Protein Tyrosine Phosphatase Receptor Type D Research Articles

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p = 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.

PTPRD (protein tyrosine phosphatase, receptor type, D)

Review on PTPRD (protein tyrosine phosphatase, receptor type, D), with data on DNA, on the protein encoded, and where the gene is implicated.

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

Single Nucleotide Polymorphism Array Analysis Defines a Specific Genetic Fingerprint for Well-Differentiated Cutaneous SCCs

Cutaneous squamous cell carcinomas (cSCCs) are the second most frequent cancers in fair-skinned populations; yet, because of their genetic heterogeneity, the key molecular events in cSCC tumorigenesis remain poorly defined. We have used single nucleotide polymorphism microarray analysis to examine genome-wide allelic imbalance in 60 cSCCs using paired non-tumor samples. The most frequent recurrent aberrations were loss of heterozygosity at 3p and 9p, observed in 39 (65%) and 45 (75%) tumors, respectively. Microdeletions at 9p23 within the protein tyrosine phosphatase receptor type D (PTPRD) locus were identified in 9 (15%) samples, supporting a tumor suppressor role for PTPRD in cSCC. In addition, microdeletions at 3p14.2 were detected in 3 (5%) cSCCs, implicating the fragile histidine triad (FHIT) gene as a possible target for inactivation. Statistical analysis revealed that well-differentiated cSCCs demonstrated significantly fewer aberrations than moderately and poorly differentiated cSCCs; yet, despite a lower rate of allelic imbalance, some specific aberrations were observed equally frequently in both groups. No correlation was established between the frequency of chromosomal aberrations and immune or human papillomavirus status. Our data suggest that well-differentiated tumors are a genetically distinct subpopulation of cSCC.

Screening of AMP-activated protein kinase α2 subunit interacting proteins by bacterial two-hybrid system

AMP-activated protein kinase (AMPK) is a ubiquitous eukaryotic protein kinase regulating cellular metabolism and energy demand. In brain AMPK plays a role as a multidimensional energy sensor and AMPK alpha2 subunit is expressed at higher levels than AMPK alpha1 subunit. In order to identify potential targets of AMPK in brain, we perform bacterial two-hybrid screening of a rat fetal brain cDNA library using AMPK alpha2 subunit as bait. Here, we present seven potential AMPK alpha2 subunit interacting proteins, including 6-phosphofructo-1-kinase (PFK-1), polyubiquitin, cytochrome c oxidase subunit I (COX I), heat shock protein 8 (HSP8), HLA-B-associated transcript 3 (BAT3) isoform 1, protein tyrosine phosphatase receptor type D (PTPRD) and islet-brain 1 (IB1). They are involved in glycolysis, protein degradation, mitochondrial electron transport and apoptosis pathways participating in energy regulation directly or indirectly. These data may provide new insight into further studying the pathways of AMPK energy regulation in brain and possible mechanisms of AMPK-mediated neuroprotective effect.

Allelic imbalances and microdeletions affecting the PTPRD gene in cutaneous squamous cell carcinomas detected using single nucleotide polymorphism microarray analysis

Cutaneous squamous cell carcinomas (SCC) are the second most commonly diagnosed cancers in fair-skinned people; yet the genetic mechanisms involved in SCC tumorigenesis remain poorly understood. We have used single nucleotide polymorphism (SNP) microarray analysis to examine genome-wide allelic imbalance in 16 primary and 2 lymph node metastatic SCC using paired non-tumour samples to counteract normal copy number variation. The most common genetic change was loss of heterozygosity (LOH) on 9p, observed in 13 of 16 primary SCC. Other recurrent events included LOH on 3p (9 tumors), 2q, 8p, and 13 (each in 8 SCC) and allelic gain on 3q and 8q (each in 6 tumors). Copy number-neutral LOH was observed in a proportion of samples, implying that somatic recombination had led to acquired uniparental disomy, an event not previously demonstrated in SCC. As well as recurrent patterns of gross chromosomal changes, SNP microarray analysis revealed, in 2 primary SCC, a homozygous microdeletion on 9p23 within the protein tyrosine phosphatase receptor type D (PTPRD) locus, an emerging frequent target of homozygous deletion in lung cancer and neuroblastoma. A third sample was heterozygously deleted within this locus and PTPRD expression was aberrant. Two of the 3 primary SCC with PTPRD deletion had demonstrated metastatic potential. Our data identify PTPRD as a candidate tumor suppressor gene in cutaneous SCC with a possible association with metastasis.

Identification of chromosome arm 9p as the most frequent target of homozygous deletions in lung cancer

Genome scanning at a 1-Mb resolution was undertaken in 29 lung cancer cell lines to clarify the distribution of homozygous (i.e., both allele) deletions along lung cancer genomes, using a high-resolution single nucleotide polymorphism array. Eighteen regions, including two known tumor suppressor loci, CDKN2A at 9p21 and FHIT at 3p14, were found homozygously deleted. Frequencies of deletions at the 18 regions were evaluated by genomic polymerase chain reaction in 78 lung cancer cell lines. Seven regions, 2q24, 3p14, 5q11, 9p21, 9p23, 11q14, and 21q21, were homozygously deleted in two or more cell lines. The CDKN2A locus at 9p21 was most frequently deleted (20/78, 26%), and the deletions were detected exclusively in non-small-cell lung carcinomas (NSCLCs). The PTPRD (protein tyrosine phosphatase receptor type D) locus at 9p23 was the second-most frequently deleted (8/78, 10%), and the deletions were detected in both small-cell lung carcinomas (SCLC) and NSCLC. In addition, the 9p24 region was deleted in a NSCLC. In total, 24 (31%) cell lines carried at least one deletion on chromosome arm 9p, while deletions on the remaining chromosome arms were observed at most in four (5%) cell lines. Deletions at 9p24, 9p23, and 9p21 were not contiguous with one another, and preferential co-occurrence or mutual exclusiveness for the deletions at these three loci was not observed. Thus, it was indicated that 9p is the most frequent target of homozygous deletions in lung cancer, suggesting that the arm contains multiple lung tumor suppressor genes and/or genomic features fragile during lung carcinogenesis.