Sted P-value represents the false discovery rate. The IPA software ranks each pathway (called networks) by a score that is the negative log of the P-value. The IPA software does not determine a false discovery rate.StatisticsP-values for contingency tables (262) were all performed using Fischer’s exact test (2-sided). Survival curve comparisons were assessed using the log-rank test supplied in GraphPad Prism 4.0 (http://www.graphpad.com). For comparison of continuous variables, a Title Loaded From File Student’s t-test (2-sided) was used.Figure 1. Mtap effect on tumor formation in Em-Myc and Pten+/2 mice. A. Tumor-free survival of Em-myc Mtap+/+ and Em-myc MtaplacZ/+ mice. Sibling Em-myc MtaplacZ/+ (n = 48) and Em-myc Mtap+/+ (n = 42) were monitored daily for tumor formation and/or death for 368 days (p,0.001) B. Tumor-free survival of Mtap+/+ Pten+/2 and MtaplacZ/+ Pten+/2 mice. Sibling of Mtap+/+ Pten+/+ (n = 32) and MtaplacZ/+ Pten+/2 (n = 32) were monitored daily and followed for 450 days (p,0.031). Tick marks show censored observations (deaths with no detectable tumor). doi:10.1371/journal.pone.0067635.gResults MtaplacZ/+ Decreases Survival in Em-myc and Pten+/2 MiceHomozygous deletion of Mtap leads to early embryonic lethality [20]. However, MtaplacZ/+ mice are entirely normal until about 18 months of age when they will start to succumb to 16985061 T-cell lymphoma. To address whether Mtap could accelerate tumorigenesis in other mouse tumor models, we crossed MtaplacZ/+ mice with Em-myc transgenic mice. Em-myc mice contain a transgene in which the immunoglobulin heavy chain enhancer is driving expression of the Myc oncogene in the B-lineage cells resulting in the development of B-cell lymphomas [37]. We followed a cohort Em-myc Mtap+/+ and Em-myc MtaplacZ/+ littermates until they either developed visible lymphoma or died with disease as determined by necropsy. We found that Em-myc Mtap+/+ animals had a median time to tumor formation of 130 days, compared to 87 days for Emmyc MtaplacZ/+ animals (P,0.001, Fig.1A). These results show that germline heterozygosity for Mtap significantly decreases tumor latency in Em-myc mice. We also examined a second mouse tumor model, Pten+/2, for interaction with Mtap. Pten (Phosphatase and Tensin Homolog) is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)trisphosphate resulting in the formation of phosphatidylinositol (4,5)-biphosphate, which causes inhibition of the AKT signaling pathway. Germline mutation in PTEN in humans is associated with Cowden’s disease, characterized by the presence of cutaneous benign hamartomas and high frequency of thyroid and breast cancer [38]. Homozygosity for Pten in mice is embryonic lethal, but heterozygous Pten mice (Pten+/2) develop a variety of tumors including lymphomas, endometrial tumors, colon cancer, Title Loaded From File andgonadal tumors that are detectable between six months and one year of age [31,39,40]. We crossed Pten+/2 mice with MtaplacZ/+ animals and followed a cohort of Mtap+/+ Pten+/2 and MtaplacZ/+ Pten+/2 for up to 450 days. We observed significantly decreased tumor-free survival in MtaplacZ/+ animals compared to Mtap+/+ (median survival 325 vs. 371 days, P,0.031, Fig. 1B). We found there were significantly more spontaneous deaths in MtaplacZ/+ compared to Mtap+/+ animals (Table 1). The most common type of tumor in both groups was lymphoma (10/32 and 4/32, respectively, Table 2). Other tumors observed included pheochromocytoma, thyroid, breast, and uterine adenocarcinomas. None of.Sted P-value represents the false discovery rate. The IPA software ranks each pathway (called networks) by a score that is the negative log of the P-value. The IPA software does not determine a false discovery rate.StatisticsP-values for contingency tables (262) were all performed using Fischer’s exact test (2-sided). Survival curve comparisons were assessed using the log-rank test supplied in GraphPad Prism 4.0 (http://www.graphpad.com). For comparison of continuous variables, a Student’s t-test (2-sided) was used.Figure 1. Mtap effect on tumor formation in Em-Myc and Pten+/2 mice. A. Tumor-free survival of Em-myc Mtap+/+ and Em-myc MtaplacZ/+ mice. Sibling Em-myc MtaplacZ/+ (n = 48) and Em-myc Mtap+/+ (n = 42) were monitored daily for tumor formation and/or death for 368 days (p,0.001) B. Tumor-free survival of Mtap+/+ Pten+/2 and MtaplacZ/+ Pten+/2 mice. Sibling of Mtap+/+ Pten+/+ (n = 32) and MtaplacZ/+ Pten+/2 (n = 32) were monitored daily and followed for 450 days (p,0.031). Tick marks show censored observations (deaths with no detectable tumor). doi:10.1371/journal.pone.0067635.gResults MtaplacZ/+ Decreases Survival in Em-myc and Pten+/2 MiceHomozygous deletion of Mtap leads to early embryonic lethality [20]. However, MtaplacZ/+ mice are entirely normal until about 18 months of age when they will start to succumb to 16985061 T-cell lymphoma. To address whether Mtap could accelerate tumorigenesis in other mouse tumor models, we crossed MtaplacZ/+ mice with Em-myc transgenic mice. Em-myc mice contain a transgene in which the immunoglobulin heavy chain enhancer is driving expression of the Myc oncogene in the B-lineage cells resulting in the development of B-cell lymphomas [37]. We followed a cohort Em-myc Mtap+/+ and Em-myc MtaplacZ/+ littermates until they either developed visible lymphoma or died with disease as determined by necropsy. We found that Em-myc Mtap+/+ animals had a median time to tumor formation of 130 days, compared to 87 days for Emmyc MtaplacZ/+ animals (P,0.001, Fig.1A). These results show that germline heterozygosity for Mtap significantly decreases tumor latency in Em-myc mice. We also examined a second mouse tumor model, Pten+/2, for interaction with Mtap. Pten (Phosphatase and Tensin Homolog) is a phosphatase that dephosphorylates phosphatidylinositol (3,4,5)trisphosphate resulting in the formation of phosphatidylinositol (4,5)-biphosphate, which causes inhibition of the AKT signaling pathway. Germline mutation in PTEN in humans is associated with Cowden’s disease, characterized by the presence of cutaneous benign hamartomas and high frequency of thyroid and breast cancer [38]. Homozygosity for Pten in mice is embryonic lethal, but heterozygous Pten mice (Pten+/2) develop a variety of tumors including lymphomas, endometrial tumors, colon cancer, andgonadal tumors that are detectable between six months and one year of age [31,39,40]. We crossed Pten+/2 mice with MtaplacZ/+ animals and followed a cohort of Mtap+/+ Pten+/2 and MtaplacZ/+ Pten+/2 for up to 450 days. We observed significantly decreased tumor-free survival in MtaplacZ/+ animals compared to Mtap+/+ (median survival 325 vs. 371 days, P,0.031, Fig. 1B). We found there were significantly more spontaneous deaths in MtaplacZ/+ compared to Mtap+/+ animals (Table 1). The most common type of tumor in both groups was lymphoma (10/32 and 4/32, respectively, Table 2). Other tumors observed included pheochromocytoma, thyroid, breast, and uterine adenocarcinomas. None of.
