Eunhyang Park1, Soyeon Ahn2, Hyojin Kim1, Soo Young Park1, Jisun Lim2, Hyun Jung Kwon1, Yeon Bi Han1, Choon-Taek Lee3, Sukki Cho4, Jin-Haeng Chung5. 1. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 2. Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 3. Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 4. Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. 5. Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. Electronic address: chungjh@snu.ac.kr.
Abstract
INTRODUCTION: Lung adenocarcinoma (ADC) with synchronous ground-glass/lepidic (GG/L) nodules is considered a distinct disease entity in multiple synchronous lung cancers. Few studies have performed next-generation sequencing analysis of these synchronous sequential lesions, and genetic alterations of GG/L nodules must be further investigated. METHODS: We performed targeted sequencing in ADC with synchronous atypical adenomatous hyperplasia (AAH), ADC in situ, or minimally invasive ADC from 16 patients. Next-generation sequencing was performed by using a customized panel including 154 cancer-associated genes. RESULTS: Multiple synchronous lesions in the same patient showed different mutation profiles, and some shared identically mutated genes. In five patients harboring EGFR-mutant ADC, their synchronous GG/L nodules had EGFR mutation; however, none was observed in EGFR wild-type ADC. The average numbers of exonic mutations were 4.2, 5.4, 4.0, and 5.4 in AAH, ADC in situ, minimally invasive ADC, and ADC, respectively. In each lesion type, various mutations, including LDL receptor related protein 1B gene (LRP1B), KRAS, EGFR, and BRAF were observed in AAH, and EGFR mutations were the most frequently observed in ADC. In all, 80% of mutations with a variant allele frequency of 20% or higher, which contained driver gene mutations, were identified in ADC. Intratumoral heterogeneity of the genetic profile was found between the lepidic and invasive areas of ADC, but the driver gene mutations were similar. CONCLUSIONS: This study suggests that ADC and synchronous GG/L nodules are genetically independent tumors. Intratumoral genetic heterogeneity of ADC was present, but driver gene mutations were homogeneously distributed. Driver gene mutations with a high variant allele frequency were identified in the invasive tumor. These findings support the relevance of molecular characterization of lung ADC and synchronous GG/L nodules.
INTRODUCTION:Lung adenocarcinoma (ADC) with synchronous ground-glass/lepidic (GG/L) nodules is considered a distinct disease entity in multiple synchronous lung cancers. Few studies have performed next-generation sequencing analysis of these synchronous sequential lesions, and genetic alterations of GG/L nodules must be further investigated. METHODS: We performed targeted sequencing in ADC with synchronous atypical adenomatous hyperplasia (AAH), ADC in situ, or minimally invasive ADC from 16 patients. Next-generation sequencing was performed by using a customized panel including 154 cancer-associated genes. RESULTS:Multiple synchronous lesions in the same patient showed different mutation profiles, and some shared identically mutated genes. In five patients harboring EGFR-mutant ADC, their synchronous GG/L nodules had EGFR mutation; however, none was observed in EGFR wild-type ADC. The average numbers of exonic mutations were 4.2, 5.4, 4.0, and 5.4 in AAH, ADC in situ, minimally invasive ADC, and ADC, respectively. In each lesion type, various mutations, including LDL receptor related protein 1B gene (LRP1B), KRAS, EGFR, and BRAF were observed in AAH, and EGFR mutations were the most frequently observed in ADC. In all, 80% of mutations with a variant allele frequency of 20% or higher, which contained driver gene mutations, were identified in ADC. Intratumoral heterogeneity of the genetic profile was found between the lepidic and invasive areas of ADC, but the driver gene mutations were similar. CONCLUSIONS: This study suggests that ADC and synchronous GG/L nodules are genetically independent tumors. Intratumoral genetic heterogeneity of ADC was present, but driver gene mutations were homogeneously distributed. Driver gene mutations with a high variant allele frequency were identified in the invasive tumor. These findings support the relevance of molecular characterization of lung ADC and synchronous GG/L nodules.
Authors: Jun Qian; Shilin Zhao; Yong Zou; S M Jamshedur Rahman; Maria-Fernanda Senosain; Thomas Stricker; Heidi Chen; Charles A Powell; Alain C Borczuk; Pierre P Massion Journal: Am J Respir Crit Care Med Date: 2020-03-15 Impact factor: 21.405
Authors: Chunxiang Li; Yalong Wang; Kai Su; Yu Liu; Liyu Wang; Bo Zheng; Na Yan; Dawei Yuan; Yanxiang Zhang; Liyan Xue; Shugeng Gao; Jie He Journal: Transl Lung Cancer Res Date: 2021-04
Authors: Yang Xiang; Karsta Luettich; Florian Martin; James N D Battey; Keyur Trivedi; Laurent Neau; Ee Tsin Wong; Emmanuel Guedj; Remi Dulize; Dariusz Peric; David Bornand; Sonia Ouadi; Nicolas Sierro; Ansgar Büttner; Nikolai V Ivanov; Patrick Vanscheeuwijck; Julia Hoeng; Manuel C Peitsch Journal: Front Toxicol Date: 2021-03-16