title: Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden.
abstract: Endometriosis is a significant risk factor for clear cell and endometrioid ovarian cancers and is often found contiguous with these cancers. Using whole-genome shotgun sequencing of seven clear cell ovarian carcinomas (CCC) and targeted sequencing in synchronous endometriosis, we have investigated how this carcinoma may evolve from endometriosis. In every case we observed multiple tumour-associated somatic mutations in at least one concurrent endometriotic lesion. ARID1A and PIK3CA mutations appeared consistently in concurrent endometriosis when present in the primary CCC. In several cases, one or more endometriotic lesions carried the near-complete complement of somatic mutations present in the index CCC tumour. Ancestral mutations were detected in both tumour-adjacent and -distant endometriotic lesions, regardless of any cytological atypia. These findings provide objective evidence that multifocal benign endometriotic lesions are clonally related and that CCCs arising in these patients progress from endometriotic lesions that may already carry sufficient cancer-associated mutations to be considered neoplasms themselves, albeit with low malignant potential. We speculate that genomically distinct classes of endometriosis exist and that ovarian endometriosis with high mutational burden represents one class at high risk for malignant transformation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Anglesio
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Yi Kan
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Winnie
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Aniba
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Leah M
authors.initials: LM
authors.lastname: Prentice
authors.affiliation: Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Hossein
authors.initials: H
authors.lastname: Farahani
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Hector
authors.initials: H
authors.lastname: Li Chang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Michael Smith Genome Science Centre, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Yong
authors.affiliation: Michael Smith Genome Science Centre, British Columbia Cancer Agency Research Center, Vancouver, Canada.|Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.|Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, Canada.
authors.forename: Blake
authors.initials: B
authors.lastname: Gilks
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.|Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.|Department of Molecular Oncology, British Columbia Cancer Agency Research Center, Vancouver, Canada.|Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins; D004715:Endometriosis / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; C112476:ARID1A protein, human; C484760:PIK3CA protein, human
keywords: cancer precursor; clear cell carcinoma; endometriosis; ovarian cancer; sequencing