title: Intraindividual genomic heterogeneity of high-grade serous carcinoma of the ovary and clinical utility of ascitic cancer cells for mutation profiling.
abstract: Intraindividual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The aim of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling and DNA methylation profiling of four OSC genomes by using multiregional biopsies from 13 intraovarian lesions, 12 extraovarian tumour lesions (omentum/peritoneum), and ascitic cells. We observed substantial levels of heterogeneity in mutations and copy number alterations (CNAs) of the OSCs. We categorized the mutations into 'common', 'shared' and 'private' according to the regional distribution. Six common, eight shared and 24 private mutations were observed in known cancer-related genes. Common mutations had a higher mutant allele frequency, and included TP53 mutations in all four OSCs. Region-specific chromosomal amplifications and deletions involving BRCA1, PIK3CA and RB1 were also identified. It is of note that the mutations detected in ascitic cancer cells represented 92.3-100% of overall somatic mutations in the given case. Phylogenetic analyses of ascitic genomes predicted a polyseeding origin of somatic mutations in ascitic cells. Our results demonstrate that, despite ITH, somatic mutations, CNAs and DNA methylations in both 'common' category and cancer-related genes were highly conserved in ascitic cells of OSCs, highlighting the clinical relevance of genome analysis of ascitic cells. Ascitic tumour cells may serve as a potential resource for discovering somatic mutations of primary OSC with diagnostic and therapeutic relevance. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Cancer Evolution Research Centre, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Youn Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Je-Keun
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Department of Obstetrics/Gynaecology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Hur
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sung Hak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Integrated Research Centre for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.|Cancer Evolution Research Centre, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D001201:Ascites / Q000473:pathology; D001706:Biopsy; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D019175:DNA Methylation; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010802:Phylogeny
chemical_list: D004273:DNA, Neoplasm
keywords: ascites; high-grade serous carcinoma; intra-individual tumoural heterogeneity; metastasis; multiregion sequencing; ovarian cancer; phylogeny