title: High resolution array comparative genomic hybridization identifies copy number alterations in diffuse large B-cell lymphoma that predict response to immuno-chemotherapy.
abstract: Despite recent attempts at sub-categorization, including gene expression profiling into prognostically different groups of "germinal center B-cell type" and "activated B-cell type," diffuse large B-cell lymphoma (DLBCL) remains a biologically heterogenous tumor with no clear prognostic biomarkers to guide therapy. Whole genome, high resolution array comparative genomic hybridization (aCGH) was performed on four cases of chemoresistant DLBCL and four cases of chemo-responsive DLBCL to identify genetic differences that may correlate with response to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Array CGH analysis identified seven DNA copy number alteration (CNA) regions exclusive to the chemoresistant group, consisting of amplifications at 1p36.13, 1q42.3, 3p21.31, 7q11.23, and 16p13.3, as well as loss at 9p21.3 and 14p21.31. Copy number loss of the tumor suppressor genes CDKN2A (p16, p14) and CDKN2B (p15) at 9p21.3 was validated by fluorescence in situ hybridization and immunohistochemistry as independent techniques. In the chemo-sensitive group, 12 CNAs were detected consisting of segment gains on 1p36.11, 1p36.22, 2q11.2, 8q24.3, 12p13.33, and 22q13.2, as well as segment loss on 6p21.32. RUNX3, a tumor suppressor gene located on 1p36.11 and MTHFR, which encodes for the enzyme methylenetetrahydrofolate reductase, located on 1p36.22, are the only known genes in this group associated with lymphoma. Whole genome aCGH analysis has detected copy number alterations exclusive to either chemoresistant or chemoresponsive DLBCL that may represent consistent clonal changes predictive for prognosis and outcome of chemotherapy.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA. fkreisel@path.wustl.edu
authors.forename: F
authors.initials: F
authors.lastname: Kreisel
authors.forename: S
authors.initials: S
authors.lastname: Kulkarni
authors.forename: R T
authors.initials: RT
authors.lastname: Kerns
authors.forename: A
authors.initials: A
authors.lastname: Hassan
authors.forename: H
authors.initials: H
authors.lastname: Deshmukh
authors.forename: R
authors.initials: R
authors.lastname: Nagarajan
authors.forename: J L
authors.initials: JL
authors.lastname: Frater
authors.forename: A
authors.initials: A
authors.lastname: Cashen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D055028:Comparative Genomic Hybridization / Q000379:methods*; D056915:DNA Copy Number Variations; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D019942:Genes, p16; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests