Deciphering Signatures of Mutational Processes Operative in Human Cancer

Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Campbell, Peter J.; Stratton, Michael R.

doi:10.1016/j.celrep.2012.12.008

Cited by 1,249 publications

(1,671 citation statements)

References 27 publications

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“…Recently, a range of distinct mutational processes was defined using whole‐exome or whole‐genome sequencing data (Alexandrov et al ., 2013a,b). Some of these processes are induced by external mutagens such as UV light and smoking.…”

Section: Resultsmentioning

confidence: 99%

“…P ‐values were calculated based on a five‐year censoring of survival data from the time of biopsy. The deconstructSigs R package was used to analyze mutational signatures in the cohort (Alexandrov et al ., 2013b). Mutational signatures were derived from the 1461 overlapping genes and included only samples with at least 50 somatic mutations.…”

Section: Methodsmentioning

confidence: 99%

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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%

Section: Methodsmentioning

confidence: 99%

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

et al. 2017

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“…In the past few years, there are 30 patterns of mutational signatures be found across the spectrum of human cancer types from many large‐scale analyses,43, 44, 45, 46, 47 including 11 types of signatures found in gastric cancer. We observed a significant association between rs1679709 and the weights of COSMIC Signature 15.…”

Section: Discussionmentioning

confidence: 99%

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

et al. 2018

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Genome‐wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common‐enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12‐0.55, P = 3.93 × 10−4). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.

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“…In general, melanoma and lung cancer accumulated a large number of somatic nucleotide variants (SNV); however, the diversity level was low and SNV were relatively ubiquitous in the tumor. Somatic mutations are present in all cells and they are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, and enzymatic modification of DNA and, at present, they have been classified into 30 signatures 35, 36, 37, 38. The nucleotide substitutions in those tumors were characterized as C>T from ultraviolet light (signature 7)23 and C>A from smoking (signature 4) 19, 20.…”

Section: General Components Of Ithmentioning

confidence: 99%

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Section: Introductionmentioning

confidence: 99%

Cancer evolution and heterogeneity

Mimori

Saito

Niida

et al. 2018

Annals of Gastroent Surgery

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Undoubtedly, intratumor heterogeneity (ITH) is one of the causes of the intractability of cancers. Recently, technological innovation in genomics has promoted studies on ITH in solid tumors and on the pattern and level of diversity, which varies among malignancies. We profiled the genome in multiple regions of nine colorectal cancer (CRC) cases. The most impressive finding was that in the late phase, a parental clone branched into numerous subclones. We found that minor mutations were dominant in advanced CRC named neutral evolution; that is, driver gene aberrations were observed with high proportion in the early‐acquired phase, but low in the late‐acquired phase. Then, we validated that neutral evolution could cause ITH in advanced CRC by super‐computational analysis. According to the clinical findings, we explored a branching evolutionary process model in cancer evolution, which assumes that each tumor cell has cellular automaton. According to the model, we verified factors to foster ITH with neutral evolution in advanced CRC. In this review, we introduce recent advances in the field of ITH including the general component of ITH, clonal selective factors that consolidate the evolutionary process, and a representative clinical application of ITH.

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Deciphering Signatures of Mutational Processes Operative in Human Cancer

Cited by 1,249 publications

References 27 publications

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

Cancer evolution and heterogeneity

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