TY - JOUR
T1 - High resolution array comparative genomic hybridization identifies copy number alterations in diffuse large B-cell lymphoma that predict response to immuno-chemotherapy
AU - Kreisel, F.
AU - Kulkarni, S.
AU - Kerns, R. T.
AU - Hassan, A.
AU - Deshmukh, H.
AU - Nagarajan, R.
AU - Frater, J. L.
AU - Cashen, A.
N1 - Funding Information:
We thank Diane H. Robirds, CLSp (CG), from the Barnes Jewish Hospital Clinical FISH Laboratory for the preparation and interpretation of the FISH slides; Kevin Selle, MT, HTL, MBA, from the Barnes Jewish Hospital Clinical Histology Laboratory for the preparation of p16 immunohistochemical slides; and Nancy L. Bartlett, MD, for her support in study design and funding. This work is supported by the Alvin J. Siteman Cancer Center Bioinformatics Core ( NIH/NCI grant no. P30 CA91842 ) and the Center for Biomedical Informatics ( NCRR grant no. UL1 RR024992 ), and the Barnes Jewish Foundation K Steinback Cancer Research Fund. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - ACGH
KW - Chemo-sensitive
KW - Chemoresponsive
KW - Copy number alterations
KW - DLBCL
UR - http://www.scopus.com/inward/record.url?scp=79960662893&partnerID=8YFLogxK
U2 - 10.1016/j.cancergen.2010.12.010
DO - 10.1016/j.cancergen.2010.12.010
M3 - Article
C2 - 21504712
AN - SCOPUS:79960662893
SN - 2210-7762
VL - 204
SP - 129
EP - 137
JO - Cancer Genetics
JF - Cancer Genetics
IS - 3
ER -