Protein-protein interaction (PPI) prediction method has provided an opportunity for elucidating potential biological processes and disease mechanisms. We integrated eight features involving proteomic, genomic, phenotype and functional annotation datasets by a mixed model consisting of full connected Bayesian (FCB) model and naive Bayesian model to predict human PPIs, resulting in 40 447 PPIs which contain 2740 common PPIs with the human protein reference database (HPRD) by a likelihood ratio cutoff of 512. Then we applied them to exploring underlying pathway crosstalk where pathways were derived from the pathway interaction database. Two pathway crosstalk networks (PCNs) were constructed based on PPI sets. The PPI sets were derived from two different sources. One source was strictly the HPRD database while the other source was a combination of HPRD and PPIs predicted by our mixed Bayesian method. We demonstrated that PCNs based on the mixed PPI set showed much more underlying pathway interactions than the HPRD PPI set. Furthermore, we mapped cancer-causing mutated somatic genes to PPIs between significant pathway crosstalk pairs. We extracted highly connected clusters from over-represented subnetworks of PCNs, which were enriched for mutated gene interactions that acted as crosstalk links. Most of the pathways in top ranking clusters were shown to play important roles in cancer. The clusters themselves showed coherent function categories pertaining to cancer development.