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Array-comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B-cell lymphoma shows distinct genomic alterations.

Guo Y, Takeuchi I, Karnan S, Miyata T, Ohshima K, Seto M - Cancer Sci. (2014)

Bottom Line: The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05).The BCL6- group had a higher frequency of genomic imbalances compared to the BCL6+ group.In conclusion, the BCL6+ and BCL6- non-GCB type of DLBCL appear to have different mechanisms of pathogenesis.

View Article: PubMed Central - PubMed

ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) displays striking heterogeneity at the clinical, genetic and molecular levels. Subtypes include germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL, according to microarray analysis, and germinal center type or non-germinal center type by immunohistochemistry. Although some reports have described genomic aberrations based upon microarray classification system, genomic aberrations based upon immunohistochemical classifications have rarely been reported. The present study aimed to ascertain the relationship between genomic aberrations and subtypes identified by immunohistochemistry, and to study the pathogenetic character of Chinese DLBCL. We conducted immunohistochemistry using antibodies against CD10, BCL6 and MUM1 in 59 samples of DLBCL from Chinese patients, and then performed microarray-based comparative genomic hybridization for each case. Characteristic genomic differences were found between GCB and non-GCB DLBCL from the array data. The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05). We found completely different mutations in BCL6+ and BCL6- non-GCB type DLBCL, whereby the BCL6- group had a higher number of gains at 1q and a loss at 14q32.13 (P ≤ 0.005), while the BCL6+ group showed a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (P = 0.07). The BCL6- group had a higher frequency of genomic imbalances compared to the BCL6+ group. In conclusion, the BCL6+ and BCL6- non-GCB type of DLBCL appear to have different mechanisms of pathogenesis.

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(a) Genome-wide frequencies of genomic imbalance in BCL6+ non-germinal center B-cell-like (GCB) and BCLl6− non-GCB groups. Horizontal lines indicate 2213 BAC/PAC clones in order from chromosomes 1 to 22 and X. Within each chromosome, clones are shown in order from the p telomere to the q telomere. Vertical lines indicate the frequency (%) of gains and losses. The genomic imbalance characteristics of BCL6+ non-GCB (11 cases) and BCL6− non-GCB (15 cases) groups were different. (b) Contrastive analysis of genomic gains of BCL6+ and BCL6− non-GCB diffuse large B-cell lymphoma (DLBCL) (NG) groups with frequency over 50% (plus BCL6) in each group. Horizontal lines indicate BAC/PAC clones of genomic gains with high frequencies (>50%) in each group in order of increasing frequency of gains in the BCL6+ non-GCB group. Vertical lines indicate the frequency (%) of gains. (c) Contrastive analysis of genomic losses of BCL6+ and BCL6− non-GCB DLBCL (NG) groups with frequencies of >40% (plus BCL6). The frequencies of genomic losses with high frequencies (>40%) differed between the BCL6+ non-GCB and BCL6− non-GCB groups.
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fig04: (a) Genome-wide frequencies of genomic imbalance in BCL6+ non-germinal center B-cell-like (GCB) and BCLl6− non-GCB groups. Horizontal lines indicate 2213 BAC/PAC clones in order from chromosomes 1 to 22 and X. Within each chromosome, clones are shown in order from the p telomere to the q telomere. Vertical lines indicate the frequency (%) of gains and losses. The genomic imbalance characteristics of BCL6+ non-GCB (11 cases) and BCL6− non-GCB (15 cases) groups were different. (b) Contrastive analysis of genomic gains of BCL6+ and BCL6− non-GCB diffuse large B-cell lymphoma (DLBCL) (NG) groups with frequency over 50% (plus BCL6) in each group. Horizontal lines indicate BAC/PAC clones of genomic gains with high frequencies (>50%) in each group in order of increasing frequency of gains in the BCL6+ non-GCB group. Vertical lines indicate the frequency (%) of gains. (c) Contrastive analysis of genomic losses of BCL6+ and BCL6− non-GCB DLBCL (NG) groups with frequencies of >40% (plus BCL6). The frequencies of genomic losses with high frequencies (>40%) differed between the BCL6+ non-GCB and BCL6− non-GCB groups.

Mentions: We examined the frequency of gains and losses in the BCL6+ non-GCB and BCL6− non-GCB groups. Frequent genomic imbalances (>40%) in the BCL6+ group were gains at 2p, 3q, 4p14, 6p12–p23, 7p11, 7p15, 7q, 11q21–q24, 14q23.1, 17q21.2, 18q21 and Bcl2, and losses at 2q14.3, 6q, 8p21.3 and 16q12.2. The most frequent genomic imbalances (>40%) in the BCL6− group were gains at 1q22–q24, 1q32, 2p16.1, 2q33.2, 3q, 4q13.3–q21.1, 6p21–p22, 6q21, 7p22.1, 7p15.2, 7q22–q31.1, 9p21–p24, 9q34, 11q13.4, 11q23–q24, 12p21, 12q, 15q15, 16p11, 17q, 18q12.1, 18q21–32, 19p13, 19q13 and 20q12, and losses at 1p36, 1q, 2q, 4p16, 5p15, 6q,7q36, 8p21, 8p23, 8q24, 9p24, 9p21, 10q, 13q34, 14q, 15q, 16q12.2, 16q23.2, 17p11.2, 20q11 and 20q13. Comparison of the genomic imbalances between the BCL6− and BCL6+ non-GCB DLBCL cases revealed a higher number of gains at 1q (1q24.2, 1q24.3, 1q25,1) (P < 0.05) and loss at 14q32.13 (P < 0.05) in the BCL6− group and a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (6q13, 6q22.31, 6q23.2, 6q24.2, 6q12) (P = 0.068) in the BCL6+ group. BCL6− non-GCB DLBCL showed a much higher number of genomic imbalances of gains and losses with high frequencies (>40%) compared to the BCL6+ non-GCB type (gains, BCL6−/BCL6+: 23/12; losses, BCL6−/BCL6+: 41/20). In the BCL6+ non-GCB group, the frequency of gains at 3q27 was 27%, compared to 40% in the Bcl6− non-GCB group. Overall, the BCL6− and BCL6+ cases had different patterns of genomic aberrations (Fig. 4a–c, Table 4c,d).


Array-comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B-cell lymphoma shows distinct genomic alterations.

Guo Y, Takeuchi I, Karnan S, Miyata T, Ohshima K, Seto M - Cancer Sci. (2014)

(a) Genome-wide frequencies of genomic imbalance in BCL6+ non-germinal center B-cell-like (GCB) and BCLl6− non-GCB groups. Horizontal lines indicate 2213 BAC/PAC clones in order from chromosomes 1 to 22 and X. Within each chromosome, clones are shown in order from the p telomere to the q telomere. Vertical lines indicate the frequency (%) of gains and losses. The genomic imbalance characteristics of BCL6+ non-GCB (11 cases) and BCL6− non-GCB (15 cases) groups were different. (b) Contrastive analysis of genomic gains of BCL6+ and BCL6− non-GCB diffuse large B-cell lymphoma (DLBCL) (NG) groups with frequency over 50% (plus BCL6) in each group. Horizontal lines indicate BAC/PAC clones of genomic gains with high frequencies (>50%) in each group in order of increasing frequency of gains in the BCL6+ non-GCB group. Vertical lines indicate the frequency (%) of gains. (c) Contrastive analysis of genomic losses of BCL6+ and BCL6− non-GCB DLBCL (NG) groups with frequencies of >40% (plus BCL6). The frequencies of genomic losses with high frequencies (>40%) differed between the BCL6+ non-GCB and BCL6− non-GCB groups.
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fig04: (a) Genome-wide frequencies of genomic imbalance in BCL6+ non-germinal center B-cell-like (GCB) and BCLl6− non-GCB groups. Horizontal lines indicate 2213 BAC/PAC clones in order from chromosomes 1 to 22 and X. Within each chromosome, clones are shown in order from the p telomere to the q telomere. Vertical lines indicate the frequency (%) of gains and losses. The genomic imbalance characteristics of BCL6+ non-GCB (11 cases) and BCL6− non-GCB (15 cases) groups were different. (b) Contrastive analysis of genomic gains of BCL6+ and BCL6− non-GCB diffuse large B-cell lymphoma (DLBCL) (NG) groups with frequency over 50% (plus BCL6) in each group. Horizontal lines indicate BAC/PAC clones of genomic gains with high frequencies (>50%) in each group in order of increasing frequency of gains in the BCL6+ non-GCB group. Vertical lines indicate the frequency (%) of gains. (c) Contrastive analysis of genomic losses of BCL6+ and BCL6− non-GCB DLBCL (NG) groups with frequencies of >40% (plus BCL6). The frequencies of genomic losses with high frequencies (>40%) differed between the BCL6+ non-GCB and BCL6− non-GCB groups.
Mentions: We examined the frequency of gains and losses in the BCL6+ non-GCB and BCL6− non-GCB groups. Frequent genomic imbalances (>40%) in the BCL6+ group were gains at 2p, 3q, 4p14, 6p12–p23, 7p11, 7p15, 7q, 11q21–q24, 14q23.1, 17q21.2, 18q21 and Bcl2, and losses at 2q14.3, 6q, 8p21.3 and 16q12.2. The most frequent genomic imbalances (>40%) in the BCL6− group were gains at 1q22–q24, 1q32, 2p16.1, 2q33.2, 3q, 4q13.3–q21.1, 6p21–p22, 6q21, 7p22.1, 7p15.2, 7q22–q31.1, 9p21–p24, 9q34, 11q13.4, 11q23–q24, 12p21, 12q, 15q15, 16p11, 17q, 18q12.1, 18q21–32, 19p13, 19q13 and 20q12, and losses at 1p36, 1q, 2q, 4p16, 5p15, 6q,7q36, 8p21, 8p23, 8q24, 9p24, 9p21, 10q, 13q34, 14q, 15q, 16q12.2, 16q23.2, 17p11.2, 20q11 and 20q13. Comparison of the genomic imbalances between the BCL6− and BCL6+ non-GCB DLBCL cases revealed a higher number of gains at 1q (1q24.2, 1q24.3, 1q25,1) (P < 0.05) and loss at 14q32.13 (P < 0.05) in the BCL6− group and a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (6q13, 6q22.31, 6q23.2, 6q24.2, 6q12) (P = 0.068) in the BCL6+ group. BCL6− non-GCB DLBCL showed a much higher number of genomic imbalances of gains and losses with high frequencies (>40%) compared to the BCL6+ non-GCB type (gains, BCL6−/BCL6+: 23/12; losses, BCL6−/BCL6+: 41/20). In the BCL6+ non-GCB group, the frequency of gains at 3q27 was 27%, compared to 40% in the Bcl6− non-GCB group. Overall, the BCL6− and BCL6+ cases had different patterns of genomic aberrations (Fig. 4a–c, Table 4c,d).

Bottom Line: The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05).The BCL6- group had a higher frequency of genomic imbalances compared to the BCL6+ group.In conclusion, the BCL6+ and BCL6- non-GCB type of DLBCL appear to have different mechanisms of pathogenesis.

View Article: PubMed Central - PubMed

ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) displays striking heterogeneity at the clinical, genetic and molecular levels. Subtypes include germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL, according to microarray analysis, and germinal center type or non-germinal center type by immunohistochemistry. Although some reports have described genomic aberrations based upon microarray classification system, genomic aberrations based upon immunohistochemical classifications have rarely been reported. The present study aimed to ascertain the relationship between genomic aberrations and subtypes identified by immunohistochemistry, and to study the pathogenetic character of Chinese DLBCL. We conducted immunohistochemistry using antibodies against CD10, BCL6 and MUM1 in 59 samples of DLBCL from Chinese patients, and then performed microarray-based comparative genomic hybridization for each case. Characteristic genomic differences were found between GCB and non-GCB DLBCL from the array data. The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05). We found completely different mutations in BCL6+ and BCL6- non-GCB type DLBCL, whereby the BCL6- group had a higher number of gains at 1q and a loss at 14q32.13 (P ≤ 0.005), while the BCL6+ group showed a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (P = 0.07). The BCL6- group had a higher frequency of genomic imbalances compared to the BCL6+ group. In conclusion, the BCL6+ and BCL6- non-GCB type of DLBCL appear to have different mechanisms of pathogenesis.

Show MeSH
Related in: MedlinePlus