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Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Weaver JM, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong CA, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O'Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavaré S, Fitzgerald RC, OCCAMS Consorti - Nat. Genet. (2014)

Bottom Line: Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE.Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively.In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Medical Research Council (MRC) Cancer Unit, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

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Related in: MedlinePlus

Mutation in esophageal adenocarcinomaThe bar graph on the top indicates the percentage of samples with aberrations for a given gene. The number in bold denotes the total number of mutations for each gene. Genes with four or more mutations in our EAC discovery and validation cohort (combined total of 112 patients) were included. The proportion of missense, nonsense/splice and indel mutations are shown. The matrix below shows the number of samples with mutations in both genes for each possible pairing of genes. The red highlighted box indicates significantly co-occurring mutations (Significance was assessed empirically from 100,000 permutations. False discovery rate was controlled using the Benjamini-Hochberg procedure.).
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Figure 2: Mutation in esophageal adenocarcinomaThe bar graph on the top indicates the percentage of samples with aberrations for a given gene. The number in bold denotes the total number of mutations for each gene. Genes with four or more mutations in our EAC discovery and validation cohort (combined total of 112 patients) were included. The proportion of missense, nonsense/splice and indel mutations are shown. The matrix below shows the number of samples with mutations in both genes for each possible pairing of genes. The red highlighted box indicates significantly co-occurring mutations (Significance was assessed empirically from 100,000 permutations. False discovery rate was controlled using the Benjamini-Hochberg procedure.).

Mentions: We next combined the data from both the discovery and validation cohorts and identified 15 genes that were mutated in four or more samples (Figure 2). These included those previously identified as EAC candidate genes, and several novel candidates: MYO18B,SEMA5A and ABCB1. Comparison with the recent EAC exome sequencing from Dulak et al confirmed that these genes were recurrently mutated in an external data set (Supplementary table 4). TP53 was mutated in the majority of cases; however 31% of cases are wild type for TP53. Although we do not have enough power to detect mutually-exclusive mutations in our cohort, we can detect significantly co-occurring mutations. SEMA5A and ABCB1 mutations occurred more commonly in the same tumor than would be expected by chance (Benjamini-Hochberg-adjusted p-value = 0.0021) although the reason for this association remains unclear.


Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

Weaver JM, Ross-Innes CS, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong CA, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O'Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavaré S, Fitzgerald RC, OCCAMS Consorti - Nat. Genet. (2014)

Mutation in esophageal adenocarcinomaThe bar graph on the top indicates the percentage of samples with aberrations for a given gene. The number in bold denotes the total number of mutations for each gene. Genes with four or more mutations in our EAC discovery and validation cohort (combined total of 112 patients) were included. The proportion of missense, nonsense/splice and indel mutations are shown. The matrix below shows the number of samples with mutations in both genes for each possible pairing of genes. The red highlighted box indicates significantly co-occurring mutations (Significance was assessed empirically from 100,000 permutations. False discovery rate was controlled using the Benjamini-Hochberg procedure.).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4116294&req=5

Figure 2: Mutation in esophageal adenocarcinomaThe bar graph on the top indicates the percentage of samples with aberrations for a given gene. The number in bold denotes the total number of mutations for each gene. Genes with four or more mutations in our EAC discovery and validation cohort (combined total of 112 patients) were included. The proportion of missense, nonsense/splice and indel mutations are shown. The matrix below shows the number of samples with mutations in both genes for each possible pairing of genes. The red highlighted box indicates significantly co-occurring mutations (Significance was assessed empirically from 100,000 permutations. False discovery rate was controlled using the Benjamini-Hochberg procedure.).
Mentions: We next combined the data from both the discovery and validation cohorts and identified 15 genes that were mutated in four or more samples (Figure 2). These included those previously identified as EAC candidate genes, and several novel candidates: MYO18B,SEMA5A and ABCB1. Comparison with the recent EAC exome sequencing from Dulak et al confirmed that these genes were recurrently mutated in an external data set (Supplementary table 4). TP53 was mutated in the majority of cases; however 31% of cases are wild type for TP53. Although we do not have enough power to detect mutually-exclusive mutations in our cohort, we can detect significantly co-occurring mutations. SEMA5A and ABCB1 mutations occurred more commonly in the same tumor than would be expected by chance (Benjamini-Hochberg-adjusted p-value = 0.0021) although the reason for this association remains unclear.

Bottom Line: Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE.Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively.In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: 1] Medical Research Council (MRC) Cancer Unit, University of Cambridge, Cambridge, UK. [2].

ABSTRACT
Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

Show MeSH
Related in: MedlinePlus