title: Genomic events associated with progression of pleural malignant mesothelioma.
abstract: Pleural malignant mesothelioma (MM) is an aggressive cancer with a very long latency and a very short median survival. Little is known about the genetic events that trigger MM and their relation to poor outcome. The goal of our study was to characterize major genomic gains and losses associated with MM origin and progression and assess their clinical significance. We performed Representative Oligonucleotide Microarray Analysis (ROMA) on DNA isolated from tumors of 22 patients who recurred at variable interval with the disease after surgery. The total number of copy number alterations (CNA) and frequent imbalances for patients with short time (<12 months from surgery) and long time to recurrence were recorded and mapped using the Analysis of Copy Errors algorithm. We report a profound increase in CNA in the short-time recurrence group with most chromosomes affected, which can be explained by chromosomal instability associated with MM. Deletions in chromosomes 22q12.2, 19q13.32 and 17p13.1 appeared to be the most frequent events (55-74%) shared between MM patients followed by deletions in 1p, 9p, 9q, 4p, 3p and gains in 5p, 18q, 8q and 17q (23-55%). Deletions in 9p21.3 encompassing CDKN2A/ARF and CDKN2B were characterized as specific for the short-term recurrence group. Analysis of the minimal common areas of frequent gains and losses identified candidate genes that may be involved in different stages of MM: OSM (22q12.2), FUS1 and PL6 (3p21.3), DNAJA1 (9p21.1) and CDH2 (18q11.2-q12.3). Imbalances seen by ROMA were confirmed by Affymetrix genome analysis in a subset of samples.
authors.affiliation: Department of Cardiothoracic Surgery, Thoracic Surgery Laboratory, NYU Langone Medical Center, New York, NY, USA. Sergey.Ivanov@med.nyu.edu
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Ivanov
authors.forename: Jeremy
authors.initials: J
authors.lastname: Miller
authors.forename: Robert
authors.initials: R
authors.lastname: Lucito
authors.forename: Chunlao
authors.initials: C
authors.lastname: Tang
authors.forename: Alla V
authors.initials: AV
authors.lastname: Ivanova
authors.forename: Jianming
authors.initials: J
authors.lastname: Pei
authors.forename: Michele
authors.initials: M
authors.lastname: Carbone
authors.forename: Christina
authors.initials: C
authors.lastname: Cruz
authors.forename: Amanda
authors.initials: A
authors.lastname: Beck
authors.forename: Craig
authors.initials: C
authors.lastname: Webb
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nonaka
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Testa
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction