1. Whole-Exome Sequencing Reveals Frequent Mutations in Chromatin Remodeling Genes in Mammary and Extramammary Paget’s Diseases
- Author
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Youwen Zhou, Liangli Hong, Yuanyuan Wang, Richard I. Crawford, Songxia Zhou, Guohong Zhang, Shanming Lu, Weixiang Zhong, Mingwan Su, Ruiqin Mai, Yuansheng Huang, and Jiankai Pan
- Subjects
Male ,0301 basic medicine ,Lineage (genetic) ,Paget's Disease, Mammary ,Breast Neoplasms ,Dermatology ,Gene mutation ,Biology ,medicine.disease_cause ,Biochemistry ,Extramammary Paget's disease ,Chromatin remodeling ,03 medical and health sciences ,0302 clinical medicine ,Mutation Rate ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Humans ,Molecular Biology ,Exome sequencing ,Mutation ,DNA, Neoplasm ,Cell Biology ,Chromatin Assembly and Disassembly ,medicine.disease ,3. Good health ,DNA-Binding Proteins ,Paget Disease, Extramammary ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Adenocarcinoma ,Female ,Carcinogenesis - Abstract
Paget's disease (PD) is an intraepidermal adenocarcinoma of the skin at the breast (mammary PD) or urogenital locations (extramammary PD [EMPD]). At present, there is lack of clarity on PD's pathogenesis, the relationship between its subtypes, and its lineage link with the underlying invasive carcinomas. Here we describe that mammary PD and EMPD have similar mutational profiles, with the most frequent recurrent mutations occurring in the chromatin remodeling genes, such as KMT2C (MLL3, 39%) and ARID2 (22%), with additional recurrent somatic mutations detected in genes previously not known to be mutated in cancers, such as CDCC168 (34%), FSIP2 (29%), CASP8AP2 (29%), and BIRC6 (24%). In paired mammary PD and underlying breast carcinoma samples, distinct gene mutations were detected, indicating that they represent independent oncogenic events. Finally, multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. Our results reveal similar genomic landscapes between mammary PD and EMPD, including early aberrations in chromatin remodeling genes. In addition, mammary PD and underlying breast ductal carcinomas represent independent oncogenic events. These findings provide approaches for developing diagnostic tools and therapeutic interventions for PD.
- Published
- 2019