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Inherited lung cancer syndromes targeting never smokers.

ABSTRACT: Lung cancer is the leading cause of cancer death worldwide. Most of lung cancers develop sporadically and thus inherited lung cancers are rare. Several reports show that germline mutations in the kinase domain of epidermal growth factor receptor (EGFR) such as R776G, R776H, T790M, V843I and P848L, predispose to develop lung cancer. Most lung cancer cases with germline EGFR T790M mutations had secondary EGFR somatic mutations. Never smokers with germline EGFR T790M mutations develop lung cancer more frequently than ever smokers. In addition, germline EGFR T790M mutations favored female gender. Therefore, germline EGFR T790M mutations result in a unique inherited lung cancer syndrome targeting never smokers. The authors previously reported a Japanese familial lung cancer pedigree with germline mutations in the transmembrane domain of human epidermal growth factor receptor 2 (HER2). The female proband and her mother in this pedigree, who were light or never smokers, developed multiple lung adenocarcinomas, and had germline HER2 G660D mutations. They had no EGFR somatic mutations or other genes known to cause lung cancers. Although we know only one pedigree with germline HER2 mutations, these mutations may also cause inherited lung cancers targeting female never smokers. Based on our in vitro analyses, we administered HER2 inhibitor afatinib to the proband and achieved partial response. These lung cancers arising from germline mutations of receptor tyrosine kinases such as EGFR and HER2 may have different features from those with sporadic mutations.

SUBMITTER: Yamamoto H

PROVIDER: S-EPMC6131180 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Inherited lung cancer syndromes targeting never smokers.

Yamamoto Hiromasa H Yatabe Yasushi Y Toyooka Shinichi S

Translational lung cancer research 20180801 4

Lung cancer is the leading cause of cancer death worldwide. Most of lung cancers develop sporadically and thus inherited lung cancers are rare. Several reports show that germline mutations in the kinase domain of epidermal growth factor receptor (EGFR) such as R776G, R776H, T790M, V843I and P848L, predispose to develop lung cancer. Most lung cancer cases with germline EGFR T790M mutations had secondary EGFR somatic mutations. Never smokers with germline EGFR T790M mut ...[more]

PMID: 30225213

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Project description:BackgroundMost lung cancer risk prediction models were developed in European and North-American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged < 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range.MethodsBased on the China Kadoorie Biobank cohort, we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines. Then, we separately developed risk prediction models to construct a lung cancer risk score (LCRS) in 159,715 ever smokers and 336,526 never smokers. The LCRS was further validated in an independent cohort over a median follow-up of 13.6 years, consisting of 14,153 never smokers and 5,890 ever smokers.ResultsA total of 13 and 9 routinely available predictors were identified for ever and never smokers, respectively. Of these predictors, cigarettes per day and quit years showed nonlinear associations with lung cancer risk (Pnon-linear < 0.001). The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day. We also observed that lung cancer risk declined sharply within the first 5 years of quitting, and then continued to decrease but at a slower rate in the subsequent years. The 6-year area under the receiver operating curve for the ever and never smokers' models were respectively 0.778 and 0.733 in the derivation cohort, and 0.774 and 0.759 in the validation cohort. In the validation cohort, the 10-year cumulative incidence of lung cancer was 0.39% and 2.57% for ever smokers with low (< 166.2) and intermediate-high LCRS (≥ 166.2), respectively. Never smokers with a high LCRS (≥ 21.2) had a higher 10-year cumulative incidence rate than those with a low LCRS (< 21.2; 1.05% vs. 0.22%). An online risk evaluation tool (LCKEY; http://ccra.njmu.edu.cn/lckey/web) was developed to facilitate the use of LCRS.ConclusionsThe LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.

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Inherited lung cancer syndromes targeting never smokers.

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Inherited lung cancer syndromes targeting never smokers.

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