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Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations  Adi Gazdar, MD, Linda Robinson, MS, Dwight Oliver, MD,

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Presentation on theme: "Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations  Adi Gazdar, MD, Linda Robinson, MS, Dwight Oliver, MD,"— Presentation transcript:

1 Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline EGFR Gene T790M Mutations 
Adi Gazdar, MD, Linda Robinson, MS, Dwight Oliver, MD, Chao Xing, PhD, William D. Travis, MD, Junichi Soh, MD, Shinichi Toyooka, MD, Lori Watumull, MD, Yang Xie, PhD, Kemp Kernstine, MD, Joan H. Schiller, MD  Journal of Thoracic Oncology  Volume 9, Issue 4, Pages (April 2014) DOI: /JTO Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

2 FIGURE 1 A cartoon of the location of the common mutations in the tyrosine kinase domain of the EGFR gene is shown in the upper part of the figure (A). Sequencing of the EGFR gene in the proband’s adenocarcinoma revealed an activating mutation (L858R) in the EGFR gene (minor peak) (B) and a prominent T790M mutation equal in size to the wild-type peak (B). The T790M mutation substitutes methionine for threonine at position 790 (nucleotide c.2369). The finding in a lung cancer of a T790M mutant band equal in size to the wild-type band before tyrosine kinase inhibitor therapy suggests a germline mutation. Examination of the proband’s blood cells confirmed a germline T790M mutation in the patient (C) and in her mother (D). Journal of Thoracic Oncology 2014 9, DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

3 FIGURE 2 Pedigree of family with germline T790M mutation. Age, smoking history, mutation status, and other cancer history are recorded. *In addition to the three obligate carriers identified in the pedigree, either individual I:1 or I:2 is a obligate carrier based on pedigree analysis. Individual III:3 is reported to have died from bladder cancer. She also had lung cancer, but it is uncertain if this was a primary cancer or a metastasis. Individual V:1 had a lung carcinoid tumor. These two cases were not considered to be lung cancer cases. There are two never smokers who developed lung cancer in the family (II:2 and III:6), given the low likelihood that they represent two sporadic cases in this family we have assumed that they are also mutation carriers, thus for a total of 14 known, obligate, or assumed mutation carriers. Journal of Thoracic Oncology 2014 9, DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

4 FIGURE 3 Hypothetical mutation-driven pathways to NSCLC development in patients with and without germline T790M mutations. In subjects without the germline mutation, the major pathways are via EGFR mutations (in NS) or via KRAS mutations (in ES), although other driver mutations may occur in either group. Subjects with germline T790M mutations, a weak driver mutation, usually require one or more other driver mutations for NSCLC development. In NS, the second mutation is usually another EGFR mutation although other pathways may occasionally be activated. In ES, the presence of the germline EGFR gene mutation and the smoking status decrease or preclude the possibility of developing a KRAS mutation, although alternative driver mutations may occasionally occur. ES, ever smoker; NS, never smoker; NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2014 9, DOI: ( /JTO ) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

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