PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers

Yokomizo, Akira; Tindall, Donald J.; Drabkin, Harry A.; Gemmill, Robert M.; Franklin, Wilbur A.; Yang, Ping; Sugio, Kenji; Smith, Jeremy C.; Liu, Wanguo

doi:10.1038/sj.onc.1201956

Cited by 147 publications

(88 citation statements)

References 17 publications

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“…[27][28][29] It was reported that PTEN mutations were identified in small cell carcinomas, but not in non-small-cell carcinomas. 30,31 We found that the frequency of the loss of expression of PTEN was higher in high-grade neuroendocrine carcinoma than in classic large cell carcinoma or carcinoid tumor, and the differences were significant; however, the difference was not significant between large cell neuroendocrine carcinoma and small cell carcinoma.…”

Section: Discussionmentioning

confidence: 75%

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

et al. 2006

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The distinction between pulmonary large cell neuroendocrine carcinoma and small cell carcinoma is difficult in some cases. Some propose that these carcinomas should be classified as one high-grade neuroendocrine carcinoma. We examined biological features of small cell carcinoma (n ¼ 23), large cell neuroendocrine carcinoma (n ¼ 17), and classic large cell carcinoma (n ¼ 12). The average ratio of nuclear diameter of the tumor cells to that of lymphocytes for small cell carcinoma was smaller than that for large cell neuroendocrine carcinoma (Po0.0001). The frequencies of the expressions of CD56, mASH1, TTF-1, and p16 were higher and that of NeuroD was lower in small cell carcinoma than in large cell neuroendocrine carcinoma. The frequency of loss of heterozygosity at 3p was higher in high-grade neuroendocrine carcinomas than in classic large cell carcinoma (P ¼ 0.0002). Allelic losses at D5S422 (5q33) were more frequent in small cell carcinoma than in large cell neuroendocrine carcinoma (P ¼ 0.0091). Mean fractional regional loss indices of the tumors were 0.38, 0.65, and 0.72 for patients with classic large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma, respectively (P ¼ 0.0003). Five-year overall survivals of patients with classic large cell carcinoma, large cell neuroendocrine carcinoma and small cell carcinoma in stage I were 67, 73, 60%, respectively. Patients with NeuroD expression had better survivals, and those with p63 expression had poorer survivals in large cell neuroendocrine carcinoma. Patients with TTF-1 expression had poorer survivals in small cell carcinoma. Our data suggest that large cell neuroendocrine carcinoma and small cell carcinoma are different morphologically, phenotypically, and genetically, although there are some overlapping features. Although further studies are needed to analyze the biological behavior of high-grade neuroendocrine carcinomas including sensitivity to chemotherapy, the pathological distinction of large cell neuroendocrine carcinoma from small cell carcinoma may be necessary to treat the patients with neuroendocrine tumors.

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Section: Discussionmentioning

confidence: 75%

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

et al. 2006

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“…21 In addition, gels need to be exposed to a sensitive film for a variable length of time, and the interpretation of band patterns can be cumbersome for the inexperienced eye. Denaturing HPLC has been successfully applied in the mutation detection of BRCA1 gene, [27][28][29] PTEN, 30,31 and the tuberous sclerosis genes TSC1 and TSC2. 24,32 It has been estimated that the sensitivity of the detection is greater than 95%; 30 similar or superior to that obtained by SSCP.…”

Section: Resultsmentioning

confidence: 99%

Validation of Denaturing High Performance Liquid Chromatography as a Rapid Detection Method for the Identification of Human INK4A Gene Mutations

Orlow

Roy

Barz

et al. 2001

The Journal of Molecular Diagnostics

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The incidence of melanoma is increasing rapidly in western countries. Genetic predisposition in familial and in some sporadic melanomas has been associated with the presence of INK4A gene mutations. To better define the risk for developing sporadic melanoma based on genetic and environmental interactions, large groups of cases need to be studied. Mutational analysis of genes lacking hot spots for sequence variations is time consuming and expensive. In this study we present the application of denaturing high performance liquid chromatography (DHPLC) for screening of mutations. Exons 1␣, 2, and 3 were amplified from 129 samples and 13 known mutants, yielding 347 products that were examined at different temperatures. Forty-two of these amplicons showed a distinct non-wild-type profile on the chromatogram. Independent sequencing analysis confirmed 16 different nucleotide variations in Leu 32 Pro; Ile49Thr; 88 del G; Gln50Arg; Arg24Pro; Met53Ile; Met53Thr; Arg58stop; Pro81Leu; Asp84Ala; Arg80stop; Gly101Trp; Val106Val; Ala148Thr; and in positions (؊2) in intron 1 (C 3 T); and in the 3 UTR, nucleotide 500 (C 3 G). No false negatives or false positives were obtained by DHPLC in samples with mutations or polymorphisms. We conclude that the DHPLC is a fast, sensitive, cost-efficient, and reliable method for the scanning of Cutaneous melanomas are being detected at an increasing rate worldwide. Even though many patients are diagnosed at an early stage, the death rate continues to rise due to the increasing incidence of more advanced lesions. 1,2 Genetic and environmental factors such as family history, skin type, previous tumors, and sun exposure have been identified as important risk factors. [3][4][5][6] In addition, germline mutations or variants of certain genes have been proposed as risk factors for the development of melanomas. One of these genes, the CDKN2A or INK4A, encodes for p16, an important cell cycle regulator capable of arresting cells in G1-phase by inhibiting the phosphorylation of the retinoblastoma protein by cyclinD1/Cdk4 complexes. 7 The INK4A gene has been found silenced by point mutation, deletion, and methylation of the promoter region in several sporadic tumor types. 8 -16 Analyses of INK4A in sporadic melanomas revealed a frequency of mutations and deletions that ranges from approximately 75% in cell lines 8 to 15% in primary multiple melanoma tumors. 17 In addition, INK4A germline mutations have been found in melanoma kindreds, ranging in prevalence from 10.3 to 72.2%, 18 -19 although in overall approximately 20% of the families that have been studied show mutations in this gene. 20 In an attempt to better define the gene-environment interactions in sporadic melanoma, our group expects to enroll 4000 newly diagnosed subjects to determine the relationship between germline INK4A mutations and environmental factors such as sun exposure. Typically, INK4A gene mutations have been analyzed by polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) and sequencing. 16,18,21 D...

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“…PTEN/MMAC1 (phosphatase and tensin homolog/ mutated in multiple advanced cancers 1) functions as a phosphoinositide 3-phosphatase that negatively regulates Phosphatidylinositol-3 kinase (PI3K)/AKT signaling, and has been suggested to be involved in the induction of anoikis and inhibition of cell migration (Yamada and Araki, 2001;Nadav and Katz, 2001). Although the chromosomal assignment of the PTEN/MMAC1 gene (10q23.3) coincides with a frequently deleted region in many malignancies including lung cancer, somatic mutations or homozygous deletions of the PTEN/MMAC1 gene are present in a relatively small subset of cell lines (*10%) and primary specimens (0*5%) of lung cancer (Forgacs et al, 1998;Yokomizo et al, 1998;Kohno et al, 1998;Cagle et al, 1997;Okami et al, 1998).…”

Section: Other Tumor Suppressor Genesmentioning

confidence: 99%

Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer

2002

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PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers

Cited by 147 publications

References 17 publications

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis

Validation of Denaturing High Performance Liquid Chromatography as a Rapid Detection Method for the Identification of Human INK4A Gene Mutations

Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer

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