Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment.
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【中文题目：罕见CRISPLD2-NRG1融合突变晚期混合型非小细胞肺癌1例并文献复习】 【中文摘要：肺癌是中国发病率和死亡率最高的恶性肿瘤。非小细胞肺癌（non-small cell lung cancer, NSCLC）占全部肺癌的80%以上，NSCLC的基因突变概率高，并且种类繁多。随着基因检测技术的进步，越来越多的罕见融合基因变异被检测出来。神经调节蛋白1（neuregulin 1, NRG1）可促使人表皮生长因子受体3（human epidermal growth factor receptor 3, Her3/ErbB3）介导的通路激活，从而导致肿瘤形成。本文报道了1例罕见CRISPLD2-NRG1融合突变的晚期混合型NSCLC颅内转移的患者，接受阿法替尼治疗1个月后头部磁共振成像（magnetic resonance imaging, MRI）显示颅内病灶明显缩小，患者对阿法替尼治疗反应良好。同时，我们对以往报道的NRG1基因融合突变的NSCLC病例进行总结，以供临床借鉴。
】 【中文关键词：肺肿瘤；阿法替尼；CRISPLD2-NRG1融合突变】.

OBJECTIVE: Moyamoya disease (MMD) is a rare and progressive stenosis of cerebral arteries characterized by abnormally proliferative vasculopathy. Current studies have demonstrated that Neuregulin 1 (NRG1) plays a key role in angiogenesis-related disorders. Thus, the aim of our study is to investigate the serum NRG1 levels and their clinical correlations in MMD patients.
METHODS: In this study, thirty adult patients with MMD and age-gender matched healthy controls were enrolled from our hospital between July 2020 and April 2022. Peripheral blood samples were collected at baseline, and clinical data were obtained from the electronic medical record system. Serum NRG1 concentrations were measured by enzyme-linked immunosorbent assay. Sanger sequencing was applied to detect the RNF213 p.R4810K mutation.
RESULTS: The serum NRG1 levels were significantly higher in MMD patients compared to controls (14.48 ± 10.81 vs.7.54 ± 6.35mmol/L, p < 0.001). No statistical difference in baseline clinical characteristics was found between both groups. Correlation analyses showed that NRG1 levels were positively associated with Suzuki staging (r = 0.4137, p = 0.023) while not related to other clinical features (reduced cerebral blood flow, posterior cerebral artery involvement, bilateral or unilateral steno-occlusive changes). Furthermore, subgroup analysis revealed that MMD patients with the RNF213 p.R4810K mutation presented with significantly higher NRG1 levels than those without the mutation (9.60 ± 0.929 vs. 25.89 ± 4.338 mmol/L, p = 0.001).
CONCLUSIONS: Our study suggests that increased serum NRG1 levels may constitute a characteristic feature of MMD, indicating a potential positive correlation with disease progression and the presence of the RNF213 mutation. This positions NRG1 as a potentially crucial target for further studies aimed at comprehending the pathogenesis of MMD.

No definite biomarker linking depression and obesity has been found yet. Our study aimed to investigate neuregulin-1 (NRG-1) as a potential blood biomarker for this association.
A case-control study was conducted on 108 obese subjects assigned for laparoscopic sleeve gastrectomy and 100 non-obese controls. Depression was assessed pre- and post-operatively. Serum NRG-1 was measured.
Pre-operatively depression was significantly higher among obese compared to non-obese patients. After the operation, 1.9% of the severely depressed subjects reported no depression, while 5.6% became moderately depressed; about 6% of the moderately depressed and 16% of the mildly depressed became not depressed. Serum NRG-1 level was significantly lower among obese and severely depressed compared to the controls. It was negatively correlated to the level of depression pre- and post-operative (r = -0.764 and -0.467 respectively). The sensitivity of serum NRG1 as a predictor for depression pre- and post-operative was 92.45% and 52.94% respectively. Specificity was 69.09% and 79.73% respectively at cut-off values of ≤ 3.5 and ≤ 2.5 ng/ml.
NRG-1 is a possible biomarker for the diagnosis of depression pre-bariatric surgery and the prediction of its prognosis post-operatively.

BACKGROUND: NRG1 fusions are rare oncogenic drivers in solid tumors, and the incidence of NRG1 fusions in non-small cell lung cancer (NSCLC) was 0.26%. It is essential to explore potential therapeutic strategies and efficacy predictors for NRG1 fusion-positive cancers.
METHODS: We report an advanced lung adenocarcinoma patient harboring a novel NPTN-NRG1 fusion identified by RNA-based next-generation sequencing (NGS), which was not detected by DNA-based NGS at initial diagnosis. Transcriptomics data of the tissue biopsy showed NRG1α isoform accounted for 30% of total NRG1 reads, and NRG1β isoform was undetectable. The patient received afatinib as fourth-line treatment and received a progression-free survival (PFS) of 14 months.
CONCLUSIONS: This report supports afatinib can provide potential benefit for NRG1 fusion patients, and RNA-based NGS is an accurate and cost-effective strategy for fusion detection and isoform identification.

Neuregulin 1 (NRG1) gene fusion is a rare oncogenic driver gene in multiple tumor types, leading to the activation of the epidermal growth factor receptor (ErbB)-mediated pathway. Therefore, afatinib, a pan-ErbB family inhibitor, may be a therapeutic candidate for NRG1 fusion-driven tumors. In this case, we report a multiple primary lung adenocarcinoma patient harboring the CD74-NRG1 fusion, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (ERBB2) mutation simultaneously. The patient received afatinib and pyrotinib combination therapy and showed a significant treatment response with a progression-free survival of 5 months. Our case further supports the use of targeted therapy for NRG1 fusion-positive non-small-cell lung cancer.

Neuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.
This report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.
The six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.
This report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.
NRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

UNASSIGNED: Genomic and transcriptomic studies in plants and, more in deep, in grapevine reveal that the disease-resistance RNL gene family is highly variable. RNLs (RPW8-NLRs) are a phylogenetically distinct class of nucleotide oligomerization domain (NOD)-like receptors (NLRs) identified in plants. Two RNLs, namely, the NRG1 (N Requirement Gene 1) and the ADR1 (Activated Disease Resistance 1), have been characterized; however, little is known about the RNL evolutionary history in higher plants. To trace the diversification of RNL gene subfamily, we scanned the NLR proteins of 73 plant genomes belonging to 29 taxa, revealing a noticeable diversification across species and within the same genus or botanic family together with a conspicuous expansion in important crop species. To explore the RNL variability in Vitis vinifera and gain information with respect to their structure, evolutionary diversification of five grape genomes (\'Aglianico\', \'Falanghina\', \'Sultanina\', \'Tannat\', and \'Nebbiolo\') has been compared to the reference genome (\'Pinot Noir\'). The number of RNLs ranged from 6 (\'Sultanina\') to 14 (\'Nebbiolo\'), in contrast to the 10 \'Pinot Noir\' RNLs. The phylogenetic study on grapevine RNLs revealed that all collapsed into NRG1-clade, rather than four. To investigate more in depth the means of intraspecific variability of grape RNL copies, a transcriptomic profiling in response to powdery mildew (PM) infection was carried out through qRT-PCRs and public databases interrogation. The RNL expression variability identified in transcriptome data sets supports the hypothesis of a functional expansion/contraction in grapevine varieties. Although no direct correlations between grapevine PM-resistance and RNL expression was identified, our work can provide good candidates for functional studies able to elucidate the putative \"helper\" role of RNLs in grape immune signalling.

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An 85-year-old woman with a history of several primary lung cancers presented with liver metastases. The primary lung cancers were all managed surgically and the patient did not receive adjuvant or neoadjuvant therapy prior to presenting with metastases. Comparison of molecular testing results from the most recent primary and the liver metastases demonstrated ( a) a clonal relationship between the 2 cancers and ( 2) the presence of a KIF13B-NRG1 fusion and KRAS amplification unique to the metastases. When integrated, the molecular surgical pathology findings in this case illustrate the extent of \"oncogenic drive\" in preterminal lung cancer.

Several new chromosomal translocations resulting in driver fusion mutations have recently been discovered in non-small-cell lung cancer. The driver mutational patterns in pulmonary mucinous adenocarcinoma, a rare subtype of non-small-cell lung cancer, have not been well studied. A single-institute cohort study in Taiwan was performed to determine the mutations of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), fusions of anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), and neuregulin 1 (NRG1) in patients diagnosed with pulmonary mucinous adenocarcinoma. We also examined NRG1 translocation in patients diagnosed as adenocarcinoma of other subtypes with wild-type EGFR, KRAS, ALK, and ROS1 genes. Surgical or biopsy specimens were collected from 13 patients with mucinous adenocarcinoma. Using the direct RNA sequencing method, we discovered a rare CD74-NRG1 fusion (8 %), an echinoderm microtubule-associated protein like 4 (EML4)-ALK fusion (17 %), and three KRAS mutations (25 %). No EGFR mutations or ROS1 rearrangements were detected. The rare CD74-NRG1 fusion positive patient presented with uncommon radiological features. We did not detect any CD74-NRG1 fusion in the 109 adenocarcinoma of other subtypes, which were all negative for EGFR, KRAS, ALK, and ROS1. The CD74-NRG1 fusion mutation is rare and may be exclusively present in patients with pulmonary mucinous adenocarcinoma. Patients harboring CD74-NRG1 positive tumors may present with uncommon imaging features.