Exome sequencing deciphers a germline <i><scp>MET</scp></i> mutation in familial epidermal growth factor receptor‐mutant lung cancer

Tode, Naoki; Kikuchi, Toshiaki; Sakakibara, Tomohiro; Hirano, Taizou; Inoue, Akira; Ohkouchi, Shinya; Tamada, Tsutomu; Okazaki, Tatsuma; Koarai, Akira; Sugiura, Hiroaki; Niihori, Tetsuya; Aoki, Yoko; Nakayama, Keiko; Matsumoto, Kunio; Matsubara, Yoichi; Yamamoto, Masayuki; Watanabe, Akira; Nukiwa, Toshihiro; Ichinose, Masakazu

doi:10.1111/cas.13233

Cited by 11 publications

(13 citation statements)

References 20 publications

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“…A nephew had non-Hodgkin’s lymphoma at 12 (germline V843I negative). A healthy daughter carried germline V843I mutation.Ohtsuka, et al 2011 [46]1713MotherF70AsianUKADCL858R1813BrotherM41AsianUKADCL858R EGFR p.V834 L1914ProbandF57SurinamSADCL858RA daughter carried germline V834 L; Father died of massive hemoptysis of unknown cause.Van der Leest, et al 2018 [47]2014BrotherM57SurinamSNSCLCL858R2114SisterF46SurinamNSNSCLCL858R2214DaughterF42SurinamNSNSCLCL858R HER2 p.G660D2315ProbandF44AsianLSMulti-ADCsWTHER2 Family history of lung cancers among multiple maternal members; Daughter with germline G660D, and CT showed multiple GGNs in bilateral lungs at 30 (light smoker).Yamamoto, et al 2014 [48]2415MotherF74AsianNSMulti-ADCsWT MET p.N375K2516ProbandF75AsianNSADCL858RAnother sister (never-smoker) clinically diagnosed with lung cancer at 80.Tode, et al 2017 [49]2616SisterF63AsianNSADC19del2716SisterF63AsianLSADC…”

Section: Resultsmentioning

confidence: 99%

“…Their mutant proteins are more stable than the wild-type and possess an oncogenic potential by activating Akt and p38 , thus facilitating cell growth and survival [48]. MET and EGFR are mutual complements, which activate the PI3K-AKT pathway by interacting with ERBB3; therefore, the inactivation of MET by its heterozygous germline mutation could complementarily enhance the EGFR-ERBB3-PI3K axis [49]. The oncogenic stress may explain the pathogenesis of EGFR mutation in lung cancer [49].…”

Section: Discussionmentioning

confidence: 99%

“…MET and EGFR are mutual complements, which activate the PI3K-AKT pathway by interacting with ERBB3; therefore, the inactivation of MET by its heterozygous germline mutation could complementarily enhance the EGFR-ERBB3-PI3K axis [49]. The oncogenic stress may explain the pathogenesis of EGFR mutation in lung cancer [49].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…11,14 Asn375 to Lys375 replacement in MET reduced the affinity to HGF. 16 Taking these findings together, α-helix-367-375 may play a role in the association with HGF; thus, a change in orientation and/ or position of α-helix-367-375 might affect interactions between MET and HGF.…”

Section: Extracellular Domains Of Met-wt (Met-ecd-wt) and Met-v370dmentioning

confidence: 99%

“…Studies based on HGF binding, molecular modeling, and apoptosis induced by MET inhibitors indicated that the N375S mutation conferred mild resistance to MET inhibition . Recently, the N375K mutation was identified in four siblings affected by epidermal growth factor receptor (EGFR)‐mutant lung adenocarcinomas . Thus, N375 is a “hotspot” for mutations and may play an important role in the normal functions of MET receptor.…”

Section: Introductionmentioning

confidence: 99%

Impaired ligand‐dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer

et al. 2019

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Aberrant activation of the MET/hepatocyte growth factor (HGF) receptor participates in the malignant behavior of cancer cells, such as invasion‐metastasis and resistance to molecular targeted drugs. Many mutations in the MET extracellular region have been reported, but their significance is largely unknown. Here, we report the dysregulation of mutant MET originally found in a lung cancer patient with Val370 to Asp370 (V370D) replacement located in the extracellular SEMA domain. MET‐knockout cells were prepared and reconstituted with WT‐MET or V370D‐MET. HGF stimulation induced MET dimerization and biological responses in cells reconstituted with WT‐MET, but HGF did not induce MET dimerization and failed to induce biological responses in V370D‐MET cells. The V370D mutation abrogated HGF‐dependent drug resistance of lung cancer cells to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI). Compared with WT‐MET cells, V370D‐MET cells showed different activation patterns in receptor tyrosine kinases upon exposure to survival/growth‐stressed conditions. Surface plasmon resonance analysis indicated that affinity between the extracellular region of V370D‐MET and HGF was reduced compared with that for WT‐MET. Further analysis of the association between V370D‐MET and the separate domains of HGF indicated that the SP domain of HGF was unchanged, but its association with the NK4 domain of HGF was mostly lost in V370D‐MET. These results indicate that the V370D mutation in the MET receptor impairs the functional association with HGF and is therefore a loss‐of‐function mutation. This mutation may change the dependence of cancer cell growth/survival on signaling molecules, which may promote cancer cell characteristics under certain conditions.

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Germline mutations in lung cancer

Shukuya

Takahashi

2019

Respiratory Investigation

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Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor‐mutant lung cancer

Cited by 11 publications

References 20 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

Impaired ligand‐dependent MET activation caused by an extracellular SEMA domain missense mutation in lung cancer

Germline mutations in lung cancer

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