DNA Copy Number Analysis and Gene Expression Profiles in Abdominal Malignant Mesothelioma (AMM)
AN Sireci, B Levy, RN Taub, JL Chen, O Nahum, AC Borczuk. Columbia University Medical Center, New York, NY
Background: AMM is a neoplasm of the abdominal serosa with two distinct prognostic subgroups. We describe recurrent genetic abnormalities in this tumor type and identify five that correlate with prognosis.
Design: Gene expression (GE) profiling (Affymetrix U133 Plus2 array) was performed on laser capture microdissected AMM from 14 patients (7 favorable prognosis and 7 poor prognosis, as defined by survival at 1000 days). Needle-dissected tumor from 13 of these patients was studied for copy number (CN) alteration (Affymetrix SNParray 6.0). GE and CN data were analyzed using Partek software. A list of CN alterations present in >35% of tumors, regardless of prognosis, was compiled. Genes with significant CN-GE correlations that predicted prognosis were identified.
Results: A list of 19 genes that exhibited CN variation in >35% of tumors is summarized in table 1 by chromosomal region. BAP1, a known BRCA1-associated tumor suppressor gene, was lost in 5 of 13 tumors. A region of genomic loss in 6/13 cases on 22q11.1 contained BCL2-like13 and BID, two genes with pro-apoptotic functions. Five genes for which CN analysis correlated significantly with GE and that clustered by prognosis were identified. DENND1B, gained in 3/6 poor prognosis tumors and 0/7 of good prognosis tumors is a known anti-apoptotic protein. Additionally, LAMC1, a laminin family member, was gained in 4/6 poor prognosis tumors and remained unchanged in all good prognosis tumors. Over-expression of laminins has been shown in aggressive gliomas.
|Chromosomal cytoband||Location||# of genes in region||# abnormal||Loss or gain|
|1q21.3||150.837000 to 150.853200||2 (Lep14, Lep15)||6||Loss|
|3p21.1||52.3 to 52.6||10 (BAP1, PBRM1)||5||Loss|
|22q11.1||15.420 to 16.890||19 (BCL2-L13, BID)||6||Loss|
|22q12.1||26.565 to 26.776||1 (sez6l)||7||Loss|
|22q21.23||22.655 to 22.727||4 (GSTT1)||5||Loss|