Predisposition to Lung Adenocarcinoma in a Family Harboring the Germline <i>EGFR</i> V843I Mutation

Ohtsuka, Kouki; Ohnìshì, H.; Fujiwara, Masachika; Morii, Takeshi; Matsushima, Satsuki; Ogura, Wataru; Yamasaki, Satoko; Kishino, Tomonori; Tanaka, Ryota; Watanabe, Takashi

doi:10.1200/po.19.00104

Cited by 4 publications

(3 citation statements)

References 13 publications

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“…We only found 3 NSCLC patients harboring the V843I mutation among 30,454 patients (12,13). However, previous studies have demonstrated that the EGFR V843I mutation contributes to tumorigenesis and provides resistance to EGFR-TKIs via structural modifications of EGFR comparable to those in the context of the EGFR T790M mutation (14,15). Here, we present a patient diagnosed with stage IV NSCLC with an EGFR L858R/V843I mutation complex who benefited remarkably from osimertinib therapy.…”

Section: Case Reportmentioning

confidence: 85%

A non-small cell lung cancer (NSCLC) patient harboring a rare epidermal growth factor receptor (EGFR) L858R/V843I mutation complex benefited from osimertinib: a case report

Zhou¹,

Qi²,

Wang³

et al. 2022

Ann Palliat Med

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Tyrosine kinase inhibitors (TKIs) have greatly improved the survival of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-TKI sensitive mutations such as L858R and exon 19 deletions. The third-generation EGFR-TKI osimertinib, an irreversible TKI, is approved as a therapy for advanced NSCLC with EGFR sensitive mutations. Recently, osimertinib showed antitumor activity against NSCLC in patients harboring an uncommon mutation such as an exon 20 insertion. Herein, we present a patient diagnosed with stage IV NSCLC with an EGFR L858R/V843I mutation complex who benefited remarkably from osimertinib therapy. The patient was a 41-year-old Chinese female who complained of backache in October 2018. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a mass in the right lung and brain metastasis. A whole-body bone scan revealed bone metastases. Targeted next-generation sequencing (NGS) of hydrothorax was performed and the coexistence of somatic L858RI and V843I mutations in EGFR exon 21 was discovered on November 13, 2018. Osimertinib therapy (80 mg daily) was administered for 12 months which resulted in an initial partial response (PR). At that point, the right lower lung lesion enlarged, indicating disease progression.Thus, the patient began combination therapy with osimertinib (80 mg daily) and bevacizumab (500 mg daily), leading to disease stabilisation until June 2020. Of note, during treatment, the patient achieved sustained control of metastatic brain and bone lesions. To the best of our knowledge, we report here the first known case of an NSCLC patient with a somatic EGFR L858R/V843I mutation complex who responded well to osimertinib. Our findings provide theoretical guidance and expand the list of potential beneficiaries of EGFR-TKI therapy.

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Section: Case Reportmentioning

confidence: 85%

A non-small cell lung cancer (NSCLC) patient harboring a rare epidermal growth factor receptor (EGFR) L858R/V843I mutation complex benefited from osimertinib: a case report

Zhou¹,

Qi²,

Wang³

et al. 2022

Ann Palliat Med

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“…It is well known that, in cancer, somatic mutations in EGFR lead to its constant activation with the result of an uncontrolled cell division [114]. On the opposite, germline EGFR missense variants, such as T790M, V834L and V843I, have been associated with rare cases of familial lung adenocarcinoma [115][116][117][118][119][120][121]. Additionally, a germline loss of function variant, affecting the extracellular domain of EGFR, has been described, but it was associated with a severe and lethal form of epithelial inflammation [122,123].…”

Section: Discussionmentioning

confidence: 99%

Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients

et al. 2020

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Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.

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“…Other EGFR germline variants located in the tyrosine kinase domain have been reported in lung cancer patients, although their role as susceptibility variants could not always be firmly established in the absence of evidence of pathogenicity or co-segregation within the family. Among those, V834L and V843I can be confidently associated with susceptibility to lung adenocarcinoma [31][32][33]. Indeed, they co-segregated with the disease within families and/or were identified by multiple research teams in distinct families.…”

Section: Egfr-associated Genetic Susceptibilitymentioning

confidence: 99%

Lung cancer is also a hereditary disease

et al. 2021

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Pathogenic genetic variants (formerly called mutations) present in the germline of some individuals are associated with a clinically relevant increased risk of developing lung cancer. These germline pathogenic variants are hereditary and are transmitted in an autosomal dominant fashion. There are two major lung cancer susceptibility syndromes, and both seem to be specifically associated with the adenocarcinoma subtype. Li-Fraumeni syndrome is caused by variants in the TP53 tumour-suppressor gene. Carriers are mainly at risk of early-onset breast cancer, sarcoma, glioma, leukaemia, adrenal cortical carcinoma and lung cancer. EGFR variants, T790M in particular, cause the EGFR susceptibility syndrome. Risk seems limited to lung cancer. Emerging data suggest that variants in ATM, the breast and pancreatic cancer susceptibility gene, also increase lung adenocarcinoma risk. As for inherited lung disease, cancer risk is increased in SFTPA1 and SFTPA2 variant carriers independently of the underlying fibrosis. In this review, we provide criteria warranting the referral of a lung cancer patient to the cancer genetics clinic. Pathogenic variants are first identified in patients with cancer, and then in a subset of their relatives. Lung cancer screening should be offered to asymptomatic carriers, with thoracic magnetic resonance imaging at its core.

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Predisposition to Lung Adenocarcinoma in a Family Harboring the Germline EGFR V843I Mutation

Cited by 4 publications

References 13 publications

A non-small cell lung cancer (NSCLC) patient harboring a rare epidermal growth factor receptor (EGFR) L858R/V843I mutation complex benefited from osimertinib: a case report

A non-small cell lung cancer (NSCLC) patient harboring a rare epidermal growth factor receptor (EGFR) L858R/V843I mutation complex benefited from osimertinib: a case report

Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients

Lung cancer is also a hereditary disease

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