Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma

Tian, Yingying; Zhao, Jiuzhou; Ren, Pengfei; Wang, Bo; Zhao, Chengzhi; Shi, Chao; Wei, Bing; Ma, Jie; Guo, Yongjun

doi:10.1371/journal.pone.0201682

Cited by 14 publications

(6 citation statements)

References 27 publications

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“…The EGFR gene contains 28 exons. Of these 28 exons, exon 19 is of particular interest in evaluation of structural variation and its potential impact on genome instability [56]. The exon 19 canonical deletion is only 15 bp but gives rise to one of the most common cancer-driver mutations in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

et al. 2020

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Structural variation (SV) is typically defined as variation within the human genome that exceeds 50 base pairs (bp). SV may be copy number neutral or it may involve duplications, deletions, and complex rearrangements. Recent studies have shown SV to be associated with many human diseases. However, studies of SV have been challenging due to technological constraints. With the advent of third generation (long-read) sequencing technology, exploration of longer stretches of DNA not easily examined previously has been made possible. In the present study, we utilized third generation (long-read) sequencing techniques to examine SV in the EGFR landscape of four haplotypes derived from two human samples. We analyzed the EGFR gene and its landscape (+/-500,000 base pairs) using this approach and were able to identify a region of non-coding DNA with over 90% similarity to the most common activating EGFR mutation in non-small cell lung cancer. Based on previously published Alu-element genome instability algorithms, we propose a molecular mechanism to explain how this non-coding region of DNA may be interacting with and impacting the stability of the EGFR gene and potentially generating this cancer-driver gene. By these techniques, we were also able to identify previously hidden structural variation in the four haplotypes and in the human reference genome (hg38). We applied previously published algorithms to compare the relative stabilities of these five different EGFR gene landscape haplotypes to estimate their relative potentials to generate the EGFR exon 19, 15 bp canonical deletion. To our knowledge, the present study is the first to use the differences in genomic architecture between targeted cancer-linked phased haplotypes to estimate their relative potentials to form a common cancer-linked driver mutation.

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Section: Discussionmentioning

confidence: 99%

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

et al. 2020

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“…The most common mutations within EGFR are the deletion of amino acids at 747–750 of exon 19 (19Del) and L858R of exon 21, discovered in 33.1% and 40.9% of the patient population, respectively. 12 …”

Section: Introductionmentioning

confidence: 99%

“…The most common mutations within EGFR are the deletion of amino acids at 747-750 of exon 19 (19Del) and L858R of exon 21, discovered in 33.1% and 40.9% of the patient population, respectively. 12 Multiple TKIs have shown activity in EGFR mutation positive NSCLC. The agents are categorized as first generation reversible agents (gefitinib, icotinib and erlotinib), second generation irreversible agents (afatinib and dacomitinib) and third generation agents with activity against secondary resistance mutation (osimertinib) and are summarized in Table 1.…”

Section: Introductionmentioning

confidence: 99%

Osimertinib in EGFR-Mutated Lung Cancer: A Review of the Existing and Emerging Clinical Data

Lee

Milone

Seetharamu

2021

OTT

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The use of epidermal growth factor receptor ( EGFR ) inhibitors such as osimertinib has improved outcomes and quality of life for patients with EGFR -mutated non-small cell lung cancer (NSCLC). Osimertinib has become the preferred EGFR tyrosine kinase inhibitor (TKIs) for patients with these mutations after demonstrating superior efficacy compared to first generation EGFR TKIs, such as erlotinib and gefitinib. More recently osimertinib has also shown to be beneficial in patients with resectable NSCLC harboring EGFR mutations irrespective of whether they received adjuvant chemotherapy or not. The drug is now FDA approved in this setting. With osimertinib being used more commonly in earlier stage and front-line settings, we are more likely to see patients who develop resistance to this drug. The aim of this review is to provide a comprehensive review of the data with osimertinib in EGFR mutation positive NSCLC, potential resistance mechanisms and an overview of key ongoing clinical trials.

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“…Insertions (ins) or deletions (indels) have been understudied, though they are the second most abundant source of human genetic variation. Selected indels have been identified as playing a key role in causing LC, such as p.E746_A750del in EGFR 14 – 16 .…”

Section: Introductionmentioning

confidence: 99%

Rare deleterious germline variants and risk of lung cancer

et al. 2021

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Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04–75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71–8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3′ UTR (OR 4.33, 95%CI 2.03–9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73–11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33–5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.

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Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma

Cited by 14 publications

References 27 publications

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

Osimertinib in EGFR-Mutated Lung Cancer: A Review of the Existing and Emerging Clinical Data

Rare deleterious germline variants and risk of lung cancer

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