PMC:4385186 / 22759-26453 JSONTXT

{"project":"2_test","denotations":[{"id":"25839328-24670651-2052574","span":{"begin":671,"end":672},"obj":"24670651"},{"id":"25839328-17932254-2052575","span":{"begin":746,"end":748},"obj":"17932254"},{"id":"25839328-23525077-2052576","span":{"begin":829,"end":831},"obj":"23525077"},{"id":"25839328-24670651-2052577","span":{"begin":1116,"end":1117},"obj":"24670651"},{"id":"25839328-23318258-2052578","span":{"begin":1380,"end":1382},"obj":"23318258"},{"id":"25839328-24670651-2052579","span":{"begin":1495,"end":1496},"obj":"24670651"},{"id":"25839328-22608084-2052580","span":{"begin":1825,"end":1827},"obj":"22608084"},{"id":"25839328-12453430-2052580","span":{"begin":1825,"end":1827},"obj":"12453430"},{"id":"25839328-24162735-2052580","span":{"begin":1825,"end":1827},"obj":"24162735"},{"id":"25839328-15466872-2052580","span":{"begin":1825,"end":1827},"obj":"15466872"},{"id":"25839328-24910434-2052580","span":{"begin":1825,"end":1827},"obj":"24910434"},{"id":"25839328-10767625-2052581","span":{"begin":2299,"end":2301},"obj":"10767625"},{"id":"25839328-10767625-2052582","span":{"begin":2491,"end":2493},"obj":"10767625"},{"id":"25839328-23629646-2052583","span":{"begin":2704,"end":2706},"obj":"23629646"},{"id":"25839328-24944476-2052584","span":{"begin":2726,"end":2728},"obj":"24944476"},{"id":"25839328-24670651-2052585","span":{"begin":2817,"end":2818},"obj":"24670651"},{"id":"25839328-23945592-2052586","span":{"begin":3008,"end":3010},"obj":"23945592"},{"id":"25839328-23525077-2052587","span":{"begin":3367,"end":3369},"obj":"23525077"},{"id":"25839328-23945592-2052587","span":{"begin":3367,"end":3369},"obj":"23945592"},{"id":"25839328-21642993-2052588","span":{"begin":3568,"end":3570},"obj":"21642993"}],"text":"Mutational Signatures of ESCC\nTo extract the mutational signatures that cause somatic mutations in ESCC and identify driver genes or pathways contributing to ESCC in Chinese individuals, we sequenced the genome of 104 ESCC tumors and matched adjacent normal tissues from individuals recruited from the Taihang Mountains in north-central China (Table S1). WGS (median coverage of 65×) of 14 tumors and WES (median coverage of 132×) of 90 tumors were performed (Figure S1). The average mutation rate was 3.9 coding mutations/Mb in WGS samples and 2.4 non-silent mutations/Mb in WES samples (Table S2). This rate is consistent with recently published mutation rates in ESCC.6 A high frequency of C\u003eT transitions was identified in the overall dataset18 (Figure S2A), and C\u003eG transversions occurred more frequently in ESCC than in EAC19 (Figure S2B). We selected candidate non-silent mutations identified in 96 tumors for validation by using the deep target capture system (at least 365×). Validation rates were 97.8% for identified SNVs and 58% for indels. We also analyzed our previously published ESCC mutation dataset6 of 17 WGS and 71 WES samples recruited from the Chaoshan District of Gongdong Province, another area of high ESCC prevalence in China (Figure S1E).\nTo identify the mutational signatures within ESCC genomes, we applied the non-negative matrix-factorization method20 to a combined mutation set of 192 ESCC tumors (14 WGS and 90 WES samples from this study and 88 from Song et al.6) and uncovered three mutational signatures (Figure 1 and Figure S3). Signature A was characterized by C\u003eG, C\u003eT, and C\u003eA mutations at TpCpX trinucleotides (suggesting collateral damage following DNA-element retrotransposition or exogenous viruses) and was associated with mutations in the APOBEC family of cytidine deaminases.21–25 Moreover, hotspot mutations (c.1624G\u003eA [p.Glu542Lys] and c.1633G\u003eA [p.Glu545Lys]) on the SMG PIK3CA (MIM 171834) were significantly enriched in ESCC tumors that had an APOBEC signature (p = 0.0028, Fisher’s exact test, one-sided), implicating APOBEC activity as a key driver of PIK3CA mutagenesis in ESCC. Signature B was characterized by an enrichment of C\u003eT mutations at XpCpG trinucleotides as a result of an elevated rate of spontaneous 5-methyl-cytosine deamination.26 The elevated C\u003eT mutation rate at XpCpG trinucleotides is a well-recognized mutational mechanism probably due to deamination to thymine of methylated cytosines, which are usually at XpCpGs.26 Signature C was represented by types that, to our knowledge, are not yet known.\nTobacco smoking is consistently reported as an important risk factor for esophageal cancer, especially for squamous cell carcinoma27 and gastric cancer.28 The combined cohort of 192 ESCC individuals (104 from this study and 88 from Song et al.6) included 153 smoking and 39 non-smoking individuals (Table S1). Notably, we observed no smoking-associated signature characterized by C\u003eA mutations, which was defined by Alexandrov et al.,29 within ESCC genomes. Furthermore, we compared the proportion of C\u003eA transversions between smoking and non-smoking individuals and observed no statistically significant difference (p = 0.687, Figure 1C). Additionally, we found no smoking-associated signature in 149 EACs (at least 49 of 149 individuals with a history of smoking) from a pan-cancer study.19,29 These results indicate that the smoking-associated signature of C\u003eA mutations is limited in EC. Considering that epidemiological studies suggest that tobacco consumption might be associated with EC,30 we speculate that other smoking-associated signatures that have not been recognized might contribute to malignancy of ESCC."}