Limits...
Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times.

Selvarajah GT, Kirpensteijn J, van Wolferen ME, Rao NA, Fieten H, Mol JA - Mol. Cancer (2009)

Bottom Line: Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors.The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis.A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Sciences of Companion Animals, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands. G.T.Selvarajah@uu.nl.

ABSTRACT

Background: Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS.

Results: The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans.

Conclusion: A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.

Show MeSH

Related in: MedlinePlus

Kaplan-Meier survival curves of dogs treated with and without postoperative chemotherapy. (A) Overall population (n = 32 dogs); (B) Among short survivors group (n = 16 dogs) and (C) long survivors (n = 16 dogs). Chemotherapy did not significantly prolong life in the overall population or the subpopulations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2746177&req=5

Figure 2: Kaplan-Meier survival curves of dogs treated with and without postoperative chemotherapy. (A) Overall population (n = 32 dogs); (B) Among short survivors group (n = 16 dogs) and (C) long survivors (n = 16 dogs). Chemotherapy did not significantly prolong life in the overall population or the subpopulations.

Mentions: Although the small population size in the present study is unlikely to show significant differences, it is important to identify any possible confounding factors that may influence survival/prognosis and should be considered when interpreting the expression data at biological levels. In both survival groups, dogs were subjected to a variety of single agent therapies, including lobaplatin, doxorubicin or carboplatin; or a combination of carboplatin and doxorubicin. Some were treated with postoperative chemotherapy and some not, and Kaplan-Meier analysis showed that chemotherapy did not significantly prolong survival in the overall population (log rank score 1.353, P value 0.245), neither among short survivors (log rank score 0.460, P value of 0.498) nor among long survivors (log rank score 0.033, P value 0.857) separately (Figure 2). Although these survival curves only represent bivariable analyses (treated vs. not treated) that do not include all confounding variables, a separate univariable and subsequent multivariable statistical model with inclusion of variables such as histological grade, alkaline phosphatase, neuter status, gender and age upon chemotherapy stratification revealed that none of the variables appeared to have influenced survival significantly (Additional file 2). An additional important insight from the long survival group is that all 4 dogs that were censored from the study (death due to other causes and no apparent metastatic disease until death) received postoperative chemotherapy, which suggests possibilities that these dogs had responded reasonably well to the chemotherapeutic regime. Finally, since both survival groups consist of comparable heterogeneous populations of dogs and poor survivors tend to have higher ALP measurements, the arbitrary but defendable approach to a binary distinction of 'good' and 'poor' outcome based on 6 month survival time is supported for further gene expression profiling.


Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times.

Selvarajah GT, Kirpensteijn J, van Wolferen ME, Rao NA, Fieten H, Mol JA - Mol. Cancer (2009)

Kaplan-Meier survival curves of dogs treated with and without postoperative chemotherapy. (A) Overall population (n = 32 dogs); (B) Among short survivors group (n = 16 dogs) and (C) long survivors (n = 16 dogs). Chemotherapy did not significantly prolong life in the overall population or the subpopulations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2746177&req=5

Figure 2: Kaplan-Meier survival curves of dogs treated with and without postoperative chemotherapy. (A) Overall population (n = 32 dogs); (B) Among short survivors group (n = 16 dogs) and (C) long survivors (n = 16 dogs). Chemotherapy did not significantly prolong life in the overall population or the subpopulations.
Mentions: Although the small population size in the present study is unlikely to show significant differences, it is important to identify any possible confounding factors that may influence survival/prognosis and should be considered when interpreting the expression data at biological levels. In both survival groups, dogs were subjected to a variety of single agent therapies, including lobaplatin, doxorubicin or carboplatin; or a combination of carboplatin and doxorubicin. Some were treated with postoperative chemotherapy and some not, and Kaplan-Meier analysis showed that chemotherapy did not significantly prolong survival in the overall population (log rank score 1.353, P value 0.245), neither among short survivors (log rank score 0.460, P value of 0.498) nor among long survivors (log rank score 0.033, P value 0.857) separately (Figure 2). Although these survival curves only represent bivariable analyses (treated vs. not treated) that do not include all confounding variables, a separate univariable and subsequent multivariable statistical model with inclusion of variables such as histological grade, alkaline phosphatase, neuter status, gender and age upon chemotherapy stratification revealed that none of the variables appeared to have influenced survival significantly (Additional file 2). An additional important insight from the long survival group is that all 4 dogs that were censored from the study (death due to other causes and no apparent metastatic disease until death) received postoperative chemotherapy, which suggests possibilities that these dogs had responded reasonably well to the chemotherapeutic regime. Finally, since both survival groups consist of comparable heterogeneous populations of dogs and poor survivors tend to have higher ALP measurements, the arbitrary but defendable approach to a binary distinction of 'good' and 'poor' outcome based on 6 month survival time is supported for further gene expression profiling.

Bottom Line: Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors.The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis.A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Sciences of Companion Animals, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands. G.T.Selvarajah@uu.nl.

ABSTRACT

Background: Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS.

Results: The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans.

Conclusion: A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression.

Show MeSH
Related in: MedlinePlus