Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB’s role in oncogenesis

Abstract

Introduction Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Materials and Methods Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed, and cellular proliferation, pAkt/Akt, and pERK levels determined. Results A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. Conclusions This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.

Targeting the EGF receptor family in non-small cell lung cancer—increased complexity and future perspectives

“…Additionally, LUX-Lung 8, which included patients with stage IIIB/IV lung squamous cell carcinoma progressing after platinum-based chemotherapy, has reported a trend toward better PFS [HR = 0.52 (0.16–1.72)] for patients with ERBB3 mutations treated with afatinib rather than erlotinib; however, the number of patients in this subgroup was small ( n = 15), and other treatment comparators were lacking 160 . ERBB3 mutations affecting the germline are also involved in the pathogenesis of familial NSCLC ( ERBB3 mutation c.1946 T>G: p.Iso649Arg) 162 and are considered an important mediator of immune escape in gallbladder cancer 163 . Despite the apparent effects of HER3 mutations on lung cancer biology, no large-scale clinical trials have been conducted to validate a specific treatment strategy for ERBB3 -mutant lung tumors, in contrast to activating EGFR mutations.…”

HER3 Alterations in Cancer and Potential Clinical Implications

“…It was previously established that HER3 germline mutations could potentially lead to familial cancer predisposition, particularly in erythroid MDS/erythroleukemia, but this also translates to other forms of cancer [ 121 ]. McInerney-Leo et al published a case study investigating the role of a germline HER3 mutation in hereditary lung adenocarcinoma [ 122 ]. Tumors from different members of a family were sequenced and found to be heterozygous for the same HER3 I649R mutation.…”