ABSTRACT
INTRODUCTION: Neuregulin 1 (NRG1) gene fusion was detected in a wide range of carcinomas. It is most frequently present in lung adenocarcinomas, especially in KRAS and BRAF wild-type cases. PURPOSE: We present a newly described diverse group of NRG1 rearranged carcinomas. The paper explains basic molecular principles associated with this oncogenic driver. It consists of ERBB3 (HER3) and ERBB2 (HER2) receptor activation with downstream activation of PIK and MAPK canonical pathways. The experience with new therapeutic modalities is summarized. CONCLUSIONS: So far, the global results of cytotoxic, immune and targeted therapies were dis-appointing. Further research (including two studies in Europe) is underway, developing new therapeutic strategies and examining this cancer bio-logy. In the meantime, it is possible to dia-gnose NRG1 rearranged carcinomas in the Czech Republic since mRNA next generation sequencing (NGS) analysis is readily available.
Subject(s)
Neoplasms , Neuregulin-1 , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/metabolism , Antineoplastic Agents/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Neuregulin-1/genetics , Neuregulin-1/metabolism , Precision Medicine , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolismABSTRACT
Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.
