Higher frequency but random distribution of <i>EGFR</i> mutation subtypes in familial lung cancer patients

Hsu, Kuo-Hsuan; Tseng, Jeng‐Sen; Wang, Chih Liang; Yang, Tsung Ying; Tseng, Chien-Hua; Chen, Hsuan Yu; Chen, Kun Chieh; Tsai, Chia-Lung; Yang, Cheng‐Ta; Yu, Sung-Liang; Su, Kang-Yi; Yu, Chong Jen; Ho, Cheng-Maw; Hsia, Te Chun; Wu, Ming-Fang; Chiu, Kuo Liang; Liu, Chien Ming; Yang, Pan Chyr; Chen, Jeremy J.W.; Chang, Gee Chen

doi:10.18632/oncotarget.10715

Cited by 11 publications

(7 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The distribution of secondary somatic mutations was not typically concordant across family members or multiple lung cancers in the same patient, similar to a previously reported small familial cohort [28]. However, there are some exceptions in our study.…”

Section: Discussionsupporting

confidence: 86%

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

et al. 2019

View full text Add to dashboard Cite

Background: Accumulating evidence indicates inherited risk in the aetiology of lung cancer, although smoking exposure is the major attributing factor. Family history is a simple substitute for inherited susceptibility. Previous studies have shown some possible yet conflicting links between family history of cancer and EGFR mutation in lung cancer. As EGFR-mutated lung cancer favours female, never-smoker, adenocarcinoma and Asians, it may be argued that there may be some underlying genetic modifiers responsible for the pathogenesis of EGFR mutation. Methods: We searched four databases for all original articles on family history of malignancy and EGFR mutation status in lung cancer published up to July 2018. We performed a meta-analysis by using a random-effects model and odds ratio estimates. Heterogeneity and sensitivity were also investigated. Then we conducted a second literature research to curate case reports of familial lung cancers who studied both germline cancer predisposing genes and their somatic EGFR mutation status; and explored the possible links between cancer predisposing genes and EGFR mutation. Results: Eleven studies have been included in the meta-analysis. There is a significantly higher likelihood of EGFR mutation in lung cancer patients with family history of cancer than their counterparts without family history, preferentially in Asians (OR = 1.35[1.06-1.71], P = 0.01), those diagnosed with adenocarcinomas ((OR = 1.47[1.14-1.89], P = 0.003) and those with lung cancer-affected relatives (first and second-degree: OR = 1.53[1.18-1.99], P = 0.001; first-degree: OR = 1.76[1.36-2.28, P < 0.0001]). Familial lung cancers more likely have concurrent EGFR mutations along with mutations in their germline cancer predisposition genes including EGFR T790 M, BRCA2 and TP53. Certain mechanisms may contribute to the combination preferences between inherited mutations and somatic ones. Conclusions: Potential genetic modifiers may contribute to somatic EGFR mutation in lung cancer, although current data is limited. Further studies on this topic are needed, which may help to unveil lung carcinogenesis pathways. However, caution is warranted in data interpretation due to limited cases available for the current study.

show abstract

Section: Discussionsupporting

confidence: 86%

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Compared to other organs, most of lung cancers develop sporadically and inherited lung cancers are rare. While inherited lung cancers are rarely observed, several reports investigated genetic susceptibility to inherited lung cancers (21)(22)(23)(24)(25)(26). Those previous reports describing inherited lung cancers did not much focus on the relationship between genetic factors and smoking status.…”

Section: Introductionmentioning

confidence: 99%

Inherited lung cancer syndromes targeting never smokers

Yamamoto¹,

Yatabe²,

Toyooka³

2018

Transl. Lung Cancer Res.

View full text Add to dashboard Cite

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 () such as R776G, R776H, T790M, V843I and P848L, predispose to develop lung cancer. Most lung cancer cases with germline T790M mutations had secondary somatic mutations. Never smokers with germline T790M mutations develop lung cancer more frequently than ever smokers. In addition, germline T790M mutations favored female gender. Therefore, germline 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 (). The female proband and her mother in this pedigree, who were light or never smokers, developed multiple lung adenocarcinomas, and had germline G660D mutations. They had no somatic mutations or other genes known to cause lung cancers. Although we know only one pedigree with germline mutations, these mutations may also cause inherited lung cancers targeting female never smokers. Based on our analyses, we administered inhibitor afatinib to the proband and achieved partial response. These lung cancers arising from germline mutations of receptor tyrosine kinases such as and may have different features from those with sporadic mutations.

show abstract

“…Evidence indicates that female NSCLC patients display higher exon-21 L858R mutation frequency than males [ 64 , 65 ], and increased frequency of lung adenocarcinomas depending on ethnicity [ 66 ]. The EGFR L858R–T790M double-mutant H1975 line originates from a female patient’s primary NSCLC, hence we used female mice for in vivo experiments.…”

Section: Discussionmentioning

confidence: 99%

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

et al. 2022

View full text Add to dashboard Cite

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

show abstract

Higher frequency but random distribution of EGFR mutation subtypes in familial lung cancer patients

Cited by 11 publications

References 33 publications

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta-analysis and literature review

Inherited lung cancer syndromes targeting never smokers

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Contact Info

Product

Resources

About