Abstract 5377: Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing

Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH) represents lung preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and furthe...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5377-5377
Main Authors: Hu, Xin, Fujimoto, Junya, Ying, Lisha, Chen, Runzhe, Estecio, Marcos Roberto, Chow, Chi-Wan, Canales, Jaime Rodriguez, Song, Xingzhi, Mao, Xizeng, Scheet, Paul, Kadara, Humam, Cuentas, Edwin R. Parra Cuentas, Behrens, Carmen, Wu, Chang-Jiun, Lee, J. Jack, Antonoff, Mara, Vaporciyan, Ara A, Swisher, Stephen, zhang, Jianhua, Heymach, John, Hong, Waun Ki, Wistuba, Ignacio I., Sun, Wenyong, Hu, Jinlin, Futreal, P. Andrew, Su, Dan, Zhang, Jianjun
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container_issue 13_Supplement
container_start_page 5377
container_title Cancer research (Chicago, Ill.)
container_volume 78
creator Hu, Xin
Fujimoto, Junya
Ying, Lisha
Chen, Runzhe
Estecio, Marcos Roberto
Chow, Chi-Wan
Canales, Jaime Rodriguez
Song, Xingzhi
Mao, Xizeng
Scheet, Paul
Kadara, Humam
Cuentas, Edwin R. Parra Cuentas
Behrens, Carmen
Wu, Chang-Jiun
Lee, J. Jack
Antonoff, Mara
Vaporciyan, Ara A
Swisher, Stephen
zhang, Jianhua
Heymach, John
Hong, Waun Ki
Wistuba, Ignacio I.
Sun, Wenyong
Hu, Jinlin
Futreal, P. Andrew
Su, Dan
Zhang, Jianjun
description Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH) represents lung preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). Yet the pathologic definition and management of these lesions remain controversial due to lack of sufficient molecular evidences. This aim of this study is to delineate the temporal molecular carcinogenetic events and evolutionary process during the evolution from preneoplastic lesions to early-stage adenocarcinoma. Methods: We have collected 116 resected pre- and early neoplastic lung lesions including AAH (N=22), AIS (N=27), MIA (N=54) and ADC (N=13) from 53 patients, including 39 patients presenting with multifocal disease and 23 patients carrying more than two different types of lesions. Two to five spatially separated regions were subjected to whole-exome sequencing and reduced representation bisulfite sequencing. Results: Mutation burden progressively increases from AAH (average SNVs 0.57/Mb) to AIS (2.04/MB), to MIA (2.98/MB) and ADC (5.4/MB), p
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Parra Cuentas ; Behrens, Carmen ; Wu, Chang-Jiun ; Lee, J. Jack ; Antonoff, Mara ; Vaporciyan, Ara A ; Swisher, Stephen ; zhang, Jianhua ; Heymach, John ; Hong, Waun Ki ; Wistuba, Ignacio I. ; Sun, Wenyong ; Hu, Jinlin ; Futreal, P. Andrew ; Su, Dan ; Zhang, Jianjun</creator><creatorcontrib>Hu, Xin ; Fujimoto, Junya ; Ying, Lisha ; Chen, Runzhe ; Estecio, Marcos Roberto ; Chow, Chi-Wan ; Canales, Jaime Rodriguez ; Song, Xingzhi ; Mao, Xizeng ; Scheet, Paul ; Kadara, Humam ; Cuentas, Edwin R. Parra Cuentas ; Behrens, Carmen ; Wu, Chang-Jiun ; Lee, J. Jack ; Antonoff, Mara ; Vaporciyan, Ara A ; Swisher, Stephen ; zhang, Jianhua ; Heymach, John ; Hong, Waun Ki ; Wistuba, Ignacio I. ; Sun, Wenyong ; Hu, Jinlin ; Futreal, P. Andrew ; Su, Dan ; Zhang, Jianjun</creatorcontrib><description>Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH) represents lung preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). Yet the pathologic definition and management of these lesions remain controversial due to lack of sufficient molecular evidences. This aim of this study is to delineate the temporal molecular carcinogenetic events and evolutionary process during the evolution from preneoplastic lesions to early-stage adenocarcinoma. Methods: We have collected 116 resected pre- and early neoplastic lung lesions including AAH (N=22), AIS (N=27), MIA (N=54) and ADC (N=13) from 53 patients, including 39 patients presenting with multifocal disease and 23 patients carrying more than two different types of lesions. Two to five spatially separated regions were subjected to whole-exome sequencing and reduced representation bisulfite sequencing. Results: Mutation burden progressively increases from AAH (average SNVs 0.57/Mb) to AIS (2.04/MB), to MIA (2.98/MB) and ADC (5.4/MB), p &lt;2.2e-16 with evidence of positive selection of non-silent mutations (60.2% in AAH, 69.7% in AIS, 74.4% in MIA, 84.4% in ADC, p = 0.009). APOBEC signature also progressively increases with APOBEC enrichment scores of 0.94 in AAH, 0.99 in AIS, 1.04 in MIA and 1.28 in ADC (p = 0.011). In addition, genomic heterogeneity becomes more complex with neoplastic evolution with tumor allelic frequency-derived median Shannon index of 1.24 in AAH, 1.52 in AIS, 1.64 in MIA and 1.79 in ADC (p = 0.0004). On the other hand, the proportion of trunk mutations (detected in all regions within the same lesion) progressively increased (35.6% in AAH, 73.6% in AIS, 73.1% in MIA, 70.8% in ADC and p = 1.758e-07). Phylogenetic analysis revealed varying evolutional processes in different pre- and early neoplastic lung lesions with progressive increase in perturbance of genes involved MAPK pathway. Certain key driver mutations were found to be early molecular events occurring at the stage of AAH (e.g., KRAS), while others tend to occur at a later stage (e.g., EGFR). Copy number alterations and genomic doubling were observed in AIS, MIA and ADC, but not in AAH. In addition, DNA methylation profiling revealed that epigenome aberrations fuel preinvasive progression from AIS to MIA and ADC, with parallel phylogenic evolution pattern of the genome. Conclusions: We provide molecular evidence supporting the pathologic model of early lung carcinogenesis from AAH, to AIS, MIA and ADC. With disease evolution, both genomic and epigenomic landscape of lung neoplastic lesions has become progressively more complex along with sequential acquisition of molecular events with concomitant selective sweep of subclone in preneoplasias. Citation Format: Xin Hu, Junya Fujimoto, Lisha Ying, Runzhe Chen, Marcos Roberto Estecio, Chi-Wan Chow, Jaime Rodriguez Canales, Xingzhi Song, Xizeng Mao, Paul Scheet, Humam Kadara, Edwin R. Parra Cuentas Cuentas, Carmen Behrens, Chang-Jiun Wu, J. Jack Lee, Mara Antonoff, Ara A Vaporciyan, Stephen Swisher, Jianhua zhang, John Heymach, Waun Ki Hong, Ignacio I. Wistuba, Wenyong Sun, Jinlin Hu, P. Andrew Futreal, Dan Su, Jianjun Zhang. Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5377.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/1538-7445.AM2018-5377</identifier><language>eng</language><ispartof>Cancer research (Chicago, Ill.), 2018-07, Vol.78 (13_Supplement), p.5377-5377</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c987-3b467da52debc5f73006cc620756d72e946d88bab0d77b8a4c4c9958105b29ca3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27900,27901</link.rule.ids></links><search><creatorcontrib>Hu, Xin</creatorcontrib><creatorcontrib>Fujimoto, Junya</creatorcontrib><creatorcontrib>Ying, Lisha</creatorcontrib><creatorcontrib>Chen, Runzhe</creatorcontrib><creatorcontrib>Estecio, Marcos Roberto</creatorcontrib><creatorcontrib>Chow, Chi-Wan</creatorcontrib><creatorcontrib>Canales, Jaime Rodriguez</creatorcontrib><creatorcontrib>Song, Xingzhi</creatorcontrib><creatorcontrib>Mao, Xizeng</creatorcontrib><creatorcontrib>Scheet, Paul</creatorcontrib><creatorcontrib>Kadara, Humam</creatorcontrib><creatorcontrib>Cuentas, Edwin R. Parra Cuentas</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Wu, Chang-Jiun</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>Antonoff, Mara</creatorcontrib><creatorcontrib>Vaporciyan, Ara A</creatorcontrib><creatorcontrib>Swisher, Stephen</creatorcontrib><creatorcontrib>zhang, Jianhua</creatorcontrib><creatorcontrib>Heymach, John</creatorcontrib><creatorcontrib>Hong, Waun Ki</creatorcontrib><creatorcontrib>Wistuba, Ignacio I.</creatorcontrib><creatorcontrib>Sun, Wenyong</creatorcontrib><creatorcontrib>Hu, Jinlin</creatorcontrib><creatorcontrib>Futreal, P. Andrew</creatorcontrib><creatorcontrib>Su, Dan</creatorcontrib><creatorcontrib>Zhang, Jianjun</creatorcontrib><title>Abstract 5377: Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing</title><title>Cancer research (Chicago, Ill.)</title><description>Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH) represents lung preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). Yet the pathologic definition and management of these lesions remain controversial due to lack of sufficient molecular evidences. This aim of this study is to delineate the temporal molecular carcinogenetic events and evolutionary process during the evolution from preneoplastic lesions to early-stage adenocarcinoma. Methods: We have collected 116 resected pre- and early neoplastic lung lesions including AAH (N=22), AIS (N=27), MIA (N=54) and ADC (N=13) from 53 patients, including 39 patients presenting with multifocal disease and 23 patients carrying more than two different types of lesions. Two to five spatially separated regions were subjected to whole-exome sequencing and reduced representation bisulfite sequencing. Results: Mutation burden progressively increases from AAH (average SNVs 0.57/Mb) to AIS (2.04/MB), to MIA (2.98/MB) and ADC (5.4/MB), p &lt;2.2e-16 with evidence of positive selection of non-silent mutations (60.2% in AAH, 69.7% in AIS, 74.4% in MIA, 84.4% in ADC, p = 0.009). APOBEC signature also progressively increases with APOBEC enrichment scores of 0.94 in AAH, 0.99 in AIS, 1.04 in MIA and 1.28 in ADC (p = 0.011). In addition, genomic heterogeneity becomes more complex with neoplastic evolution with tumor allelic frequency-derived median Shannon index of 1.24 in AAH, 1.52 in AIS, 1.64 in MIA and 1.79 in ADC (p = 0.0004). On the other hand, the proportion of trunk mutations (detected in all regions within the same lesion) progressively increased (35.6% in AAH, 73.6% in AIS, 73.1% in MIA, 70.8% in ADC and p = 1.758e-07). Phylogenetic analysis revealed varying evolutional processes in different pre- and early neoplastic lung lesions with progressive increase in perturbance of genes involved MAPK pathway. Certain key driver mutations were found to be early molecular events occurring at the stage of AAH (e.g., KRAS), while others tend to occur at a later stage (e.g., EGFR). Copy number alterations and genomic doubling were observed in AIS, MIA and ADC, but not in AAH. In addition, DNA methylation profiling revealed that epigenome aberrations fuel preinvasive progression from AIS to MIA and ADC, with parallel phylogenic evolution pattern of the genome. Conclusions: We provide molecular evidence supporting the pathologic model of early lung carcinogenesis from AAH, to AIS, MIA and ADC. With disease evolution, both genomic and epigenomic landscape of lung neoplastic lesions has become progressively more complex along with sequential acquisition of molecular events with concomitant selective sweep of subclone in preneoplasias. Citation Format: Xin Hu, Junya Fujimoto, Lisha Ying, Runzhe Chen, Marcos Roberto Estecio, Chi-Wan Chow, Jaime Rodriguez Canales, Xingzhi Song, Xizeng Mao, Paul Scheet, Humam Kadara, Edwin R. Parra Cuentas Cuentas, Carmen Behrens, Chang-Jiun Wu, J. Jack Lee, Mara Antonoff, Ara A Vaporciyan, Stephen Swisher, Jianhua zhang, John Heymach, Waun Ki Hong, Ignacio I. Wistuba, Wenyong Sun, Jinlin Hu, P. Andrew Futreal, Dan Su, Jianjun Zhang. Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5377.</description><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNo9kM1KxDAUhYMoWEcfQcgLdEzapEndDYN_MOKm-5C_lmjb1KQVZu-DmzLq6t57DufA_QC4xWiLMeV3mJY8Z4TQ7e61QJjntGTsDGT_-jnIEEJJJ6y4BFcxvqeTYkQz8L1TcQ5Sz3AN3cMm7R9u7GBnRz84DeVooJ3c32m_fL_Mzo-wDX6AU7Cj9VMv45zM3sbkRDh72C-pQ5qU0jJol8ISqiMcln52wXZrQbSfix2T112Di1b20d78zg1oHh-a_XN-eHt62e8Oua45y0tFKmYkLYxVmrasRKjSuioQo5Vhha1JZThXUiHDmOKSaKLrmvL0pypqLcsNoKdaHXyMwbZiCm6Q4SgwEitJsRITKzFxIilWKOUPRr1qBA</recordid><startdate>20180701</startdate><enddate>20180701</enddate><creator>Hu, Xin</creator><creator>Fujimoto, Junya</creator><creator>Ying, Lisha</creator><creator>Chen, Runzhe</creator><creator>Estecio, Marcos Roberto</creator><creator>Chow, Chi-Wan</creator><creator>Canales, Jaime Rodriguez</creator><creator>Song, Xingzhi</creator><creator>Mao, Xizeng</creator><creator>Scheet, Paul</creator><creator>Kadara, Humam</creator><creator>Cuentas, Edwin R. Parra Cuentas</creator><creator>Behrens, Carmen</creator><creator>Wu, Chang-Jiun</creator><creator>Lee, J. Jack</creator><creator>Antonoff, Mara</creator><creator>Vaporciyan, Ara A</creator><creator>Swisher, Stephen</creator><creator>zhang, Jianhua</creator><creator>Heymach, John</creator><creator>Hong, Waun Ki</creator><creator>Wistuba, Ignacio I.</creator><creator>Sun, Wenyong</creator><creator>Hu, Jinlin</creator><creator>Futreal, P. Andrew</creator><creator>Su, Dan</creator><creator>Zhang, Jianjun</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20180701</creationdate><title>Abstract 5377: Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing</title><author>Hu, Xin ; Fujimoto, Junya ; Ying, Lisha ; Chen, Runzhe ; Estecio, Marcos Roberto ; Chow, Chi-Wan ; Canales, Jaime Rodriguez ; Song, Xingzhi ; Mao, Xizeng ; Scheet, Paul ; Kadara, Humam ; Cuentas, Edwin R. Parra Cuentas ; Behrens, Carmen ; Wu, Chang-Jiun ; Lee, J. Jack ; Antonoff, Mara ; Vaporciyan, Ara A ; Swisher, Stephen ; zhang, Jianhua ; Heymach, John ; Hong, Waun Ki ; Wistuba, Ignacio I. ; Sun, Wenyong ; Hu, Jinlin ; Futreal, P. 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Parra Cuentas</creatorcontrib><creatorcontrib>Behrens, Carmen</creatorcontrib><creatorcontrib>Wu, Chang-Jiun</creatorcontrib><creatorcontrib>Lee, J. Jack</creatorcontrib><creatorcontrib>Antonoff, Mara</creatorcontrib><creatorcontrib>Vaporciyan, Ara A</creatorcontrib><creatorcontrib>Swisher, Stephen</creatorcontrib><creatorcontrib>zhang, Jianhua</creatorcontrib><creatorcontrib>Heymach, John</creatorcontrib><creatorcontrib>Hong, Waun Ki</creatorcontrib><creatorcontrib>Wistuba, Ignacio I.</creatorcontrib><creatorcontrib>Sun, Wenyong</creatorcontrib><creatorcontrib>Hu, Jinlin</creatorcontrib><creatorcontrib>Futreal, P. Andrew</creatorcontrib><creatorcontrib>Su, Dan</creatorcontrib><creatorcontrib>Zhang, Jianjun</creatorcontrib><collection>CrossRef</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Xin</au><au>Fujimoto, Junya</au><au>Ying, Lisha</au><au>Chen, Runzhe</au><au>Estecio, Marcos Roberto</au><au>Chow, Chi-Wan</au><au>Canales, Jaime Rodriguez</au><au>Song, Xingzhi</au><au>Mao, Xizeng</au><au>Scheet, Paul</au><au>Kadara, Humam</au><au>Cuentas, Edwin R. Parra Cuentas</au><au>Behrens, Carmen</au><au>Wu, Chang-Jiun</au><au>Lee, J. Jack</au><au>Antonoff, Mara</au><au>Vaporciyan, Ara A</au><au>Swisher, Stephen</au><au>zhang, Jianhua</au><au>Heymach, John</au><au>Hong, Waun Ki</au><au>Wistuba, Ignacio I.</au><au>Sun, Wenyong</au><au>Hu, Jinlin</au><au>Futreal, P. Andrew</au><au>Su, Dan</au><au>Zhang, Jianjun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abstract 5377: Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><date>2018-07-01</date><risdate>2018</risdate><volume>78</volume><issue>13_Supplement</issue><spage>5377</spage><epage>5377</epage><pages>5377-5377</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Background: Carcinogenesis may result from accumulation of genomic and epigenomic aberrations. It has been postulated that atypical adenomatous hyperplasia (AAH) represents lung preneoplastic lesion that may progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). Yet the pathologic definition and management of these lesions remain controversial due to lack of sufficient molecular evidences. This aim of this study is to delineate the temporal molecular carcinogenetic events and evolutionary process during the evolution from preneoplastic lesions to early-stage adenocarcinoma. Methods: We have collected 116 resected pre- and early neoplastic lung lesions including AAH (N=22), AIS (N=27), MIA (N=54) and ADC (N=13) from 53 patients, including 39 patients presenting with multifocal disease and 23 patients carrying more than two different types of lesions. Two to five spatially separated regions were subjected to whole-exome sequencing and reduced representation bisulfite sequencing. Results: Mutation burden progressively increases from AAH (average SNVs 0.57/Mb) to AIS (2.04/MB), to MIA (2.98/MB) and ADC (5.4/MB), p &lt;2.2e-16 with evidence of positive selection of non-silent mutations (60.2% in AAH, 69.7% in AIS, 74.4% in MIA, 84.4% in ADC, p = 0.009). APOBEC signature also progressively increases with APOBEC enrichment scores of 0.94 in AAH, 0.99 in AIS, 1.04 in MIA and 1.28 in ADC (p = 0.011). In addition, genomic heterogeneity becomes more complex with neoplastic evolution with tumor allelic frequency-derived median Shannon index of 1.24 in AAH, 1.52 in AIS, 1.64 in MIA and 1.79 in ADC (p = 0.0004). On the other hand, the proportion of trunk mutations (detected in all regions within the same lesion) progressively increased (35.6% in AAH, 73.6% in AIS, 73.1% in MIA, 70.8% in ADC and p = 1.758e-07). Phylogenetic analysis revealed varying evolutional processes in different pre- and early neoplastic lung lesions with progressive increase in perturbance of genes involved MAPK pathway. Certain key driver mutations were found to be early molecular events occurring at the stage of AAH (e.g., KRAS), while others tend to occur at a later stage (e.g., EGFR). Copy number alterations and genomic doubling were observed in AIS, MIA and ADC, but not in AAH. In addition, DNA methylation profiling revealed that epigenome aberrations fuel preinvasive progression from AIS to MIA and ADC, with parallel phylogenic evolution pattern of the genome. Conclusions: We provide molecular evidence supporting the pathologic model of early lung carcinogenesis from AAH, to AIS, MIA and ADC. With disease evolution, both genomic and epigenomic landscape of lung neoplastic lesions has become progressively more complex along with sequential acquisition of molecular events with concomitant selective sweep of subclone in preneoplasias. Citation Format: Xin Hu, Junya Fujimoto, Lisha Ying, Runzhe Chen, Marcos Roberto Estecio, Chi-Wan Chow, Jaime Rodriguez Canales, Xingzhi Song, Xizeng Mao, Paul Scheet, Humam Kadara, Edwin R. Parra Cuentas Cuentas, Carmen Behrens, Chang-Jiun Wu, J. Jack Lee, Mara Antonoff, Ara A Vaporciyan, Stephen Swisher, Jianhua zhang, John Heymach, Waun Ki Hong, Ignacio I. Wistuba, Wenyong Sun, Jinlin Hu, P. Andrew Futreal, Dan Su, Jianjun Zhang. Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5377.</abstract><doi>10.1158/1538-7445.AM2018-5377</doi><tpages>1</tpages></addata></record>
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title Abstract 5377: Tracking genomic and epigenomic evolution from preneoplastic lesions to lung adenocarcinoma by multiregion sequencing
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