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Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

Ortiz B, White JR, Wu WH, Chan TA - Oncotarget (2014)

Bottom Line: PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers.The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas.In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

View Article: PubMed Central - PubMed

Affiliation: Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

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Ptprd loss cooperates with Cdkn2a deletion to promote tumorigenesis(A) Kaplan-Meier survival curve of Ptprd+/+Cdkn2a+/+ (n=35), Ptprd+/−Cdkn2a+/+ (n=36), Ptprd−/−Cdkn2a+/+ (n=31), Ptprd+/+Cdkn2a−/− (n=31), Ptprd+/−Cdkn2a−/− (n=18), and Ptprd−/−Cdkn2a−/− (n=10) mice followed for 52 weeks. *Ptprd+/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/− and ** Ptprd−/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/−, p-value < 0.0001. (B) PCR genotyping of tumor tissue (histiocytic sarcoma) and (C) normal tissue for Ptprd. Tumors from Ptprd+/−Cdkn2a−/− mice retain an intact wild-type Ptprd allele. H = Ptprd+/−Cdkn2a−/−, W = Ptprd+/+ control, K = Ptprd−/− control.
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Figure 2: Ptprd loss cooperates with Cdkn2a deletion to promote tumorigenesis(A) Kaplan-Meier survival curve of Ptprd+/+Cdkn2a+/+ (n=35), Ptprd+/−Cdkn2a+/+ (n=36), Ptprd−/−Cdkn2a+/+ (n=31), Ptprd+/+Cdkn2a−/− (n=31), Ptprd+/−Cdkn2a−/− (n=18), and Ptprd−/−Cdkn2a−/− (n=10) mice followed for 52 weeks. *Ptprd+/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/− and ** Ptprd−/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/−, p-value < 0.0001. (B) PCR genotyping of tumor tissue (histiocytic sarcoma) and (C) normal tissue for Ptprd. Tumors from Ptprd+/−Cdkn2a−/− mice retain an intact wild-type Ptprd allele. H = Ptprd+/−Cdkn2a−/−, W = Ptprd+/+ control, K = Ptprd−/− control.

Mentions: To investigate the role of Ptprd loss in tumorigenesis, we generated mice with loss of Ptprd alone, Cdkn2a, or both, and determined disease-free survival in each genotype. Mice were euthanized and necropsied at the time of onset of clinical signs (hunched, showing a swollen abdomen, or palpable lumps) or at a pre-determined endpoint. In accordance with Uetani et al. (2000), we did not observe tumor development in Ptprd+/− and Ptprd−/− mice (Figure 2A) [15]. However interestingly, Ptprd+/−Cdkn2a−/− and Ptprd−/−Cdkn2a−/− had significantly worse survival times than Ptprd+/+Cdkn2a−/− mice (Figure 2A, p<0.0001). These data suggest that Ptprd loss alone is not sufficient to initiate tumorigenesis but that in the context of Cdkn2a loss, Ptprd loss can cooperate to accelerate tumor development.


Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

Ortiz B, White JR, Wu WH, Chan TA - Oncotarget (2014)

Ptprd loss cooperates with Cdkn2a deletion to promote tumorigenesis(A) Kaplan-Meier survival curve of Ptprd+/+Cdkn2a+/+ (n=35), Ptprd+/−Cdkn2a+/+ (n=36), Ptprd−/−Cdkn2a+/+ (n=31), Ptprd+/+Cdkn2a−/− (n=31), Ptprd+/−Cdkn2a−/− (n=18), and Ptprd−/−Cdkn2a−/− (n=10) mice followed for 52 weeks. *Ptprd+/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/− and ** Ptprd−/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/−, p-value < 0.0001. (B) PCR genotyping of tumor tissue (histiocytic sarcoma) and (C) normal tissue for Ptprd. Tumors from Ptprd+/−Cdkn2a−/− mice retain an intact wild-type Ptprd allele. H = Ptprd+/−Cdkn2a−/−, W = Ptprd+/+ control, K = Ptprd−/− control.
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Figure 2: Ptprd loss cooperates with Cdkn2a deletion to promote tumorigenesis(A) Kaplan-Meier survival curve of Ptprd+/+Cdkn2a+/+ (n=35), Ptprd+/−Cdkn2a+/+ (n=36), Ptprd−/−Cdkn2a+/+ (n=31), Ptprd+/+Cdkn2a−/− (n=31), Ptprd+/−Cdkn2a−/− (n=18), and Ptprd−/−Cdkn2a−/− (n=10) mice followed for 52 weeks. *Ptprd+/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/− and ** Ptprd−/−Cdkn2a−/− vs. Ptprd+/+Cdkn2a−/−, p-value < 0.0001. (B) PCR genotyping of tumor tissue (histiocytic sarcoma) and (C) normal tissue for Ptprd. Tumors from Ptprd+/−Cdkn2a−/− mice retain an intact wild-type Ptprd allele. H = Ptprd+/−Cdkn2a−/−, W = Ptprd+/+ control, K = Ptprd−/− control.
Mentions: To investigate the role of Ptprd loss in tumorigenesis, we generated mice with loss of Ptprd alone, Cdkn2a, or both, and determined disease-free survival in each genotype. Mice were euthanized and necropsied at the time of onset of clinical signs (hunched, showing a swollen abdomen, or palpable lumps) or at a pre-determined endpoint. In accordance with Uetani et al. (2000), we did not observe tumor development in Ptprd+/− and Ptprd−/− mice (Figure 2A) [15]. However interestingly, Ptprd+/−Cdkn2a−/− and Ptprd−/−Cdkn2a−/− had significantly worse survival times than Ptprd+/+Cdkn2a−/− mice (Figure 2A, p<0.0001). These data suggest that Ptprd loss alone is not sufficient to initiate tumorigenesis but that in the context of Cdkn2a loss, Ptprd loss can cooperate to accelerate tumor development.

Bottom Line: PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers.The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas.In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

View Article: PubMed Central - PubMed

Affiliation: Gerstner Sloan-Kettering Graduate School, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

ABSTRACT
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

Show MeSH
Related in: MedlinePlus