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Integrative genome comparison of primary and metastatic melanomas.

Kabbarah O, Nogueira C, Feng B, Nazarian RM, Bosenberg M, Wu M, Scott KL, Kwong LN, Xiao Y, Cordon-Cardo C, Granter SR, Ramaswamy S, Golub T, Duncan LM, Wagner SN, Brennan C, Chin L - PLoS ONE (2010)

Bottom Line: A cardinal feature of malignant melanoma is its metastatic propensity.In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression.Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.

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Integrative genomics identify high-confidence metastasis candidate melanoma genes.(A) Flow chart of integrating copy number and expression analysis to compare primary and metastastic melanoma genomes. (B) Whole genome q-value profiles based on Fisher's Exact Test between primary and metastastic melanomas. X axis coordinates represent genomic map position and Y axis indicates q-value log10 of Fisher's Exact Test between primary and metastastic melanomas at each R-segment.
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pone-0010770-g002: Integrative genomics identify high-confidence metastasis candidate melanoma genes.(A) Flow chart of integrating copy number and expression analysis to compare primary and metastastic melanoma genomes. (B) Whole genome q-value profiles based on Fisher's Exact Test between primary and metastastic melanomas. X axis coordinates represent genomic map position and Y axis indicates q-value log10 of Fisher's Exact Test between primary and metastastic melanomas at each R-segment.

Mentions: Evolution from primary to metastatic disease is expected to be accompanied by the acquisition of, or selection for, genomic and genetic events that confer biologic capabilities necessary for mestastasis [22]. We thus hypothesized that CNAs observed in metastasis but not detected in primary disease would be more likely to represent potential drivers of metastasis. To define such events, we adopted an integrative genome comparison approach to define genes that were statistically different between primary and metastatic samples based on DNA and RNA data (Figure 2A). First, we employed a statistical test, Fisher-Exact, to delineate regions that were differentially altered in metastatic versus primary melanoma. Briefly, we collapsed all CBS-processed array-CGH profiles of primary or metastatic cohorts down to 2,907 reduced-segments (hereafter as “R-segments”) to generate two R-segment profiles corresponding to primary and metastatic melanoma genomes, respectively. For each R-segments above noise threshold (i.e. Log2 of +/−0.15), Fisher's Exact test p-values were calculated and corrected for multiple testing (see Methods) to define statistically significant events that were different between these two classes. At a false discovery rate (FDR) of 10% (q< = 0.1), 300 R-segments spanning 32 contiguous regions of interest (ROIs) were found to be preferentially gained in metastatic relative to primary melanomas in a non-random fashion (Figure 2B). Many of these 32 ROIs clustered predominantly in several chromosomal regions, including 1q, 6p, 7, 17q and 22, and many of the regions were gained in poor-prognosis K3-1 and K3-2 subclasses (Figure 1C and 1D). Of note, no R-segments were found to be preferentially gained in primary relative to metastatic melanomas and no regions of loss were significantly different between primary and metastasis.


Integrative genome comparison of primary and metastatic melanomas.

Kabbarah O, Nogueira C, Feng B, Nazarian RM, Bosenberg M, Wu M, Scott KL, Kwong LN, Xiao Y, Cordon-Cardo C, Granter SR, Ramaswamy S, Golub T, Duncan LM, Wagner SN, Brennan C, Chin L - PLoS ONE (2010)

Integrative genomics identify high-confidence metastasis candidate melanoma genes.(A) Flow chart of integrating copy number and expression analysis to compare primary and metastastic melanoma genomes. (B) Whole genome q-value profiles based on Fisher's Exact Test between primary and metastastic melanomas. X axis coordinates represent genomic map position and Y axis indicates q-value log10 of Fisher's Exact Test between primary and metastastic melanomas at each R-segment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2875381&req=5

pone-0010770-g002: Integrative genomics identify high-confidence metastasis candidate melanoma genes.(A) Flow chart of integrating copy number and expression analysis to compare primary and metastastic melanoma genomes. (B) Whole genome q-value profiles based on Fisher's Exact Test between primary and metastastic melanomas. X axis coordinates represent genomic map position and Y axis indicates q-value log10 of Fisher's Exact Test between primary and metastastic melanomas at each R-segment.
Mentions: Evolution from primary to metastatic disease is expected to be accompanied by the acquisition of, or selection for, genomic and genetic events that confer biologic capabilities necessary for mestastasis [22]. We thus hypothesized that CNAs observed in metastasis but not detected in primary disease would be more likely to represent potential drivers of metastasis. To define such events, we adopted an integrative genome comparison approach to define genes that were statistically different between primary and metastatic samples based on DNA and RNA data (Figure 2A). First, we employed a statistical test, Fisher-Exact, to delineate regions that were differentially altered in metastatic versus primary melanoma. Briefly, we collapsed all CBS-processed array-CGH profiles of primary or metastatic cohorts down to 2,907 reduced-segments (hereafter as “R-segments”) to generate two R-segment profiles corresponding to primary and metastatic melanoma genomes, respectively. For each R-segments above noise threshold (i.e. Log2 of +/−0.15), Fisher's Exact test p-values were calculated and corrected for multiple testing (see Methods) to define statistically significant events that were different between these two classes. At a false discovery rate (FDR) of 10% (q< = 0.1), 300 R-segments spanning 32 contiguous regions of interest (ROIs) were found to be preferentially gained in metastatic relative to primary melanomas in a non-random fashion (Figure 2B). Many of these 32 ROIs clustered predominantly in several chromosomal regions, including 1q, 6p, 7, 17q and 22, and many of the regions were gained in poor-prognosis K3-1 and K3-2 subclasses (Figure 1C and 1D). Of note, no R-segments were found to be preferentially gained in primary relative to metastatic melanomas and no regions of loss were significantly different between primary and metastasis.

Bottom Line: A cardinal feature of malignant melanoma is its metastatic propensity.In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression.Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

ABSTRACT
A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.

Show MeSH
Related in: MedlinePlus