Genome-Wide Array-Based CGH for Mantle Cell Lymphoma: Precise Mapping of Genomic Aberrations and Identification of Novel Candidate Genes.

Mantle cell lymphoma (MCL) is characterized by 11q13 chromosomal translocation and CCND1 overexpression, but the additional genomic changes are also important for lymphomagenesis. To identify the genomic aberrations of MCL in higher resolution, we analyzed 29 patient samples and seven cell lines (SP-53, Z-138C, Granta 519, REC-1, NCEB-1, Jeko-1 and JVM2) using array-based comparative genomic hybridization (array CGH) that consisted of 2,304 BAC/PAC artificial chromosome clones, covering the whole genome at a 1.3 mega base resolution. Tumor specimens obtained from 29 MCL patients, comprising 16 males and 13 females all from the Aichi Cancer Center, were included in the study. The median age of the patient was 67 years (49–92 years old). 67% of cases were leukemic, 93% were in an advanced stage III-IV, 30% had elevated LDH, 18% had a poor performance status and 78% had more than one extranodal site of involvement. Genomic profiles of MCL were significantly different from those of other B-cell lymphomas such as diffuse large B-cell lymphoma (n=66) (Cancer Res 2004: 64, in press) and follicular cell lymphoma (n=13). Frequent imbalances detected by array CGH in patients were gains of chromosomes 3q26, 7p21, 6p21, 8q13-8q24, 10p12 and 17q23 (frequencies: 21%–48%), and losses of chromosomes 1p36, 1p21–p32, 1q42, 2p11, 2q13, 5q21, 6q16–q24, 8p12–p23, 9p21–p24, 10p14, 9q22, 11q22, 13q21, 13q34, 17p11.2–p13, 19p13 and 22q12 (frequencies: 17%–83%). Among these gains and losses, patents with a gain of 8q13-q24, and losses of 1p22–p32, 6q16–q24, 8p12–p23 and 17p11.2–p13 showed prognostically inferior survival rate to those without such a gain or losses (P<0.001). The incidence of genomic aberrations identified by array CGH was generally higher than that of chromosomal CGH studies. For example, our data show more frequent losses of 1p21–p22 (52%) and 9p21 (41%, INK4/ARF locus) as well as of 11q22 (55%, ATM locus), than the corresponding losses detected by chromosomal CGH (e.g., loss of 1p21–p22: 24%; 9p21: 28%; 11q22: 24%). We found recurrent regions of high-level genomic gains (amplifications) at 10p12 (BMI-1 locus), 13q31–q32 and 18q21 (BCL2 locus), and homozygous losses (deletions) such as 2p11 (Igk locus), 2q13 and 9p21.3–p24.1 (INK4a/ARF locus) in either patient or cell line. Furthermore, we investigated genomic gain of 13q31–q32 and homozygous loss of 2q13 and identified the C13orf25 as a candidate gene at 13q31 gain (Cancer Res 2004: 64, p3087) and the BIM gene at 2q13 loss. Precise mapping of genomic aberrations by array CGH allowed identification of novel candidate genes that might be associated with the lymphomagenesis of MCL.