, Anne‐Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam; Caldas, Carlos; Davies, Helen; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn E.; Foekens, John A.; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imieliński, Marcin; Jäger, Natalie; Jones, David; Jones, David R.; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R.; López-Otı́n, Carlos; Martin, Sancha; Munshi, Nikhil C.; Nakamura, Hiromi; Northcott, Paul A.; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V.; Puente, Xosé S.; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L.; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N.; Span, Paul N.; Teague, Jon W.; Totoki, Yasushi; Tutt, Andrew; Valdés-Mas, Rafael; Buuren, Marit M. van; Veer, Laura van ‘t; Vincent‐Salomon, Anne; Waddell, Nicola; Yates, Lucy R.; Zucman‐Rossi, Jessica; Futreal, P. Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M.; Siebert, Reiner; Campo, Elı́as; Shibata, Tatsuhiro; Pfister, Stefan M.; Campbell, Peter J.; Stratton, Michael R.

doi:10.1038/nature12477

Cited by 8,511 publications

(9,857 citation statements)

References 65 publications

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“…We used the compiled data and excluded samples with fewer than 50 somatic mutations due to statistical power, leaving us with 513 tumors, and used the R package deconstructSigs to derive the impact of the 30 mutational signatures put forward by Alexandrov et al . (2013a). As expected, we found signature 7, which is associated with UV exposure, to have the highest signature weight (Fig.…”

Section: Resultsmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF,RAS,NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.

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Section: Resultsmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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“…(A) The mutation spectra across 96 mutational channels (each representing a trinucleotide context, as described previously 37). (B) Mutational signature activity plot, indicating the proportion of somatic mutations found in adenomas from MAP and FAP patients that can be attributed to either signature A or signature B; the validated positions in Table S3 (see supplementary material) were used for this analysis…”

Section: Resultsmentioning

confidence: 99%

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

Rashid

Fischer

Wilson

et al. 2015

The Journal of Pathology

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Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…In particular, comprehensive molecular profiling of tumors has identified new disease subtypes and signatures reflective of particular exposures. 84 However, much less is known about pathogenesis of SN. Most previous research has focused on immune drivers because the post-HCT milieu is associated with unique alterations that may promote the development of SN.…”

Section: Pathogenesismentioning

confidence: 99%

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Morton

Saber

Baker

et al. 2017

Biology of Blood and Marrow Transplantation

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Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists in order to reduce the burden of SN in the rapidly growing population of HCT survivors.

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Signatures of mutational processes in human cancer

Cited by 8,511 publications

References 65 publications

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Adenoma development in familial adenomatous polyposis and MUTYH‐associated polyposis: somatic landscape and driver genes

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

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