Identification of candidate tumour suppressor gene loci for Hodgkin and Reed‐Sternberg cells by characterisation of homozygous deletions in classical Hodgkin lymphoma cell lines

Abstract

SummarySeveral tumour suppressor genes (TSG) have been identified as a result of mapping homozygous deletions in cancer cells. To identify putative TSG involved in the pathogenesis of classical Hodgkin lymphoma (cHL), we investigated four cHL cell lines (L428, HDLM2, KMH2, L1236) using four different array-Comparative Genomic Hybridisation (array-CGH) platforms and focused on high resolution identification of homozygous deletions. Out of 79 candidate regions of bi-allelic loss identified by array-CGH, besides previously described regions, 28 novel regions of homozygous deletions could be verified by polymerase chain reaction. These regions ranged from 13 kb to 619 kb in size. Eleven of the 28 novel bi-allelic losses were putative copy number polymorphisms. This left 17 regions that might harbour novel tumour suppressors involved in Hodgkin lymphoma. Expression profiling with two different platforms confirmed lack of expression of the majority of the genes located in the homozygous deletions. Furthermore, analysis of ontology annotations of genes located in the homozygously deleted regions indicated an enrichment of genes involved in apoptosis and cell death. In summary, through the mapping of homozygous deletions in cell lines this study identified a series of genes, such as SEPT9, GNG7 and CYBB, which might encode candidate tumour suppressors involved in the pathogenesis of cHL.

Recurrent genetic defects in classical Hodgkin lymphoma cell lines

“…[7] In another array CGH study of 4 HL cell lines, 47 potential tumor suppressor genes were identified. [8] More recently, a whole-exome DNA sequencing study of 7 HL cell lines identified 463 mutated genes. [9] In a recent study of primary flow-sorted HRS cells, [10] a large number of genomic gains and losses were identified, with a median of 75 genomic segments lost and gained per case.…”

Septin roles in tumorigenesis

“…Gene fusion AML (Ono et al, 2002;Kadkol et al, 2006;Cerveira et al, 2008) Melanoma (Jaeger et al, 2007) SEPT7 Downregulation Glioma (Nagata et al, 2000;Jiang, 2002;Jiang, 2004;Jia et al, 2010;Tanaka et al, 2010) SEPT8 None None None SEPT9 Amplification/ Breast (Montagna et al, 2003;Scott et al, 2005;overexpression Gonzalez et al, 2007overexpression Gonzalez et al, , 2009) Upregulation Ovary Gene fusion AML, ALL (Strehl et al, 2006;Gulten et al, 2009;Saito et al, 2010) (Santos et al, 2010a,b) (Osaka et al, 1999;Yamamoto et al, 2002;Strehl et al, 2006;Kreuziger et al, 2007) Hypermethylation Colon and head and neck (He et al, 2010;Tierling et al, 2010;Quyun et al, 2010) (Grutzmann et al, 2008;deVos et al, 2009) (Bennett et al, 2008;Lofton-Day et al, 2008;Stanbery et al, 2010) Deletion Ovary, breast Russell et al, 2000) Hodgkin lymphoma (Giefing et al, 2008) SEPT10 None None SEPT11 Gene fusion Deletion AML (Santos et al, 2010b;Stevens et al, 2010) Deletion Liver SEPT12 None None SEPT13 None None SEPT14 None None (Montagna et al, 2003) and the Russell group established that SEPT9 overexpression occurs in various human tumors (Scott et al, 2005). The discovery of DNA hypermethylation at the promoter region of SEPT9 in colorectal (deVos et al, 2009) and head and neck cancer patients (Bennett et al, 2008) complicated the conflicti...…”

Frequent PVT1 Rearrangement and Novel Chimeric Genes PVT1-NBEA and PVT1-WWOX Occur in Multiple Myeloma with 8q24 Abnormality

“…located at translocation/insertion breakpoints, identified by copy number analysis, have been frequently associated with cancer (43)(44)(45)(46)(47)(48)(49). No chimeric genes could be cloned in other samples.…”