<i>PTEN</i>
            , a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer

Li, Jing; Yen, Clifford; Liaw, Danny; Podsypanina, Katrina; Bose, Shikha; Wang, Steven I.; Puc, Janusz; Miliaresis, Christa; Rodgers, Linda; McCombie, W. Richard; Bigner, Sandra H.; Giovanella, Beppino C.; Ittmann, Michael; Tycko, Ben; Hibshoosh, Hanina; Wigler, Michael; Parsons, Ramon

doi:10.1126/science.275.5308.1943

Cited by 4,392 publications

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“…Very recently, a new tumour-suppressor gene has been identified on chromosome lOq23, which was termed PTEN and MMAC1 by two groups who discovered the gene almost simultaneously (Li et al, 1997;Steck et al, 1997). As it is mutated in advanced gliomas, breast and prostate carcinomas, it is an important candidate gene for late-stage lung carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype

Petersen

Wolf²,

Bockmühl³

et al. 1998

Br J Cancer

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Summary We analysed 78 carcinomas of the lung for allelic losses on chromosome 1 Oq. The tumours were of different stage and grade and comprised 22 small-cell lung carcinomas (SCLC), 40 squamous cell carcinomas (SCC), 11 adenocarcinomas, four large-cell carcinomas and one carcinoid. They were investigated by six polymorphic markers located between 1 0q21 and 1 Oqter. We observed a high incidence of loss of heterozygosity (LOH) in SCLC (91%) and metastatic SCC (56%). Non-metastatic SCC showed deletions in three cases (14%) and no LOH was found in the other types of non-small-cell lung cancer. The statistical analysis indicated that the presence of LOH correlated significantly with advanced tumour stages in the entire collective and in particular within the SCLC and SCC subgroups. For SCC, a positive association was found between LOH and metastases formation, while in SCLC the number of non-metastatic tumours was too small for a final conclusion. Whereas SCLC was frequently characterized by multiple allelic losses, suggesting the deletion of the entire chromosomal arm, SCC showed interstitial imbalances. A high incidence of allelic loss was observed between the markers D10S677 and D10S1223. The analysis of five informative cases suggested the presence of two non-overlapping regions between the loci Dl 0S677/D10S1237 and Dl OS1213/Dl OS1223. In SCLC, we did not find mutations in the putative tumour-suppressor gene MXI1. The data indicate that LOH on chromosome 10q is associated with tumour progression in SCC and SCLC. Thus it may become a useful genetic marker in the assessment of the malignant potential of these tumour types.Keywords: small-cell lung cancer; squamous cell carcinomas of the lung; loss of heterozygosity; tumour genetics Cancer of the lung has the highest incidence of all solid tumours and is the leading cause of cancer deaths (Pisani et al, 1993). The major histopathological distinction of clinical relevance is between small-cell and non-small-cell lung carcinomas. SCLC has to be considered a systemic disease at the time of diagnosis as the majority of cases show early metastases formation. It is preferentially treated by chemotherapy and radiotherapy. The NSCLC consist mainly of three subtypes, i.e. adenocarcinomas, squamous cell carcinomas (SCC) and large-cell carcinomas (LCLC). The significance of the latter group is unclear as LCLC frequently show features of either adenocarcinomas or SCC; they can usually be attributed to these two subgroups by ultrastructural examination. There is a prevailing pattern of distribution within the lung. Whereas adenocarcinomas tend to be located in the periphery, SCC and SCLC arise preferentially from the central bronchi near the hilus.A distinct histopathological diagnosis with far-reaching clinical consequences, i.e. possibly curative operation vs palliative chemotherapy, is often complicated by the morphological heterogeneity that occurs in up to 30% of cases (Muller and FisselerEckhoff, 1989). The tumour heterogeneity is reflected in the World Health Organiza...

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Section: Discussionmentioning

confidence: 99%

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype

Petersen

Wolf²,

Bockmühl³

et al. 1998

Br J Cancer

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“…Although several TSGs, such as SMAD4, RB1, PTEN and p16INK4A, were originally identified from homozygous deletions in cancer cells (Friend et al, 1986;Kamb et al, 1994;Hahn et al, 1996;Li et al, 1997), genetic and epigenetic mechanisms other than homozygous loss could contribute to the loss of function of TSGs in tumors. Indeed, epigenetic inactivation of TSGs, including DNA hypermethylation in their CpGrich promoter or exonic regions, has been believed to occur frequently and play important roles during the pathogenesis of human cancers, including oral cancer (Jones and Baylin, 2002;Ha and Califano, 2006).…”

Section: Introductionmentioning

confidence: 99%

PRTFDC1, a possible tumor-suppressor gene, is frequently silenced in oral squamous-cell carcinomas by aberrant promoter hypermethylation

et al. 2007

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Array-based comparative genomic hybridization (array-CGH) has good potential for the high-throughput identification of genetic aberrations in cell genomes. In the course of a program to screen a panel of oral squamouscell carcinoma (OSCC), cell lines for genomic copynumber aberrations by array-CGH using our in-house arrays, we identified a 3-Mb homozygous deletion at 10p12 in 1 of 18 cell lines (5.6%). Among seven genes located within this region, expression of PRTFDC1 mRNA was not detected in 50% (9/18) or decreased in 5.6% (1/18) of OSCC cell lines, but detected in normal oral epithelia and restored in gene-silenced OSCC cells without its homozygous loss after treatment with 5-aza-2 0 -deoxycytidine. Among 17 cell lines without a homozygous deletion, the hypermethylation of the PRTFDC1 CpG island, which showed promoter activity, was observed in all nine cell lines with no or reduced PRTFDC1 expression (52.9%). Methylation of this CpG island was also observed in primary OSCC tissues (8/47, 17.0%). In addition, restoration of PRTFDC1 in OSCC cells lacking its expression inhibited cell growth in colony-formation assays, whereas knockdown of PRTFDC1 expression in OSCC cells expressing the gene promoted cell growth. These results suggest that epigenetic silencing of PRTFDC1 by hypermethylation of the CpG island leads to a loss of PRTFDC1 function, which might be involved in squamous cell oral carcinogenesis.

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“…To investigate further the association of these types of PTEN locus structural mutation (hereafter termed 'gross' PTEN mutations; GPMs) with BRCA1 status, we sequenced BRCA1 in three breast cancer xenografts with identified homozygous deletions of PTEN 21 ( Table 1 , Supplementary Table 3 and Supplementary Fig. 1 online).…”

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confidence: 99%

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis [1][2][3] . Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype [3][4][5] ; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent Correspondence should be addressed to R.P. (rep15@columbia.edu). 14 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS L.H.S., S.K.G.-S., R.P. and Å.B conceived and designed the study; L.H.S., S.K.G.-S., J.S., G.J., K.H., S.K., J.V.-C., H.O., T.S., L.M., S.P.E., H.H., R.P. and Å.B. collected the samples; L.H.S., K.L., M.J., L.M., T.L., M.S., J.I. and H.H. performed and analyzed immunohistochemistry experiments; L.H.S. and C.P. designed and performed methylation analyses; L.H.S., C.P., M.M. and K.H. performed nucleotide sequencing experiments; L.H.S., J.S., G.J. and K.H. performed and analyzed aCGH experiments; L.H.S., M.M.P., S.S. and V.V.V.S.M. designed and performed FISH experiments; L.H.S., S.K.G.-S. and M.K. performed statistical analyses; R.P. and Å.B. supervised the study; and L.H.S. wrote the paper with assistance from R.P. and Å.B. and input from all coauthors.Note: Supplementary information is available on the Nature Genetics website. [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 . The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs. 1,3,5 ). In addition to having characteristic cytokeratin expression, BBCs are highly proliferative, poorly differentiated and genomically unstable, and they pose clinical challenges because they rarely express the three most common therapeutically targeted 'Achilles' heels' of breast cancer: the estrogen receptor (ER), progesterone receptor and HER2 receptor (refs. 1,3,5,7 ).Intriguingly, breast tumors initiated by an inherited mutation of BRCA1 are nearly always basal-like 3,5 . BRCA1 dysfunction is thought to be tumorigenic primarily owing to defective BRCA1-dependent DSB repair, which precipitates an accumulation of secondary mutations 10 ; however, only general genomic patterns at relatively low resolution have been described (reviewed in ref. 5 ). Despite these advances in delineating BBC, the molecu...

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PTEN , a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer

Cited by 4,392 publications

References 19 publications

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype

Allelic loss on chromosome 10q in human lung cancer: association with tumour progression and metastatic phenotype

PRTFDC1, a possible tumor-suppressor gene, is frequently silenced in oral squamous-cell carcinomas by aberrant promoter hypermethylation

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

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