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Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations.

Nishiyama N, Arai E, Nagashio R, Fujimoto H, Hosoda F, Shibata T, Tsukamoto T, Yokoi S, Imoto I, Inazawa J, Kanai Y - Carcinogenesis (2010)

Bottom Line: Losses of 1p32.2-p31.3, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence.Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B(1) and B(2), respectively.Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.

View Article: PubMed Central - PubMed

Affiliation: Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

ABSTRACT
The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Array comparative genomic hybridization analysis using a 244K oligonucleotide array was performed on 49 samples of UC tissue. Losses of 2q33.3-q37.3, 4p15.2-q13.1 and 5q13.3-q35.3 and gains of 7p11.2-q11.23 and 20q13.12-q13.2 were correlated with higher histological grade, and gain of 7p21.2-p21.12 was correlated with deeper invasion. Losses of 6q14.1-q27 and 17p13.3-q11.1 and gains of 19q13.12-q13.2 and 20q13.12-q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2-p12.1 and gain of 3q26.32-q29 were correlated with vascular involvement. Losses of 5q14.1-q23.1, 6q14.1-q27, 8p22-p21.3, 11q13.5-q14.1 and 15q11.2-q22.2 and gains of 7p11.2-q11.22 and 19q13.12-q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p32.2-p31.3, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B(1) and B(2), respectively. Tumor-related genes that may encode therapeutic targets and/or indicators useful for the diagnosis and prognostication of UCs should be explored in the above regions. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.

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Correlations between copy number alterations on representative chromosomes and clinicopathological parameters of UCs. The 49 UCs (T1 to T49) were divided into recurrence-negative (n = 42) and -positive (n = 7) cases (A, C and J), histologically low-grade (n = 19) and high-grade (n = 30) tumors (B, E, F, H and O), lymph node metastasis (pN)-negative (n = 44) and -positive (n = 5) tumors (D), lymph vessel involvement (Ly)-negative (n = 33) and -positive (n = 16) tumors (G, L and M), and papillary (n = 28) and non-papillary (n = 21) tumors (I, K and N). −, negative; +, positive. The incidence of copy number alterations on chromosomes 1 (A), 2 (B and C), 3 (D), 4 (E), 5 (F), 6 (G), 7 (H), 8 (I), 10 (J), 15 (K), 17 (L), 19 (M and N) and 20 (O) in each of the UC groups is shown. Gains (copy number: ≥3) and losses (copy number: 1 or 0) are indicated in the upper and lower halves, respectively. Copy numbers of 0, 1, 3 and more are shown in dark red, light red, light blue and dark blue, respectively.
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fig3: Correlations between copy number alterations on representative chromosomes and clinicopathological parameters of UCs. The 49 UCs (T1 to T49) were divided into recurrence-negative (n = 42) and -positive (n = 7) cases (A, C and J), histologically low-grade (n = 19) and high-grade (n = 30) tumors (B, E, F, H and O), lymph node metastasis (pN)-negative (n = 44) and -positive (n = 5) tumors (D), lymph vessel involvement (Ly)-negative (n = 33) and -positive (n = 16) tumors (G, L and M), and papillary (n = 28) and non-papillary (n = 21) tumors (I, K and N). −, negative; +, positive. The incidence of copy number alterations on chromosomes 1 (A), 2 (B and C), 3 (D), 4 (E), 5 (F), 6 (G), 7 (H), 8 (I), 10 (J), 15 (K), 17 (L), 19 (M and N) and 20 (O) in each of the UC groups is shown. Gains (copy number: ≥3) and losses (copy number: 1 or 0) are indicated in the upper and lower halves, respectively. Copy numbers of 0, 1, 3 and more are shown in dark red, light red, light blue and dark blue, respectively.

Mentions: Chromosomal loci on which copy number alterations were significantly correlated with clinicopathological parameters of UCs are shown in Figure 2. The clinicopathological impacts of the copy number alterations are also summarized in Figure 3. For example, loss of 1p32.2–p31.3 was correlated with UC recurrence. Loss of 2q33.3–q37.3 was correlated with higher histological grade. Gain of 3q26.32–q29 was correlated with vascular involvement. Loss of 4p15.2–q13.1 was correlated with higher histological grade. Losses of 5q13.3–q35.3 and 5q14.1–q23.1 were correlated with higher histological grade and tumor configuration (development of non-papillary tumors), respectively. Loss of 6q14.1–q27 was correlated with both lymph vessel involvement and tumor configuration. Gains of 7p21.2–p21.12, 7p11.2–q11.22 and 7p11.2–q11.23 were correlated with deeper invasion, tumor configuration and higher histological grade, respectively. Loss of 8p22–p21.3 was correlated with tumor configuration. Loss of 10q11.23–q21.1 was correlated with UC recurrence. Loss of 11q13.5–q14.1 was correlated with tumor configuration. Losses of 15q11.2–q22.2 and 15q21.3 were correlated with tumor configuration and recurrence, respectively. Loss of 16p12.2–p12.1 was correlated with vascular involvement of UCs. Loss of 17p13.3–q11.1 was correlated with lymph vessel involvement. Gain of 19q13.12–q13.2 was correlated with lymph vessel involvement and tumor configuration. Gains of 20q13.12–q13.2 and 20q13.12–q13.33 were correlated with higher histological grade and lymph vessel involvement, respectively. On the other hand, although the incidences of 8q gain and 9p, 11p and 14q loss were generally high in UCs, such copy number alterations were not evidently correlated with any clinicopathological parameters.


Copy number alterations in urothelial carcinomas: their clinicopathological significance and correlation with DNA methylation alterations.

Nishiyama N, Arai E, Nagashio R, Fujimoto H, Hosoda F, Shibata T, Tsukamoto T, Yokoi S, Imoto I, Inazawa J, Kanai Y - Carcinogenesis (2010)

Correlations between copy number alterations on representative chromosomes and clinicopathological parameters of UCs. The 49 UCs (T1 to T49) were divided into recurrence-negative (n = 42) and -positive (n = 7) cases (A, C and J), histologically low-grade (n = 19) and high-grade (n = 30) tumors (B, E, F, H and O), lymph node metastasis (pN)-negative (n = 44) and -positive (n = 5) tumors (D), lymph vessel involvement (Ly)-negative (n = 33) and -positive (n = 16) tumors (G, L and M), and papillary (n = 28) and non-papillary (n = 21) tumors (I, K and N). −, negative; +, positive. The incidence of copy number alterations on chromosomes 1 (A), 2 (B and C), 3 (D), 4 (E), 5 (F), 6 (G), 7 (H), 8 (I), 10 (J), 15 (K), 17 (L), 19 (M and N) and 20 (O) in each of the UC groups is shown. Gains (copy number: ≥3) and losses (copy number: 1 or 0) are indicated in the upper and lower halves, respectively. Copy numbers of 0, 1, 3 and more are shown in dark red, light red, light blue and dark blue, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3066412&req=5

fig3: Correlations between copy number alterations on representative chromosomes and clinicopathological parameters of UCs. The 49 UCs (T1 to T49) were divided into recurrence-negative (n = 42) and -positive (n = 7) cases (A, C and J), histologically low-grade (n = 19) and high-grade (n = 30) tumors (B, E, F, H and O), lymph node metastasis (pN)-negative (n = 44) and -positive (n = 5) tumors (D), lymph vessel involvement (Ly)-negative (n = 33) and -positive (n = 16) tumors (G, L and M), and papillary (n = 28) and non-papillary (n = 21) tumors (I, K and N). −, negative; +, positive. The incidence of copy number alterations on chromosomes 1 (A), 2 (B and C), 3 (D), 4 (E), 5 (F), 6 (G), 7 (H), 8 (I), 10 (J), 15 (K), 17 (L), 19 (M and N) and 20 (O) in each of the UC groups is shown. Gains (copy number: ≥3) and losses (copy number: 1 or 0) are indicated in the upper and lower halves, respectively. Copy numbers of 0, 1, 3 and more are shown in dark red, light red, light blue and dark blue, respectively.
Mentions: Chromosomal loci on which copy number alterations were significantly correlated with clinicopathological parameters of UCs are shown in Figure 2. The clinicopathological impacts of the copy number alterations are also summarized in Figure 3. For example, loss of 1p32.2–p31.3 was correlated with UC recurrence. Loss of 2q33.3–q37.3 was correlated with higher histological grade. Gain of 3q26.32–q29 was correlated with vascular involvement. Loss of 4p15.2–q13.1 was correlated with higher histological grade. Losses of 5q13.3–q35.3 and 5q14.1–q23.1 were correlated with higher histological grade and tumor configuration (development of non-papillary tumors), respectively. Loss of 6q14.1–q27 was correlated with both lymph vessel involvement and tumor configuration. Gains of 7p21.2–p21.12, 7p11.2–q11.22 and 7p11.2–q11.23 were correlated with deeper invasion, tumor configuration and higher histological grade, respectively. Loss of 8p22–p21.3 was correlated with tumor configuration. Loss of 10q11.23–q21.1 was correlated with UC recurrence. Loss of 11q13.5–q14.1 was correlated with tumor configuration. Losses of 15q11.2–q22.2 and 15q21.3 were correlated with tumor configuration and recurrence, respectively. Loss of 16p12.2–p12.1 was correlated with vascular involvement of UCs. Loss of 17p13.3–q11.1 was correlated with lymph vessel involvement. Gain of 19q13.12–q13.2 was correlated with lymph vessel involvement and tumor configuration. Gains of 20q13.12–q13.2 and 20q13.12–q13.33 were correlated with higher histological grade and lymph vessel involvement, respectively. On the other hand, although the incidences of 8q gain and 9p, 11p and 14q loss were generally high in UCs, such copy number alterations were not evidently correlated with any clinicopathological parameters.

Bottom Line: Losses of 1p32.2-p31.3, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence.Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B(1) and B(2), respectively.Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.

View Article: PubMed Central - PubMed

Affiliation: Pathology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.

ABSTRACT
The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Array comparative genomic hybridization analysis using a 244K oligonucleotide array was performed on 49 samples of UC tissue. Losses of 2q33.3-q37.3, 4p15.2-q13.1 and 5q13.3-q35.3 and gains of 7p11.2-q11.23 and 20q13.12-q13.2 were correlated with higher histological grade, and gain of 7p21.2-p21.12 was correlated with deeper invasion. Losses of 6q14.1-q27 and 17p13.3-q11.1 and gains of 19q13.12-q13.2 and 20q13.12-q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2-p12.1 and gain of 3q26.32-q29 were correlated with vascular involvement. Losses of 5q14.1-q23.1, 6q14.1-q27, 8p22-p21.3, 11q13.5-q14.1 and 15q11.2-q22.2 and gains of 7p11.2-q11.22 and 19q13.12-q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p32.2-p31.3, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B(1) and B(2), respectively. Tumor-related genes that may encode therapeutic targets and/or indicators useful for the diagnosis and prognostication of UCs should be explored in the above regions. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.

Show MeSH
Related in: MedlinePlus