Novel HER2 mutation identified in familial lung adenocarcinomas

Researchers have identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene in familial lung adenocarcinomas.

And further research in a larger group of patients also suggests that somatic mutations in this same domain may lead to sporadic lung adenocarcinomas.

The team, led by Shinichi Toyooka (Okoyama University Graduate School of Medicine, Japan), identified a family of Japanese descent in which multiple members had developed lung cancer, which appeared to be inherited in an autosomal dominant manner.

The proband was a 53-year-old woman, and light smoker, with multiple lung adenocarcinomas in both lungs who had previously undergone a left lower lobectomy for multiple lung adenocarcinomas. Her mother, a never smoker, also had multiple lung adenocarcinomas.

Sequencing showed no genetic alterations in EGFR exons 18 to 21 or KRAS, and immunohistochemical staining for ALK protein in resected tumors was negative.

Through a whole-exome sequencing study including the proband, her mother, and two unaffected family members, the researchers identified a point mutation (G660D) in the HER2/neu gene in exon 17, encoding the transmembrane domain. This germline alteration was confirmed by direct sequencing.

To extend their findings, the research team sequenced exon 17 of HER2 in tumor samples, 253 of which were adenocarcinomas, from 315 sporadic non-small-cell lung cancer patients. They did not detect the same G660D mutation identified in the familial study, but one patient with no smoking history or family history of lung cancer had a novel mutation, V659E, next to codon 660. They confirmed that this was a somatic mutation as it was not found in the peritumoral tissue.

HER2 somatic mutations have been reported in 2% to 4% of lung adenocarcinomas,” comment Toyooka et al. “However, all reported mutations were restricted to its tyrosine kinase domain.”

Noting several previous studies indicating that mutations in the transmembrane domain are associated with the stability of HER2 dimers, Toyooka and team analyzed the degradation of HER2 proteins on administration of cyclohexamide. They found that G660D and V659E mutants degraded slower than wild-type HER2, suggesting increased stability of the mutant proteins.

Additionally, the team found that both G660D and V659E mutants activated Akt and p38.

Writing in the Journal of the National Cancer Institute, Toyooka and colleagues note that their findings will need to be confirmed in other models, such as transgenic mice.

Nevertheless, the team concludes that the results “strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.”

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