title: Clonally related uterine leiomyomas are common and display branched tumor evolution.
abstract: Uterine leiomyomas are extremely frequent benign smooth muscle tumors often presenting as multiple concurrent lesions and causing symptoms such as abnormal menstrual bleeding, abdominal pain and infertility. While most leiomyomas are believed to arise independently, a few studies have encountered separate lesions harboring identical genetic changes, suggesting a common clonal origin. To investigate the frequency of clonally related leiomyomas, genome-wide tools need to be utilized, and thus little is known about this phenomenon. Using MED12 sequencing and SNP arrays, we searched for clonally related uterine leiomyomas in a set of 103 tumors from 14 consecutive patients who entered hysterectomy owing to symptomatic lesions. Whole-genome sequencing was also utilized to study the genomic architecture of clonally related tumors. This revealed four patients to have two or more tumors that were clonally related, all of which lacked MED12 mutations. Furthermore, some tumors were composed of genetically distinct subclones, indicating a nonlinear, branched model of tumor evolution. DEPDC5 was discovered as a novel tumor suppressor gene playing a role in the progression of uterine leiomyomas. Perhaps counterintuitively—considering Knudson's two-hit hypothesis—a large shared deletion was followed by different truncating DEPDC5 mutations in four clonally related leiomyomas. This study provides insight into the intratumor heterogeneity of these tumors and suggests that a shared clonal origin is a common feature of leiomyomas that do not carry an MED12 mutation. These observations also offer one explanation to the common occurrence of multiple concurrent lesions.
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Miika
authors.initials: M
authors.lastname: Mehine
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Hanna-Riikka
authors.initials: HR
authors.lastname: Heinonen
authors.affiliation: Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland, Obstetrics and Gynecology, Helsinki University Hospital, PO Box 140, Helsinki FIN-00029, Finland.
authors.forename: Nanna
authors.initials: N
authors.lastname: Sarvilinna
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Pitkänen
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Netta
authors.initials: N
authors.lastname: Mäkinen
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Katainen
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.affiliation: Department of Pathology, Haartman Institute and HUSLAB, University of Helsinki and Helsinki University Central Hospital, PO Box 21, Helsinki FIN-00014, Finland and.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.affiliation: Obstetrics and Gynecology, Helsinki University Hospital, PO Box 140, Helsinki FIN-00029, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Sjöberg
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, Research Programs Unit, Genome-Scale Biology, University of Helsinki, PO Box 63, Helsinki FIN-00014, Finland, lauri.aaltonen@helsinki.fi.
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D002999:Clone Cells; D005260:Female; D020690:GTPase-Activating Proteins; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D056892:Mediator Complex / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; C460107:MED12 protein, human; D056892:Mediator Complex; D012097:Repressor Proteins