Mutation profile and chromosomal abnormality in adenomyosis.

In brief: By tissue-selective next-generation sequencing, we showed that adenomyotic epithelium harbored genomic alterations thought to be relevant to the development and progression of adenomyosis, including somatic mutations in several cancer-associated genes with high mutant allele frequencies and the gain of chromosome 1q. Clonal relationships among multiple adenomyotic lesions and the normal uterine endometrium delineate the oligoclonal origin of adenomyosis and the spatial expansion of mutant clones. Abstract: To identify the distinctive features of mutation profiles in adenomyosis compared to the coexisting normal endometrium, multi-regional sampling was performed to collect samples of adenomyotic epithelium (n = 41), adenomyotic stroma (n = 12), and uterine endometrial epithelium (n = 53) from 21 patients with adenomyosis. To enhance the purity in this genomic study, laser microdissection was used to isolate all the samples. Target-gene sequencing and whole-exome sequencing were performed to identify somatic mutations in cancer-associated genes and the pattern of cellular expansion in adenomyosis and clonality between adenomyosis and uterine endometrium. In adenomyotic epithelium, we identified somatic mutations in cancer-associated genes such as KRAS (34.1%), PIK3CA (12.2%), ARID1A (12.1%), and FBXW7 (9.8%) with high mutant allele frequency. In uterine endometrial epithelium, frequently mutated genes included KRAS (47.2%), PIK3CA (37.8%), and ARHGAP35 (28.3%). Whole-exome sequencing revealed clonal relationships among adenomyotic lesions, and between adenomyosis and uterine endometrium. The analysis of somatic copy number alterations (SCNAs) showed recurring gain of chromosome 1q in the adenomyotic epithelium but not in the uterine endometrial endometrium. Mutational signature analysis for SNVs revealed that similar mutational processes were shared in adenomyosis and uterine endometrium. In this study, we identified multiple cancer-associated gene mutations and SCNAs relevant to the development of adenomyosis, and also clonal relationships among multiple adenomyotic lesions and normal uterine endometrium.