American Association for Cancer Research
00085472can171605-sup-184065_2_supp_4280408_zwkjcx.pdf (86.39 kB)

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

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journal contribution
posted on 2023-03-31, 01:01 authored by Smruthy Sivakumar, F. Anthony San Lucas, Tina L. McDowell, Wenhua Lang, Li Xu, Junya Fujimoto, Jianjun Zhang, P. Andrew Futreal, Junya Fukuoka, Yasushi Yatabe, Steven M. Dubinett, Avrum E. Spira, Jerry Fowler, Ernest T. Hawk, Ignacio I. Wistuba, Paul Scheet, Humam Kadara

Supplementary methods including detailed methods on specimen collection and evaluation; DNA and RNA isolation; deep DNA targeted sequencing and transcriptome sequencing; identification and validation of somatic mutations; and expression analysis.


Cancer Prevention and Research Institute of Texas




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.

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