Non-amplification genetic alterations of HER2 gene in non-small cell lung carcinoma

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).

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).

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.

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).