Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AA...

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Veröffentlicht in:	Cancer research (Chicago, Ill.) Jg. 77; H. 22; S. 6119
Hauptverfasser:	Sivakumar, Smruthy, Lucas, F Anthony San, McDowell, Tina L, Lang, Wenhua, Xu, Li, Fujimoto, Junya, Zhang, Jianjun, Futreal, P Andrew, Fukuoka, Junya, Yatabe, Yasushi, Dubinett, Steven M, Spira, Avrum E, Fowler, Jerry, Hawk, Ernest T, Wistuba, Ignacio I, Scheet, Paul, Kadara, Humam
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 15.11.2017
Schlagworte:	Adenocarcinoma - genetics Adenocarcinoma - pathology Aged Disease Progression Female Gene Expression Profiling Genomics Humans Hyperplasia - genetics Lung - metabolism Lung - pathology Lung Neoplasms - genetics Lung Neoplasms - pathology Male Middle Aged Mutation Precancerous Conditions - genetics Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics
ISSN:	1538-7445, 1538-7445
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Abstract	There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver mutations. mutations were present in AAHs from 4 of 22 (18%) of patients. mutations in AAH were only found in ever-smokers and were exclusive to -mutant cases. Integrative analysis revealed profiles expressed in -mutant cases ( ) and -mutant cases ( ) of AAH, or common to both sets of cases (suppressed ). Gene sets associated with suppressed antitumor (Th1; ) and elevated protumor ( ) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent or pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. .
AbstractList	There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR.There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR. There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver mutations. mutations were present in AAHs from 4 of 22 (18%) of patients. mutations in AAH were only found in ever-smokers and were exclusive to -mutant cases. Integrative analysis revealed profiles expressed in -mutant cases ( ) and -mutant cases ( ) of AAH, or common to both sets of cases (suppressed ). Gene sets associated with suppressed antitumor (Th1; ) and elevated protumor ( ) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent or pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. .
Author	Xu, Li Fujimoto, Junya Fukuoka, Junya Fowler, Jerry Futreal, P Andrew Lucas, F Anthony San Spira, Avrum E Yatabe, Yasushi Dubinett, Steven M Kadara, Humam Hawk, Ernest T Wistuba, Ignacio I Zhang, Jianjun Sivakumar, Smruthy Lang, Wenhua McDowell, Tina L Scheet, Paul
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Snippet	There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known...
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SubjectTerms	Adenocarcinoma - genetics Adenocarcinoma - pathology Aged Disease Progression Female Gene Expression Profiling Genomics Humans Hyperplasia - genetics Lung - metabolism Lung - pathology Lung Neoplasms - genetics Lung Neoplasms - pathology Male Middle Aged Mutation Precancerous Conditions - genetics Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics
Title	Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma
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