Abstract
Purpose: Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. The extensive and complex karyotypic abnormalities seen in many solid tumors could hinder the identification of pathogenetically relevant chromosomal alterations. Uveal melanoma is an attractive solid tumor for studying aneuploidy because it is a relatively homogeneous cancer that is highly metastatic and has low nonspecific chromosomal instability. Experimental Design: Comparative genomic hybridization and gene expression profiling were used to analyze patterns of aneuploidy in 49 primary uveal melanomas. This analysis was supplemented by a review of cytogenetic findings in 336 published cases. Results: Three prognostically significant tumor subgroups were identified based on the status of chromosomes 3 and 6p. Discrete patterns of chromosomal alterations accumulated in these three subgroups in a nonrandom temporal sequence. Poor clinical outcome was associated with early chromosomal alterations rather than over all aneuploidy. A gene expression signature associated with aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function, and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P = 0.003). Conclusions: The relationship between aneuploidy and poor prognosis may be determined by specific, pathogenetically relevant chromosomal alterations, rather than overall aneuploidy. Such alterations can be identified using integrative genomic methods and may provide insights for novel therapeutic approaches.
| Original language | English |
|---|---|
| Pages (from-to) | 115-122 |
| Number of pages | 8 |
| Journal | Clinical Cancer Research |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Integrative genomic analysis of aneuploidy in uveal melanoma. / Ehlers, Justis P.; Worley, Lori; Onken, Michael D.; William Harbour, J.
In: Clinical Cancer Research, Vol. 14, No. 1, 01.01.2008, p. 115-122.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Integrative genomic analysis of aneuploidy in uveal melanoma
AU - Ehlers, Justis P.
AU - Worley, Lori
AU - Onken, Michael D.
AU - William Harbour, J.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - Purpose: Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. The extensive and complex karyotypic abnormalities seen in many solid tumors could hinder the identification of pathogenetically relevant chromosomal alterations. Uveal melanoma is an attractive solid tumor for studying aneuploidy because it is a relatively homogeneous cancer that is highly metastatic and has low nonspecific chromosomal instability. Experimental Design: Comparative genomic hybridization and gene expression profiling were used to analyze patterns of aneuploidy in 49 primary uveal melanomas. This analysis was supplemented by a review of cytogenetic findings in 336 published cases. Results: Three prognostically significant tumor subgroups were identified based on the status of chromosomes 3 and 6p. Discrete patterns of chromosomal alterations accumulated in these three subgroups in a nonrandom temporal sequence. Poor clinical outcome was associated with early chromosomal alterations rather than over all aneuploidy. A gene expression signature associated with aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function, and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P = 0.003). Conclusions: The relationship between aneuploidy and poor prognosis may be determined by specific, pathogenetically relevant chromosomal alterations, rather than overall aneuploidy. Such alterations can be identified using integrative genomic methods and may provide insights for novel therapeutic approaches.
AB - Purpose: Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. The extensive and complex karyotypic abnormalities seen in many solid tumors could hinder the identification of pathogenetically relevant chromosomal alterations. Uveal melanoma is an attractive solid tumor for studying aneuploidy because it is a relatively homogeneous cancer that is highly metastatic and has low nonspecific chromosomal instability. Experimental Design: Comparative genomic hybridization and gene expression profiling were used to analyze patterns of aneuploidy in 49 primary uveal melanomas. This analysis was supplemented by a review of cytogenetic findings in 336 published cases. Results: Three prognostically significant tumor subgroups were identified based on the status of chromosomes 3 and 6p. Discrete patterns of chromosomal alterations accumulated in these three subgroups in a nonrandom temporal sequence. Poor clinical outcome was associated with early chromosomal alterations rather than over all aneuploidy. A gene expression signature associated with aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function, and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P = 0.003). Conclusions: The relationship between aneuploidy and poor prognosis may be determined by specific, pathogenetically relevant chromosomal alterations, rather than overall aneuploidy. Such alterations can be identified using integrative genomic methods and may provide insights for novel therapeutic approaches.
UR - http://www.scopus.com/inward/record.url?scp=40749137815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=40749137815&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-07-1825
DO - 10.1158/1078-0432.CCR-07-1825
M3 - Article
C2 - 18172260
AN - SCOPUS:40749137815
VL - 14
SP - 115
EP - 122
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 1
ER -