Abstract 4208: Integrated oligo aCGH and SKY analysis of genomic alterations in malignant mesothelioma cell lines.
Authors: Rozenblum Ester , Klorin Geula , Glebov Oleg , Walker Robert L. , Park Yoonsoo , Meltzer Paul S. , Kirsch Ilan R. , Kaye Frederic J. , Roschke Anna V. 
Published: August 2014

Malignant mesothelioma (MMt) is a rare and very aggressive tumor of the mesothelium. It's most prevalent subtype is malignant pleural mesothelioma, eighty percent of which are associated with asbestos exposure. MMt incidence is 0.9 new cases per 100,000 persons per year. The five year relative survival is 7% overall, which positions MMt immediately above pancreatic cancer (6%), at the bottom of the survival list by cancer site.

We applied a comprehensive molecular cytogenetic analysis using spectral karyotyping (SKY) and oligo aCGH to a panel of MMt cell lines. We found the largest set of recurrent and non-recurrent homozygous deletions (HD) for MMt (88 HDs in 17 cell lines; 52 recurrent HDs that fall into ten genomic areas). Detailed analysis of the most frequently homozygously deleted area located at 9p21.3 revealed that the main targets are CDKN2A/p14ARF (in 100% of the MM cell lines), CDKN2A/p16INK4A and CDKN2B /p15 (94% of cell lines). p14ARF seems to be the main target of HDs in the 9p21.3 area (deleted in all 17 MMt cell lines studied), followed by p16INK4A (deleted in 16 cell lines) indicating the inactivation of two major tumor suppressing pathways, p53 and Rb. Accordingly, mutations or HDs of p53 and Rb are infrequent events in MMt tumors. Other recurrent HDs were located at 9p21.2 (targeting LINGO2) and at16p13.3 (RBFOX1) in 41% of cell lines, 22q11.23 (GSTT1) in 29%, 22q12.2 (NF2) and 3q26 (no known genes) in 23% each, 8p11.22 -23 (ADAM5P/ADAM3A) in 18%, 3p21.3-p21.2 (RPL29), 3p21 (DUSP7), 4q22.1 (FAM190A) and 13q11-q12 (LATS2) in 12% each of the 17 MM cell lines While p16INK4A, p14ARF, p15, LATS2 and NF2 have been shown to behave as tumor suppressors in MMts, other genes in the HD areas presented here could be new tumor suppressor candidates.

Structural chromosomal rearrangements were mainly non-reciprocal translocations (74% of aberrations detected by SKY) and deletions (23%). No recurrent balanced or unbalanced translocations have been found. Structural chromosomal rearrangements resulted in recurrent losses of fragments or whole chromosomal arms of 1p, 3p, 8p, 9p, 13q, 14q, 15q, 18q, 22q and gains of 1q, 5p, 7p, 8q, 17q, 20q. Small HDs were frequently embedded in the areas of focal losses. Integration of SKY and aCGH data allowed reconstruction of chromosomal rearrangements leading to the formation of HDs. Our data imply that only with acquisition of structural or numerical karyotypic abnormalities can MMt cells attain a complete loss of the 9p21.3 genomic area and loss of tumor suppressor genes located there. Tetraploidization seems to be a late event in the karyotypic progression of MMt cells, after HD in the 9p21.3 area has already been acquired.

Citation Format: Ester Rozenblum, Geula Klorin, Oleg Glebov, Robert L. Walker, Yoonsoo Park, Paul S. Meltzer, Ilan R. Kirsch, Frederic J. Kaye, Anna V. Roschke. Integrated oligo aCGH and SKY analysis of genomic alterations in malignant mesothelioma cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2013-4208