p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma
BACKGROUND Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations. ME...
Gespeichert in:
| Veröffentlicht in: | Cancer 2004-04, Vol.100 (8), p.1673-1682 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1682 |
|---|---|
| container_issue | 8 |
| container_start_page | 1673 |
| container_title | Cancer |
| container_volume | 100 |
| creator | Mori, Shoichi Ito, Genshi Usami, Noriyasu Yoshioka, Hiromu Ueda, Yuichi Kodama, Yoshinori Takahashi, Masahide Fong, Kwun M. Shimokata, Kaoru Sekido, Yoshitaka |
| description | BACKGROUND
Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations.
METHODS
p53, its upstream regulators (p14ARF and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single‐stranded conformation polymorphism analysis covering exons 2–11 and by immunohistochemistry (IHC). p14ARF was analyzed by methylation‐specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied.
RESULTS
Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14ARF inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down‐regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several‐fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis.
CONCLUSIONS
Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14ARF, or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. Cancer 2004. © 2004 American Cancer Society.
The authors performed a comprehensive analysis of the p53 apoptotic pathway in 118 patients with nonsmall cell lung carcinoma (NSCLCs) to study whether this pathway is inactivated in tumors without mutation in p53 itself. Two or more p53 pathway components were found to be frequently altered, with > 90% of the alterations resulting from abnorma |
| doi_str_mv | 10.1002/cncr.20164 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_71809170</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>71809170</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4904-63df697e5c6c07be6a21a161964c0a22353fe3fd7b0e53a864a5008f43b361e33</originalsourceid><addsrcrecordid>eNqFkUGL1TAUhYM4OG9GN_4AyUYXQsd7myZtl_IYHWGYgUHBXbkvvdVImtakZXj_3tY-0JVuEnL5OOfcHCFeIlwhQP7OBhuvckBTPBE7hLrMAIv8qdgBQJXpQn09Fxcp_VieZa7VM3GOGkpVabMTbtRK0jiM0zA5K0eavj_SUfaDZzt7TpIiyy7yz5nD5I-SQiuT62c_UeBhTuvITxy5lS7IMITUk_fS8nL4OXyTlqJ1YejpuTjryCd-cbovxZcP15_3N9nt_cdP-_e3mS1qKDKj2s7UJWtrLJQHNpQjocHaFBYoz5VWHauuLQ_AWlFlCtLLml2hDsogK3Up3my6YxyW1GlqepfWPFvgpsQKaizhvyCWtcaqWhXfbqCNQ0qRu2aMrqd4bBCatYFmbaD53cACvzqpzoee2z_o6csX4PUJoGTJd5GCdekvzgBqXDncuEfn-fgPy2Z_t3_YzH8B38KeoA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17951883</pqid></control><display><type>article</type><title>p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Mori, Shoichi ; Ito, Genshi ; Usami, Noriyasu ; Yoshioka, Hiromu ; Ueda, Yuichi ; Kodama, Yoshinori ; Takahashi, Masahide ; Fong, Kwun M. ; Shimokata, Kaoru ; Sekido, Yoshitaka</creator><creatorcontrib>Mori, Shoichi ; Ito, Genshi ; Usami, Noriyasu ; Yoshioka, Hiromu ; Ueda, Yuichi ; Kodama, Yoshinori ; Takahashi, Masahide ; Fong, Kwun M. ; Shimokata, Kaoru ; Sekido, Yoshitaka</creatorcontrib><description>BACKGROUND
Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations.
METHODS
p53, its upstream regulators (p14ARF and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single‐stranded conformation polymorphism analysis covering exons 2–11 and by immunohistochemistry (IHC). p14ARF was analyzed by methylation‐specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied.
RESULTS
Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14ARF inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down‐regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several‐fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis.
CONCLUSIONS
Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14ARF, or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. Cancer 2004. © 2004 American Cancer Society.
The authors performed a comprehensive analysis of the p53 apoptotic pathway in 118 patients with nonsmall cell lung carcinoma (NSCLCs) to study whether this pathway is inactivated in tumors without mutation in p53 itself. Two or more p53 pathway components were found to be frequently altered, with > 90% of the alterations resulting from abnormalities of p53, p14ARF, or HDM2. The data indicated that inactivation of the p53 pathway is a prerequisite for the development of most NSCLCs.</description><identifier>ISSN: 0008-543X</identifier><identifier>EISSN: 1097-0142</identifier><identifier>DOI: 10.1002/cncr.20164</identifier><identifier>PMID: 15073856</identifier><identifier>CODEN: CANCAR</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Apoptosis ; Biological and medical sciences ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - physiopathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Lung Neoplasms - genetics ; Lung Neoplasms - physiopathology ; Male ; Medical sciences ; Middle Aged ; mutation ; Neoplasm Proteins ; nonsmall cell lung carcinoma (NSCLC) ; Nuclear Proteins ; p53 ; Pneumology ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins - pharmacology ; Proto-Oncogene Proteins c-mdm2 ; Tumor Suppressor Protein p14ARF - genetics ; Tumor Suppressor Protein p14ARF - metabolism ; Tumor Suppressor Protein p14ARF - pharmacology ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Protein p53 - pharmacology ; Tumors of the respiratory system and mediastinum ; Zinc Fingers</subject><ispartof>Cancer, 2004-04, Vol.100 (8), p.1673-1682</ispartof><rights>Copyright © 2004 American Cancer Society</rights><rights>2004 INIST-CNRS</rights><rights>Copyright 2004 American Cancer Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4904-63df697e5c6c07be6a21a161964c0a22353fe3fd7b0e53a864a5008f43b361e33</citedby><cites>FETCH-LOGICAL-c4904-63df697e5c6c07be6a21a161964c0a22353fe3fd7b0e53a864a5008f43b361e33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcncr.20164$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcncr.20164$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,1427,27901,27902,45550,45551,46384,46808</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15601516$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15073856$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mori, Shoichi</creatorcontrib><creatorcontrib>Ito, Genshi</creatorcontrib><creatorcontrib>Usami, Noriyasu</creatorcontrib><creatorcontrib>Yoshioka, Hiromu</creatorcontrib><creatorcontrib>Ueda, Yuichi</creatorcontrib><creatorcontrib>Kodama, Yoshinori</creatorcontrib><creatorcontrib>Takahashi, Masahide</creatorcontrib><creatorcontrib>Fong, Kwun M.</creatorcontrib><creatorcontrib>Shimokata, Kaoru</creatorcontrib><creatorcontrib>Sekido, Yoshitaka</creatorcontrib><title>p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma</title><title>Cancer</title><addtitle>Cancer</addtitle><description>BACKGROUND
Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations.
METHODS
p53, its upstream regulators (p14ARF and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single‐stranded conformation polymorphism analysis covering exons 2–11 and by immunohistochemistry (IHC). p14ARF was analyzed by methylation‐specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied.
RESULTS
Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14ARF inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down‐regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several‐fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis.
CONCLUSIONS
Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14ARF, or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. Cancer 2004. © 2004 American Cancer Society.
The authors performed a comprehensive analysis of the p53 apoptotic pathway in 118 patients with nonsmall cell lung carcinoma (NSCLCs) to study whether this pathway is inactivated in tumors without mutation in p53 itself. Two or more p53 pathway components were found to be frequently altered, with > 90% of the alterations resulting from abnormalities of p53, p14ARF, or HDM2. The data indicated that inactivation of the p53 pathway is a prerequisite for the development of most NSCLCs.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - physiopathology</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - physiopathology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>mutation</subject><subject>Neoplasm Proteins</subject><subject>nonsmall cell lung carcinoma (NSCLC)</subject><subject>Nuclear Proteins</subject><subject>p53</subject><subject>Pneumology</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism, Single-Stranded Conformational</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - pharmacology</subject><subject>Proto-Oncogene Proteins c-mdm2</subject><subject>Tumor Suppressor Protein p14ARF - genetics</subject><subject>Tumor Suppressor Protein p14ARF - metabolism</subject><subject>Tumor Suppressor Protein p14ARF - pharmacology</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Protein p53 - pharmacology</subject><subject>Tumors of the respiratory system and mediastinum</subject><subject>Zinc Fingers</subject><issn>0008-543X</issn><issn>1097-0142</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUGL1TAUhYM4OG9GN_4AyUYXQsd7myZtl_IYHWGYgUHBXbkvvdVImtakZXj_3tY-0JVuEnL5OOfcHCFeIlwhQP7OBhuvckBTPBE7hLrMAIv8qdgBQJXpQn09Fxcp_VieZa7VM3GOGkpVabMTbtRK0jiM0zA5K0eavj_SUfaDZzt7TpIiyy7yz5nD5I-SQiuT62c_UeBhTuvITxy5lS7IMITUk_fS8nL4OXyTlqJ1YejpuTjryCd-cbovxZcP15_3N9nt_cdP-_e3mS1qKDKj2s7UJWtrLJQHNpQjocHaFBYoz5VWHauuLQ_AWlFlCtLLml2hDsogK3Up3my6YxyW1GlqepfWPFvgpsQKaizhvyCWtcaqWhXfbqCNQ0qRu2aMrqd4bBCatYFmbaD53cACvzqpzoee2z_o6csX4PUJoGTJd5GCdekvzgBqXDncuEfn-fgPy2Z_t3_YzH8B38KeoA</recordid><startdate>20040415</startdate><enddate>20040415</enddate><creator>Mori, Shoichi</creator><creator>Ito, Genshi</creator><creator>Usami, Noriyasu</creator><creator>Yoshioka, Hiromu</creator><creator>Ueda, Yuichi</creator><creator>Kodama, Yoshinori</creator><creator>Takahashi, Masahide</creator><creator>Fong, Kwun M.</creator><creator>Shimokata, Kaoru</creator><creator>Sekido, Yoshitaka</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Liss</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20040415</creationdate><title>p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma</title><author>Mori, Shoichi ; Ito, Genshi ; Usami, Noriyasu ; Yoshioka, Hiromu ; Ueda, Yuichi ; Kodama, Yoshinori ; Takahashi, Masahide ; Fong, Kwun M. ; Shimokata, Kaoru ; Sekido, Yoshitaka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4904-63df697e5c6c07be6a21a161964c0a22353fe3fd7b0e53a864a5008f43b361e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - physiopathology</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - physiopathology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>mutation</topic><topic>Neoplasm Proteins</topic><topic>nonsmall cell lung carcinoma (NSCLC)</topic><topic>Nuclear Proteins</topic><topic>p53</topic><topic>Pneumology</topic><topic>Polymerase Chain Reaction</topic><topic>Polymorphism, Single-Stranded Conformational</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins - pharmacology</topic><topic>Proto-Oncogene Proteins c-mdm2</topic><topic>Tumor Suppressor Protein p14ARF - genetics</topic><topic>Tumor Suppressor Protein p14ARF - metabolism</topic><topic>Tumor Suppressor Protein p14ARF - pharmacology</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Protein p53 - pharmacology</topic><topic>Tumors of the respiratory system and mediastinum</topic><topic>Zinc Fingers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mori, Shoichi</creatorcontrib><creatorcontrib>Ito, Genshi</creatorcontrib><creatorcontrib>Usami, Noriyasu</creatorcontrib><creatorcontrib>Yoshioka, Hiromu</creatorcontrib><creatorcontrib>Ueda, Yuichi</creatorcontrib><creatorcontrib>Kodama, Yoshinori</creatorcontrib><creatorcontrib>Takahashi, Masahide</creatorcontrib><creatorcontrib>Fong, Kwun M.</creatorcontrib><creatorcontrib>Shimokata, Kaoru</creatorcontrib><creatorcontrib>Sekido, Yoshitaka</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mori, Shoichi</au><au>Ito, Genshi</au><au>Usami, Noriyasu</au><au>Yoshioka, Hiromu</au><au>Ueda, Yuichi</au><au>Kodama, Yoshinori</au><au>Takahashi, Masahide</au><au>Fong, Kwun M.</au><au>Shimokata, Kaoru</au><au>Sekido, Yoshitaka</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma</atitle><jtitle>Cancer</jtitle><addtitle>Cancer</addtitle><date>2004-04-15</date><risdate>2004</risdate><volume>100</volume><issue>8</issue><spage>1673</spage><epage>1682</epage><pages>1673-1682</pages><issn>0008-543X</issn><eissn>1097-0142</eissn><coden>CANCAR</coden><abstract>BACKGROUND
Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations.
METHODS
p53, its upstream regulators (p14ARF and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single‐stranded conformation polymorphism analysis covering exons 2–11 and by immunohistochemistry (IHC). p14ARF was analyzed by methylation‐specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied.
RESULTS
Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14ARF inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down‐regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several‐fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis.
CONCLUSIONS
Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14ARF, or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. Cancer 2004. © 2004 American Cancer Society.
The authors performed a comprehensive analysis of the p53 apoptotic pathway in 118 patients with nonsmall cell lung carcinoma (NSCLCs) to study whether this pathway is inactivated in tumors without mutation in p53 itself. Two or more p53 pathway components were found to be frequently altered, with > 90% of the alterations resulting from abnormalities of p53, p14ARF, or HDM2. The data indicated that inactivation of the p53 pathway is a prerequisite for the development of most NSCLCs.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>15073856</pmid><doi>10.1002/cncr.20164</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0008-543X |
| ispartof | Cancer, 2004-04, Vol.100 (8), p.1673-1682 |
| issn | 0008-543X 1097-0142 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_71809170 |
| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adult Aged Aged, 80 and over Apoptosis Biological and medical sciences Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - physiopathology Female Gene Expression Regulation, Neoplastic Humans Immunohistochemistry Lung Neoplasms - genetics Lung Neoplasms - physiopathology Male Medical sciences Middle Aged mutation Neoplasm Proteins nonsmall cell lung carcinoma (NSCLC) Nuclear Proteins p53 Pneumology Polymerase Chain Reaction Polymorphism, Single-Stranded Conformational Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins - pharmacology Proto-Oncogene Proteins c-mdm2 Tumor Suppressor Protein p14ARF - genetics Tumor Suppressor Protein p14ARF - metabolism Tumor Suppressor Protein p14ARF - pharmacology Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Protein p53 - pharmacology Tumors of the respiratory system and mediastinum Zinc Fingers |
| title | p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T16%3A18%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=p53%20apoptotic%20pathway%20molecules%20are%20frequently%20and%20simultaneously%20altered%20in%20nonsmall%20cell%20lung%20carcinoma&rft.jtitle=Cancer&rft.au=Mori,%20Shoichi&rft.date=2004-04-15&rft.volume=100&rft.issue=8&rft.spage=1673&rft.epage=1682&rft.pages=1673-1682&rft.issn=0008-543X&rft.eissn=1097-0142&rft.coden=CANCAR&rft_id=info:doi/10.1002/cncr.20164&rft_dat=%3Cproquest_cross%3E71809170%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=17951883&rft_id=info:pmid/15073856&rfr_iscdi=true |