Comprehensive investigation of mutational features of adenocarcinoma in situ and invasive adenocarcinoma among Chinese lung cancer patients.

9051 Background: Lung adenocarcinoma (LUAD) is further classified into several histological subtypes with adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC) as the three major subtypes according to the extent of invasion. AIS has been considered as a precursor of IAC. Considering the significantly higher mutation burden among IAC tumors than AIS tumors, it seems likely that AIS tumors undergo a process of accumulating various somatic mutations to gain invasive ability. To understand the gene mutations involved in this transformation, we compared the mutational features of AIS and IAC tumors. Methods: This retrospective study included 2,769 Chinese patients diagnosed with stage 0-IIIA LUAD. Targeted sequencing was performed on tissue DNA isolated from 246 AIS tumors and 2,523 IAC tumors using 68 lung cancer-related genes (Lung Core, Burning Rock Biotech). Results: Analysis of mutation profiles revealed that mutation count was significantly lower for AIS ( P< 0.01) as compared to IAC tumors. Moreover, AIS tumors had significantly higher mutation detection rates for ERBB2 exon 20 insertion (20ins) ( P≤0.05), EGFR 20ins ( P≤0.05), non-V600E BRAF mutations ( P≤0.05), and MAP2K1 small insertion-deletion variants ( P≤0.05). These 4 gene mutations were grouped and referred to as AIS-like mutations for further analysis. Detection rates of AIS-like mutations were 54.9% for AIS tumors and 7.8% for IAC tumors. Patients with AIS-like mutation-positive AIS tumors were significantly younger than those with AIS tumors without AIS-like mutations ( P =0.018), while age were similar for IAC tumors with or without AIS-like mutations. Mutation count was similar between AIS tumors with or without AIS-like mutations. Interestingly, IAC tumors harboring AIS-like mutations had a significantly higher mutation count than those harboring known oncogenic drivers ( P= 0.045). Further investigation of the molecular profiles of IAC tumors harboring AIS-like mutations (n = 198) revealed the presence of various concurrent mutations in 8 genes including TP53 (39.4%), EGFR (non-20ins) (16.7%), RB1 (7.1%), PIK3CA (6.6%), MET (5.1%), ROS1 (4.0%), FLT3 (4.0%), and PTEN (3.5%), which were absent among AIS tumors, particularly those that harbor AIS-like mutations. In addition to TP53 (35.8%), PIK3CA (4.5%), and RB1 (4.0%), IAC tumors without AIS-like mutations (n = 2,324) had additional concurrent mutations in 2 other genes CDK4 (5.7%) and STK11 (3.9%) as compared to AIS tumors. Conclusions: Our data suggest that AIS-like mutations could be involved in the early stages of tumorigenesis by initiating the accumulation of other gene mutations that are required for the transformation of AIS tumors into IAC tumors. Our study contributes to a deeper understanding of the distinct gene mutations between AIS and IAC tumors among Chinese LUAD patients.

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Multiregion whole exome seuquencing of pre- and early neoplastic lung lesions.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20042 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20042-e20042

Author(s):

Jianjun Zhang ◽

Dan Su ◽

Junya Fujimoto ◽

Lisa Ying ◽

Chi-Wan Chow ◽

...

Keyword(s):

Lung Cancer ◽

Gene Mutations ◽

Lung Cancer Screening ◽

Adenocarcinoma In Situ ◽

Invasive Adenocarcinoma ◽

Lung Cancers ◽

Molecular Events ◽

Whole Exome ◽

Incidence And Mortality ◽

Early Carcinogenesis

e20042 Background: The widespread use of CT for lung cancer screening and other reasons has resulted in a dramatic increase in the number of indeterminate ground glass opacities (GGOs). While many of GGOs can be resected with minimal morbidity, the cost has been called into question. Furthermore, multifocality is a relatively common, which makes decisions on extent of surgical resection and potential benefit less clear. Chemoprevention is a theoretically appealing approach to reduce lung cancer incidence and mortality. However, randomized trials have been disappointing to date. This may be due to the constellation of many factors including lack of reliable biomarkers to identify high-risk patients, lack of appropriate molecular targets and appropriate drugs because of our rudimentary knowledge on early carcinogenesis of lung cancers. It has been postulated that atypical adenomatous hyperplasia (AAH) represents preneoplastic lesion that can progress to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and further to frankly invasive adenocarcinoma (ADC). However, the biology of these lesions is poorly understood and the definition and management of these lesions remain controversial. Methods: Study on early carcinogenesis is hampered by the small size of lesions and challenge of obtaining longitudinal samples at different stages of disease progression. Multiregion sequencing can depict genomic events relative to molecular time with early events ubiquitously present in all regions and late mutations confined to spatially separated regions of lesions. Using this approach, our recent work has reported that 20/21 canonical cancer gene mutations were early genetic events. Results: With intent to delineate the pivotal molecular events driving early carcinogenesis of lung cancer, we have collected 154 resected GGOs with including AAH (N = 40), AIS (N = 39), MIA (N = 55) and ADC (N = 20) based on the IASLC/ATS/ERS classification from 89 patients including 38 patients presenting with multifocal GGOs and 18 patients carry more than one type of pathology. Two to five spatially separated regions from each of the 154 lesions are subjected to whole exome sequencing. Conclusions: The data will be ready to present at the meeting.

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Mutational distinction between adenocarcinoma in situ, minimally invasive adenocarcinoma and invasive adenocarcinoma in lung cancer patients with multiple tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21089 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21089-e21089

Author(s):

Jixian Liu ◽

Yingmei Li ◽

Yuancai Xie ◽

Xinyu Luan ◽

Xuxing Peng ◽

...

Keyword(s):

Lung Cancer ◽

Minimally Invasive ◽

Driver Mutations ◽

Adenocarcinoma In Situ ◽

Cancer Type ◽

Invasive Adenocarcinoma ◽

Multiple Tumors ◽

Origin And Evolution ◽

Minimally Invasive Adenocarcinoma

e21089 Background: Lung adenocarcinoma is the most popular lung cancer type, and it can be classified as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA) based on histology. The mutational similarities and differences have not been discussed in these subtypes. Methods: Targeted deep sequencing was performed on 31 lung adenocarcinomas with matched blood samples from 15 patients with multiple tumors. We compared mutations among each subtype. Results: The 31 tumors consisted of 10 AIS, 6 MIA and 15 IA subtypes; the median mutation number in each type was 1, 1 and 3 respectively. Eleven, six and fifty-three mutations were identified in AIS, MIA, and IA respectively. Among all the 67 mutations, only EGFR_p.L858R was found in all three types; BRAF_p.K601E was found in AIS and IA. Conclusions: AIS, MIA and IA harbor distinct mutational signatures, except for several popular driver mutations, suggesting their distinct origin and evolution path.

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Comprehensive investigation of mutational features of various lung adenocarcinoma histological subtypes among Chinese patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21090 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21090-e21090

Author(s):

Yuchen Han ◽

Chan Xiang ◽

Haohua Teng ◽

Lei Zhu ◽

Jinchen Shao ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

World Health ◽

Chinese Patients ◽

Molecular Profile ◽

Adenocarcinoma In Situ ◽

Histological Subtype ◽

Histological Subtypes ◽

Invasive Adenocarcinoma ◽

Detection Rates ◽

Histologic Subtype

e21090 Background: Lung adenocarcinoma (LUAD) is further classified into several histological subtypes according to the World Health Organization classification; however, data on the molecular profile of these histological subtypes are limited. In this study, we aimed to investigate the mutational features of various LUAD histological subtypes among Chinese patients. Methods: We retrospectively analyzed clinical, histopathologic, and sequencing data from 3,425 consecutive patients diagnosed with stage IA-IVB LUAD between January 2017 to December 2019 at the Department of Pathology. Results: Based on histologic subtype, the cohort comprised of 0.2% atypical adenomatous hyperplasia (AAH, n = 6), 7.2% adenocarcinoma in situ (AIS, n = 246), 14.0% minimally invasive adenocarcinoma (MIA, n = 479), and 78.6% invasive adenocarcinoma (INV, n = 2,694), including 42.0% acinar (n = 1,438), 12.7% papillary (n = 435), 8.8% lepidic (n = 302), 8.5% solid (n = 290), 3.2% micropapillary (n = 109), 2.8% invasive mucinous (n = 95), 0.6% enteric (n = 21), 0.1% fetal (n = 3), and 0.1% colloid (n = 1). Analysis of mutation profiles revealed significantly higher mutation detection rates of ERBB2 ( P< 0.01), BRAF ( P< 0.01), and MAP2K1 ( P= < 0.01) among patients with AIS, AAH and MIA as compared to patients with INV. Meanwhile, TP53 ( P< 0.01) and EGFR ( P< 0.01) mutations were significantly higher among patients with INV as compared to patients with AIS and MIA. Among the invasive subtypes, patients with invasive mucinous adenocarcinoma had significantly higher KRAS mutation rate (75%, P< 0.01). Lepidic (81%), acinar (80%), papillary (77%), and micropapillary (66%) were the subtypes with the highest EGFR mutation rates. Conclusions: By analyzing the genomic data of a large cohort of patients, our study provides a more comprehensive outlook of gene mutations according to LUAD histological subtypes. Enrichement of actionable mutation in particular histological subtype contributes to more treatment option and better clinical outcomes as compared to other histological subtype, indicating the clinical relevance of performing comprehensive mutation profiling in addition to histopathologic analysis in all LUAD patients.

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A Clinicopathological Study of Small Lung Adenocarcinoma 1 cm or Less in Size: Emphasis on Histological Subtypes Associated With Lymph Node Metastasis and Recurrence

International Journal of Surgical Pathology ◽

10.1177/1066896917721649 ◽

2017 ◽

Vol 26 (1) ◽

pp. 4-11 ◽

Cited By ~ 6

Author(s):

Wei Zhao ◽

Hui Wang ◽

Jun Xie ◽

Bo Tian

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Lung Adenocarcinoma ◽

Who Classification ◽

Limited Resection ◽

Adenocarcinoma In Situ ◽

Invasive Adenocarcinoma ◽

Node Metastasis ◽

Minimally Invasive Adenocarcinoma

Background. The aim of this study was to assess the prognostic significance of the newly proposed 2015 World Health Organization (WHO) lung adenocarcinoma classification for patients undergoing resection for small (≤1 cm) lung adenocarcinoma. We also investigated whether lobectomy offers prognostic advantage over limited resection for this category of tumors. Methods. A retrospective study of resected pulmonary adenocarcinomas (n = 83) in sizes 1 cm or less was carried out in which comprehensive histologic subtyping was assessed according to the 2015 WHO classification on all consecutive patients who underwent lobectomy or limited resection between 1998 and 2012. Correlation between clinicopathologic parameters and the difference in recurrence between lobectomy and limited resection group was evaluated. Results. Our data show that the proposed 2015 WHO classification identifies histological subsets of small lung adenocarcinomas with significant differences in prognosis. No recurrence was noted for patients with adenocarcinoma in situ and minimally invasive adenocarcinoma. Invasive adenocarcinomas displayed high heterogeneity and the presence of micropapillary component of 5% or greater in adenocarcinomas was significantly related to lymph node involvement and recurrence ( P < .001). Stage IA patients who underwent limited resection had a higher risk of recurrence than did those treated by lobectomy ( P < .05). Conclusions. Application of the 2015 WHO classification identifies patients with adenocarcinoma in situ and minimally invasive adenocarcinoma had excellent prognosis. Micropapillary pattern was associated with high risk of lymph node metastasis and recurrence.

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Radiopathologic correlation of collision lung cancer with ground-glass opacity

Asian Cardiovascular and Thoracic Annals ◽

10.1177/0218492318811549 ◽

2018 ◽

Vol 27 (1) ◽

pp. 45-48

Author(s):

Shinsuke Uchida ◽

Koji Tsuta ◽

Masahiko Kusumoto ◽

Kouya Shiraishi ◽

Takashi Kohno ◽

...

Keyword(s):

Lung Cancer ◽

Ground Glass Opacity ◽

Ground Glass ◽

Adenocarcinoma In Situ ◽

Invasive Adenocarcinoma ◽

Ki 67 ◽

Lung Cancers ◽

Collision Tumors ◽

Minimally Invasive Adenocarcinoma ◽

Epidermal Growth

Pulmonary collision tumors have been described as a special entity of synchronous multiple lung cancer. There have been no reports detailing the chronological changes in primary collision lung cancers on chest computed tomography. We report a case of ground-glass lung nodules gradually colliding with each other. The collision tumors of the lung were composed of minimally invasive adenocarcinoma and adenocarcinoma in situ with epidermal growth factor mutations. Immunohistochemically, the Ki-67 labeling indices were different in the 2 components. Ki-67 staining was useful to distinguish the 2 components. The 2 dominant ground-glass tumors grew slowly with radiologic and pathologic heterogeneity.

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Morphological and Genetic Heterogeneity of Synchronous Multifocal Lung Adenocarcinoma in a Chinese Cohort

10.21203/rs.3.rs-77421/v1 ◽

2020 ◽

Author(s):

Donglin Zhu ◽

Dan Cao ◽

Minghong Shen ◽

Jinghuan Lv

Keyword(s):

Lung Cancer ◽

Primary Lung Cancer ◽

Gene Mutations ◽

Tumor Location ◽

Chinese Patients ◽

Molecular Testing ◽

Additional Tool ◽

Molecular Features ◽

Pathologic Features ◽

Genotypic Analysis

Abstract Background: Synchronous multifocal lung cancer (SMLC) is seen with increasing frequency in clinical practice globally. Because of innate variation in clinical management and outcome, it is vital to distinguish properly between synchronous multifocal primary lung cancer (SMPLC) and intrapulmonary metastasis (IM). The pathologic features and principal classification criteria of multifocal lung cancer remain unclear. Methods: We have collected a unique cohort of Chinese patients with SMLC, and fully explored the morphologic, immunohistochemical, and molecular features of the disease. Twenty-one SMLC patients with a total of 50 tumors were included in our study. The pathological features presented by these cases were analyzed, including tumor location, tumor size, pathological types, predominant pattern of adenocarcinoma, and immunohistochemical staining. We undertook molecular testing of nine driver oncogenes associated with lung cancer, including EGER, KRAS, BRAF, NRAS, ALK, ROS1, RET, HER2, and PIK3CA. Results: According to Martini-Melamed classification and refined standard, 8 and 17 cases were considered as SMPLC respectively. Gene mutations were identified in 18 tumors (36%). There were 12 patients had different gene mutations. Conclusions: We demonstrate that conventional morphological assessment is not sufficient to establish clearly the clonal relationship of SMPLC. Instead the evaluation of histological subtypes, including non-mucinous adherent components, is required. Multiplex genotypic analysis may also prove a useful additional tool.

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Detection of clinically relevant epidermal growth factor receptor pathway mutations in circulating cell-free tumor DNA using next generation sequencing in squamous cell carcinoma lung

South Asian Journal of Cancer ◽

10.4103/sajc.sajc_281_18 ◽

2019 ◽

Vol 08 (04) ◽

pp. 247-249

Author(s):

Kanakasetty Babu Govind ◽

Deepak Koppaka ◽

Lokanatha Dasappa ◽

Linu Abraham Jacob ◽

Suresh M.C. Babu ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell Carcinoma ◽

Epidermal Growth Factor Receptor ◽

Cell Carcinoma ◽

Squamous Cell ◽

Growth Factor Receptor ◽

Braf Mutations ◽

Lung Cancer Patients ◽

Epidermal Growth ◽

Generation Sequencing

Abstract Background: Limited repertoires of targets are available in the management of squamous cell carcinoma lung. In this study, we analyzed epidermal growth factor receptor (EGFR), RAS, BRAF mutations in lung cancer patients of squamous cell histology using next-generation sequencing (NGS) on the circulating cell-free DNA (cf-DNA). Materials and Methods: In this prospective observational study, patients with squamous cell carcinoma lung, either newly diagnosed or having a progressive disease on prior therapy were eligible. Cf-DNA was extracted from peripheral blood and analyzed for EGFR, KRAS, NRAS, and BRAF mutations using NGS. Results: Sixteen patients were enrolled over a period of 1 month. The mean cf-DNA quantity extracted from the plasma was 96.5 ng (range, 15–200 ng). Eight clinically relevant mutations in the EGFR pathway were identified. These include Exon 21 mutations in 4 patients, Exon 20 mutation in onepatient, complex mutations with coexisting Exon 21 and Exon18 in one patient and KRAS Exon 2 mutations in two patients. Conclusion: cf-DNA is a minimally invasive technique for detection of clinically relevant mutations in lung cancer patients. The use of novel advanced techniques such as NGS may help in detecting EGFR pathway mutations in patients with squamous cell carcinoma lung.

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