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Non-amplification genetic alterations of HER2 gene in non-small cell lung carcinoma
  1. Anurag Mehta1,
  2. Shrinidhi Nathany2,
  3. Rupal Tripathi3,
  4. Sanjeev Kumar Sharma2,
  5. Mumtaz Saifi2,
  6. Ullas Batra4
  1. 1 Deapartment of Laboratory Medicine, Transfusion Services and Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
  2. 2 Section of Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
  3. 3 Department of Research, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
  4. 4 Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Delhi, India
  1. Correspondence to Dr Anurag Mehta, Rajiv Gandhi Cancer Institute and Research Centre, Delhi 110085, India; anumehta11{at}


Aims The present study investigated the incidence and spectrum of human epidermal growth factor receptor 2 (HER2) mutations, associated clinicopathological characteristics and the co-occurrence of HER2 gene amplification in the HER2 gene mutated cases in non-small cell lung cancer (NSCLC).

Methods All patients with advanced lung adenocarcinoma (LUAD) who underwent broad genomic profiling by next generation sequencing (NGS) from 2015 to 2019 were included in the study. HER2 gene amplification was checked in all the HER2 gene mutated cases. Tumour tissues of all the mutated cases were examined by fluorescent in situ hybridisation (FISH).

Results Fifty-four (37.2%) out of the 145 cases harboured tier 1 driver mutations comprising EGFR in 22.1%, ALK rearrangements in 7.6% cases, ROS1 rearrangements and BRAF V600E in 3.5% cases each, and NTRK fusion in 0.7% cases. Nine (6.2%) cases exhibited a significant genetic alteration in HER2 gene (tiers 2 and 3) on NGS. The most common alteration was exon 20 insertion of amino acid sequence AYVM in five cases (p.E770_A771insAYVM) followed by insertion of YVMA (p.A771_Y772insYVMA) in one case, insGSP (p.V777_G778insGSP) in one case and two missense mutations: p.G776C and p.QA795C (novel variant). The median copy number of the HER2 gene was 3.21 while on FISH, the median HER2/CEP17 ratio was 2.0.

Conclusions There is a relatively higher occurrence of HER2 exon 20 mutations as primary oncogenic driver in NSCLC especially LUAD. Our cohort has demonstrated (p.E770_A771insAYVM) as the strikingly dominant insertion mutation against the most often globally reported (p.A771_Y772insYVMA).

  • pathology, molecular
  • lung neoplasms
  • pathology department, hospital

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  • Handling editor Runjan Chetty.

  • Contributors On behalf of all the contributors, AM will act and guarantor and will correspond with the journal this point onward. This manuscript is original research work, and all authors have seen and agreed to the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Review Board of the Hospital (vide letter no. 748/RE/AMH-36).

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.