Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers
The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experi...
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| creator | Nomura, Masaharu Shigematsu, Hisayuki Li, Lin Suzuki, Makoto Takahashi, Takao Estess, Pila Siegelman, Mark Feng, Ziding Kato, Harubumi Marchetti, Antonio Shay, Jerry W Spitz, Margaret R Wistuba, Ignacio I Minna, John D Gazdar, Adi F |
| description | The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, -216 (G/T or T/T) and -191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.
We examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African-Americans, and Mexican-Americans. We sequenced the four exons (18-21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP -216 (G/T or T/T) and SNP -191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP -216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%-54.7%) of mutant tumors compared with 25.9% (20.6%-31.2%) of wild-type tumors |
| doi_str_mv | 10.1371/journal.pmed.0040125 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1288079357</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A165914462</galeid><doaj_id>oai_doaj_org_article_bf5f3aeb4aee4b0f8a4cfea185b8ce06</doaj_id><sourcerecordid>A165914462</sourcerecordid><originalsourceid>FETCH-LOGICAL-c828t-4f6f986e89e009883a4882360d9f17cb6b59ec959cc51854dcfbec3172d837c3</originalsourceid><addsrcrecordid>eNqVk1GL1DAQx4so3nn6DUQLwoFg16RN2uRFOI67c-Hw5Dx88SGk6aSbpU32mla8b2-6W3Ur-6AEkjD9zX8mM50oeonRAmcFfr92Q2dls9i0UC0QIgin9FF0jCnhCc6L_PHe_Sh65v0aoZQjjp5GR7gglHJWHEffPrvmoXXdZmV869_F7dDL3jgbrtJWsWw3jdFGbW2x03G_gvji6vI2rsFCbGxsnU18K5smVhC2ZrB1rKRV0Pnn0RMtGw8vpvMkuru8uDv_mFzfXC3Pz64TxVLWJ0TnmrMcGAeEOGOZJIylWY4qrnGhyrykHBSnXCmKGSWV0iWoDBdpxbJCZSfR653spnFeTGXxAqeMoYJntAjEckdUTq7FpjOt7B6Ek0ZsDa6rhex6oxoQpaY6k1ASCUBKpJkkSoMMcUumAOVB68MUbShD5RXYvpPNTHT-xZqVqN13gVmREzQmczoJdO5-AN-L1vixdtKCG7woEEk5pyyAb_4CD79tomoZ0jdWuxBVjZLiDOeUY0LyNFDJAWrsYUjRWdAmmGf84gAfVgWtUQcd3s4cAtPDj76Wg_di-eX2P9hP_87efJ2zp3vsCmTTr7xrhu3_PAfJDlSd874D_bt9GIlxuH5VWozDJabhCm6v9lv_x2mapuwn1qAeHA</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1288079357</pqid></control><display><type>article</type><title>Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Public Library of Science (PLoS) Journals Open Access</source><source>PubMed Central</source><creator>Nomura, Masaharu ; Shigematsu, Hisayuki ; Li, Lin ; Suzuki, Makoto ; Takahashi, Takao ; Estess, Pila ; Siegelman, Mark ; Feng, Ziding ; Kato, Harubumi ; Marchetti, Antonio ; Shay, Jerry W ; Spitz, Margaret R ; Wistuba, Ignacio I ; Minna, John D ; Gazdar, Adi F</creator><contributor>Pao, William</contributor><creatorcontrib>Nomura, Masaharu ; Shigematsu, Hisayuki ; Li, Lin ; Suzuki, Makoto ; Takahashi, Takao ; Estess, Pila ; Siegelman, Mark ; Feng, Ziding ; Kato, Harubumi ; Marchetti, Antonio ; Shay, Jerry W ; Spitz, Margaret R ; Wistuba, Ignacio I ; Minna, John D ; Gazdar, Adi F ; Pao, William</creatorcontrib><description>The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, -216 (G/T or T/T) and -191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.
We examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African-Americans, and Mexican-Americans. We sequenced the four exons (18-21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP -216 (G/T or T/T) and SNP -191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP -216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%-54.7%) of mutant tumors compared with 25.9% (20.6%-31.2%) of wild-type tumors (p = 0.002). The shorter allele in tumors with AI in East Asian individuals was selectively amplified (shorter allele dominant) more often in mutant tumors (75.0%, 61.6%-88.4%) than in wild-type tumors (43.5%, 31.8%-55.2%, p = 0.003). In addition, there was a strong positive association between AI ratios of CA-SSR1 alleles and AI of mutant alleles.
The three polymorphisms associated with increased EGFR protein production (shorter CA-SSR1 length and variant forms of SNPs -216 and -191) were found to be rare in East Asians as compared to other ethnicities, suggesting that the cells of East Asians may make relatively less intrinsic EGFR protein. Interestingly, especially in tumors from patients of East Asian ethnicity, EGFR mutations were found to favor the shorter allele of CA-SSR1, and selective amplification of the shorter allele of CA-SSR1 occurred frequently in tumors harboring a mutation. These distinct molecular events targeting the same allele would both be predicted to result in greater EGFR protein production and/or activity. Our findings may help explain to some of the ethnic differences observed in mutational frequencies and responses to TK inhibitors.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.0040125</identifier><identifier>PMID: 17455987</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alleles ; Asian people ; Cancer therapies ; Cancer: Lung ; Carcinoma, Non-Small-Cell Lung - epidemiology ; Carcinoma, Non-Small-Cell Lung - ethnology ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Cell proliferation ; Epidemiology ; Epidermal growth factor ; Ethnicity ; Gene Amplification ; Gene Expression Regulation, Neoplastic - genetics ; Genes, erbB-1 - genetics ; Genetic aspects ; Genetic engineering ; Genetic Variation - genetics ; Genetics ; Genetics and Genomics ; Humans ; Kinases ; Lung cancer ; Lung cancer, Non-small cell ; Lung Neoplasms - epidemiology ; Lung Neoplasms - ethnology ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Mutation ; Mutation - genetics ; Oncology ; Pathology ; Polymorphism, Genetic - genetics ; Proteins ; Receptor, Epidermal Growth Factor - biosynthesis ; Receptor, Epidermal Growth Factor - genetics ; Reorganization and restructuring ; Single nucleotide polymorphisms ; Tumors ; Tyrosine</subject><ispartof>PLoS medicine, 2007-04, Vol.4 (4), p.e125-e125</ispartof><rights>COPYRIGHT 2007 Public Library of Science</rights><rights>2007 Nomura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Nomura M, Shigematsu H, Li L, Suzuki M, Takahashi T, et al. (2007) Polymorphisms, Mutations, and Amplification of the EGFR Gene in Non-Small Cell Lung Cancers. PLoS Med 4(4): e125. doi:10.1371/journal.pmed.0040125</rights><rights>2007 Nomura et al. 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c828t-4f6f986e89e009883a4882360d9f17cb6b59ec959cc51854dcfbec3172d837c3</citedby><cites>FETCH-LOGICAL-c828t-4f6f986e89e009883a4882360d9f17cb6b59ec959cc51854dcfbec3172d837c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876407/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876407/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17455987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pao, William</contributor><creatorcontrib>Nomura, Masaharu</creatorcontrib><creatorcontrib>Shigematsu, Hisayuki</creatorcontrib><creatorcontrib>Li, Lin</creatorcontrib><creatorcontrib>Suzuki, Makoto</creatorcontrib><creatorcontrib>Takahashi, Takao</creatorcontrib><creatorcontrib>Estess, Pila</creatorcontrib><creatorcontrib>Siegelman, Mark</creatorcontrib><creatorcontrib>Feng, Ziding</creatorcontrib><creatorcontrib>Kato, Harubumi</creatorcontrib><creatorcontrib>Marchetti, Antonio</creatorcontrib><creatorcontrib>Shay, Jerry W</creatorcontrib><creatorcontrib>Spitz, Margaret R</creatorcontrib><creatorcontrib>Wistuba, Ignacio I</creatorcontrib><creatorcontrib>Minna, John D</creatorcontrib><creatorcontrib>Gazdar, Adi F</creatorcontrib><title>Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, -216 (G/T or T/T) and -191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.
We examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African-Americans, and Mexican-Americans. We sequenced the four exons (18-21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP -216 (G/T or T/T) and SNP -191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP -216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%-54.7%) of mutant tumors compared with 25.9% (20.6%-31.2%) of wild-type tumors (p = 0.002). The shorter allele in tumors with AI in East Asian individuals was selectively amplified (shorter allele dominant) more often in mutant tumors (75.0%, 61.6%-88.4%) than in wild-type tumors (43.5%, 31.8%-55.2%, p = 0.003). In addition, there was a strong positive association between AI ratios of CA-SSR1 alleles and AI of mutant alleles.
The three polymorphisms associated with increased EGFR protein production (shorter CA-SSR1 length and variant forms of SNPs -216 and -191) were found to be rare in East Asians as compared to other ethnicities, suggesting that the cells of East Asians may make relatively less intrinsic EGFR protein. Interestingly, especially in tumors from patients of East Asian ethnicity, EGFR mutations were found to favor the shorter allele of CA-SSR1, and selective amplification of the shorter allele of CA-SSR1 occurred frequently in tumors harboring a mutation. These distinct molecular events targeting the same allele would both be predicted to result in greater EGFR protein production and/or activity. Our findings may help explain to some of the ethnic differences observed in mutational frequencies and responses to TK inhibitors.</description><subject>Alleles</subject><subject>Asian people</subject><subject>Cancer therapies</subject><subject>Cancer: Lung</subject><subject>Carcinoma, Non-Small-Cell Lung - epidemiology</subject><subject>Carcinoma, Non-Small-Cell Lung - ethnology</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Cell proliferation</subject><subject>Epidemiology</subject><subject>Epidermal growth factor</subject><subject>Ethnicity</subject><subject>Gene Amplification</subject><subject>Gene Expression Regulation, Neoplastic - genetics</subject><subject>Genes, erbB-1 - genetics</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Genetic Variation - genetics</subject><subject>Genetics</subject><subject>Genetics and Genomics</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung cancer, Non-small cell</subject><subject>Lung Neoplasms - epidemiology</subject><subject>Lung Neoplasms - ethnology</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Oncology</subject><subject>Pathology</subject><subject>Polymorphism, Genetic - genetics</subject><subject>Proteins</subject><subject>Receptor, Epidermal Growth Factor - biosynthesis</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Reorganization and restructuring</subject><subject>Single nucleotide polymorphisms</subject><subject>Tumors</subject><subject>Tyrosine</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqVk1GL1DAQx4so3nn6DUQLwoFg16RN2uRFOI67c-Hw5Dx88SGk6aSbpU32mla8b2-6W3Ur-6AEkjD9zX8mM50oeonRAmcFfr92Q2dls9i0UC0QIgin9FF0jCnhCc6L_PHe_Sh65v0aoZQjjp5GR7gglHJWHEffPrvmoXXdZmV869_F7dDL3jgbrtJWsWw3jdFGbW2x03G_gvji6vI2rsFCbGxsnU18K5smVhC2ZrB1rKRV0Pnn0RMtGw8vpvMkuru8uDv_mFzfXC3Pz64TxVLWJ0TnmrMcGAeEOGOZJIylWY4qrnGhyrykHBSnXCmKGSWV0iWoDBdpxbJCZSfR653spnFeTGXxAqeMoYJntAjEckdUTq7FpjOt7B6Ek0ZsDa6rhex6oxoQpaY6k1ASCUBKpJkkSoMMcUumAOVB68MUbShD5RXYvpPNTHT-xZqVqN13gVmREzQmczoJdO5-AN-L1vixdtKCG7woEEk5pyyAb_4CD79tomoZ0jdWuxBVjZLiDOeUY0LyNFDJAWrsYUjRWdAmmGf84gAfVgWtUQcd3s4cAtPDj76Wg_di-eX2P9hP_87efJ2zp3vsCmTTr7xrhu3_PAfJDlSd874D_bt9GIlxuH5VWozDJabhCm6v9lv_x2mapuwn1qAeHA</recordid><startdate>20070401</startdate><enddate>20070401</enddate><creator>Nomura, Masaharu</creator><creator>Shigematsu, Hisayuki</creator><creator>Li, Lin</creator><creator>Suzuki, Makoto</creator><creator>Takahashi, Takao</creator><creator>Estess, Pila</creator><creator>Siegelman, Mark</creator><creator>Feng, Ziding</creator><creator>Kato, Harubumi</creator><creator>Marchetti, Antonio</creator><creator>Shay, Jerry W</creator><creator>Spitz, Margaret R</creator><creator>Wistuba, Ignacio I</creator><creator>Minna, John D</creator><creator>Gazdar, Adi F</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope></search><sort><creationdate>20070401</creationdate><title>Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers</title><author>Nomura, Masaharu ; Shigematsu, Hisayuki ; Li, Lin ; Suzuki, Makoto ; Takahashi, Takao ; Estess, Pila ; Siegelman, Mark ; Feng, Ziding ; Kato, Harubumi ; Marchetti, Antonio ; Shay, Jerry W ; Spitz, Margaret R ; Wistuba, Ignacio I ; Minna, John D ; Gazdar, Adi F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c828t-4f6f986e89e009883a4882360d9f17cb6b59ec959cc51854dcfbec3172d837c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Alleles</topic><topic>Asian people</topic><topic>Cancer therapies</topic><topic>Cancer: Lung</topic><topic>Carcinoma, Non-Small-Cell Lung - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nomura, Masaharu</au><au>Shigematsu, Hisayuki</au><au>Li, Lin</au><au>Suzuki, Makoto</au><au>Takahashi, Takao</au><au>Estess, Pila</au><au>Siegelman, Mark</au><au>Feng, Ziding</au><au>Kato, Harubumi</au><au>Marchetti, Antonio</au><au>Shay, Jerry W</au><au>Spitz, Margaret R</au><au>Wistuba, Ignacio I</au><au>Minna, John D</au><au>Gazdar, Adi F</au><au>Pao, William</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2007-04-01</date><risdate>2007</risdate><volume>4</volume><issue>4</issue><spage>e125</spage><epage>e125</epage><pages>e125-e125</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>The epidermal growth factor receptor (EGFR) gene is the prototype member of the type I receptor tyrosine kinase (TK) family and plays a pivotal role in cell proliferation and differentiation. There are three well described polymorphisms that are associated with increased protein production in experimental systems: a polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one (lower number of repeats) and two single nucleotide polymorphisms (SNPs) in the promoter region, -216 (G/T or T/T) and -191 (C/A or A/A). The objective of this study was to examine distributions of these three polymorphisms and their relationships to each other and to EGFR gene mutations and allelic imbalance (AI) in non-small cell lung cancers.
We examined the frequencies of the three polymorphisms of EGFR in 556 resected lung cancers and corresponding non-malignant lung tissues from 336 East Asians, 213 individuals of Northern European descent, and seven of other ethnicities. We also studied the EGFR gene in 93 corresponding non-malignant lung tissue samples from European-descent patients from Italy and in peripheral blood mononuclear cells from 250 normal healthy US individuals enrolled in epidemiological studies including individuals of European descent, African-Americans, and Mexican-Americans. We sequenced the four exons (18-21) of the TK domain known to harbor activating mutations in tumors and examined the status of the CA-SSR1 alleles (presence of heterozygosity, repeat number of the alleles, and relative amplification of one allele) and allele-specific amplification of mutant tumors as determined by a standardized semiautomated method of microsatellite analysis. Variant forms of SNP -216 (G/T or T/T) and SNP -191 (C/A or A/A) (associated with higher protein production in experimental systems) were less frequent in East Asians than in individuals of other ethnicities (p < 0.001). Both alleles of CA-SSR1 were significantly longer in East Asians than in individuals of other ethnicities (p < 0.001). Expression studies using bronchial epithelial cultures demonstrated a trend towards increased mRNA expression in cultures having the variant SNP -216 G/T or T/T genotypes. Monoallelic amplification of the CA-SSR1 locus was present in 30.6% of the informative cases and occurred more often in individuals of East Asian ethnicity. AI was present in 44.4% (95% confidence interval: 34.1%-54.7%) of mutant tumors compared with 25.9% (20.6%-31.2%) of wild-type tumors (p = 0.002). The shorter allele in tumors with AI in East Asian individuals was selectively amplified (shorter allele dominant) more often in mutant tumors (75.0%, 61.6%-88.4%) than in wild-type tumors (43.5%, 31.8%-55.2%, p = 0.003). In addition, there was a strong positive association between AI ratios of CA-SSR1 alleles and AI of mutant alleles.
The three polymorphisms associated with increased EGFR protein production (shorter CA-SSR1 length and variant forms of SNPs -216 and -191) were found to be rare in East Asians as compared to other ethnicities, suggesting that the cells of East Asians may make relatively less intrinsic EGFR protein. Interestingly, especially in tumors from patients of East Asian ethnicity, EGFR mutations were found to favor the shorter allele of CA-SSR1, and selective amplification of the shorter allele of CA-SSR1 occurred frequently in tumors harboring a mutation. These distinct molecular events targeting the same allele would both be predicted to result in greater EGFR protein production and/or activity. Our findings may help explain to some of the ethnic differences observed in mutational frequencies and responses to TK inhibitors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>17455987</pmid><doi>10.1371/journal.pmed.0040125</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2007-04, Vol.4 (4), p.e125-e125 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_1288079357 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central |
| subjects | Alleles Asian people Cancer therapies Cancer: Lung Carcinoma, Non-Small-Cell Lung - epidemiology Carcinoma, Non-Small-Cell Lung - ethnology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell proliferation Epidemiology Epidermal growth factor Ethnicity Gene Amplification Gene Expression Regulation, Neoplastic - genetics Genes, erbB-1 - genetics Genetic aspects Genetic engineering Genetic Variation - genetics Genetics Genetics and Genomics Humans Kinases Lung cancer Lung cancer, Non-small cell Lung Neoplasms - epidemiology Lung Neoplasms - ethnology Lung Neoplasms - genetics Lung Neoplasms - metabolism Mutation Mutation - genetics Oncology Pathology Polymorphism, Genetic - genetics Proteins Receptor, Epidermal Growth Factor - biosynthesis Receptor, Epidermal Growth Factor - genetics Reorganization and restructuring Single nucleotide polymorphisms Tumors Tyrosine |
| title | Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers |
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