PMC:4385186 / 24025-25332 JSONTXT

{"project":"2_test","denotations":[{"id":"25839328-23318258-2052578","span":{"begin":114,"end":116},"obj":"23318258"},{"id":"25839328-24670651-2052579","span":{"begin":229,"end":230},"obj":"24670651"},{"id":"25839328-22608084-2052580","span":{"begin":559,"end":561},"obj":"22608084"},{"id":"25839328-12453430-2052580","span":{"begin":559,"end":561},"obj":"12453430"},{"id":"25839328-24162735-2052580","span":{"begin":559,"end":561},"obj":"24162735"},{"id":"25839328-15466872-2052580","span":{"begin":559,"end":561},"obj":"15466872"},{"id":"25839328-24910434-2052580","span":{"begin":559,"end":561},"obj":"24910434"},{"id":"25839328-10767625-2052581","span":{"begin":1033,"end":1035},"obj":"10767625"},{"id":"25839328-10767625-2052582","span":{"begin":1225,"end":1227},"obj":"10767625"}],"text":"To 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."}