Interaction of PTEN and CDKN1B in Pca susceptibility

描述（由申请人提供）：前列腺癌是美国男性中最常见的癌症，遗传易感性是该疾病最强的危险因素之一。尽管肿瘤抑制基因如PTEN和CDKN1B在包括前列腺在内的多种癌症的肿瘤发生中的作用已经得到了很好的证实，但研究PTEN和CDKN1B种系突变对前列腺癌风险的独立影响的研究仍然有限，而且通常不成功。最近，一项对小鼠的研究清楚地表明，Pten和Cdknlb基因的联合作用，而不是单个基因，会导致小鼠患前列腺癌。此外，我们的全基因组筛选的连锁结果也显示了10q23 （PTEN）和12pl 3 （CDKNIB）染色体区域之间的强相互作用。因此，我们假设两种肿瘤抑制基因（PTEN和CDKNIB）的种系突变相互作用影响个体对遗传性和非遗传性前列腺癌的易感性。为了验证这一假设，我们提出了四个具体目标：1)对CDKNIB的整个转录本和启动子区域以及PTEN的潜在重要区域进行测序，以鉴定188个HPC高危先证的突变和变异序列，并进行生物信息学分析，预测所鉴定的变异的生物学意义；2)利用单位点和双位点连锁和关联分析，检测188个HPC家族中所鉴定的突变/序列变异与前列腺癌的连锁和关联，评估各基因在遗传性前列腺癌中的主作用和相互作用；3)在病例对照人群中，采用单SNP、单倍型和多药耐药方法检测所鉴定的突变/序列变异与前列腺癌的相关性，评估各基因在非遗传性前列腺癌中的主要作用和相互作用；4)通过测量mRNA和蛋白质水平的表达以及蛋白质功能的改变，评估突变/序列变异对连锁和关联分析中涉及的突变/序列变异子集的功能影响。这项研究的结果可能会大大提高我们对前列腺癌风险的认识，并开始探索任何观察到的差异的潜在生物学机制。

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer among men in the United States and genetic susceptibility is one of the strongest risk factors for this disease. Although the roles of tumor suppressor genes such as PTEN and CDKN1B in tumorigenesis have been well established in multiple cancers, including prostate, studies that examined the independent effect of germline mutations of PTEN and CDKN1B on prostate cancer risk have been limited and generally unsuccessful. Recently, a mouse study clearly demonstrated that combinations of genetic effects at both Pten and Cdknlb, rather than a single gene, cause prostate cancer in mice. In addition, the linkage results from our genome-wide screen also demonstrated a strong interaction between the chromosomal regions at 10q23 (PTEN) and 12pl 3 (CDKNIB). We therefore hypothesize that the interaction of germline mutations in two tumor suppressor genes (PTEN and CDKNIB) affects individual susceptibility to hereditary and non-hereditary prostate cancer. Four specific aims are proposed to test this hypothesis: 1) To sequence the entire transcript and promoter regions of CDKNIB and potentially important regions of PTEN to identify mutations and sequence variants among 188 high risk HPC probands and perform bioinformatic analysis to predict the biological significance of the identified variants; 2) To assess the main effect of each gene and the interaction effect of the two genes in hereditary prostate cancer by testing for linkage and association of the identified mutations/sequence variants with prostate cancer in all 188 HPC families using one-locus and two-locus linkage and association analyses; 3) To assess the main effect of each gene and the interaction effect of the two genes in non-hereditary prostate cancer by testing for association between the identified mutations/sequence variants and prostate cancer in a case-control population using single SNP, haplotype, and MDR approaches; and 4) To evaluate the functional impact of the mutations/sequence variants by measuring the expression of mRNA and protein levels, and alteration in protein functions, for a subset of mutations/sequence variants that are implicated in linkage and association analyses. The results from this study are likely to significant advance our knowledge of prostate cancer risk and begin to explore the underlying biological mechanisms for any observed differences.