Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.

BACKGROUND: Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese. METHODS: We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis. RESULTS: 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235). CONCLUSION: Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.

Identification of MET fusions in solid tumors: A multicenter, large scale study in China.

MET amplification and exon 14 skipping are well known as oncogenic drivers in multiple cancer types. However, MET fusions in most cancer types are poorly defined. To explore the profile and analyze the characteristics of MET fusions, a large-cohort study was conducted to screen MET fusions in clinical samples (n = 10 882) using DNA-based NGS. A total of 37 potentially functional MET fusions containing the intact tyrosine kinase domain (TKD) of MET were identified in 36 samples. Further, 15 novel MET fusions were identified in five cancer types, and the incidence of novel MET fusions accounted for 40.5% (15/37). Brain cancer had the highest incidence of MET fusion, with PTPRZ1-MET as the most common fusion (37.0%). All MET breakpoints in brain cancer (n = 27) were also located in intron 1, while those in lung cancer (n = 4) occurred in intron 1, intron 11, intron 14 and exon 14, respectively. The positive consistency of the common fusion group was 100% (11/11), while that of the rare fusion group was 53.8% (7/13). In conclusion, we provided a comprehensive genomic landscape of MET rearrangement and updated the MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.

The new role of riluzole in the treatment of pancreatic cancer through the apoptosis and autophagy pathways.

Pancreatic cancer is always diagnosed at an advanced stage. Hence, chemotherapy becomes the best choice for patients. Therefore, new anticancer drugs for pancreatic cancer are needed. Riluzole (RIL) is mainly used to treat amyotrophic lateral sclerosis clinically, but many previous studies have shown that RIL could inhibit tumors. However, no report has explored the association between RIL and pancreatic cancer. To validate this association, we performed this study. Our data showed that RIL could induce cytotoxicity, block the cell cycle, and inhibit clone formation, apoptosis, and migration in pancreatic cancer cells. Moreover, we demonstrated that RIL could suppress autophagy. However, more experiments will be needed to validate the reliability of our conclusions. In summary, our data suggest that RIL might provide clues for the development of a treatment for human pancreatic cancer in the future.

Protective effect of sinomenine on isoproterenol-induced cardiac hypertrophy in mice.

To study the effect of sinomenine (Sin) on isoproterenol (Iso, ß-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, ß blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1ß levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1ß levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1ß, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.

The CDH1 -160C/A polymorphism is associated with breast cancer: evidence from a meta-analysis.

BACKGROUND: Numerous epidemiological studies have evaluated the association between the CDH1 -160C/A polymorphism and the risk of breast cancers. However, these studies have yielded conflicting results. To derive a more precise estimation of this association, this meta-analysis was conducted. METHODS: A comprehensive search using the keywords "CDH1," "E-Cadherin," "polymorphism," "SNP," and "variant" combined with "breast," "cancer," "tumor," or "carcinomas" was conducted. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were appropriately calculated using a fixed effect or random effect model. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist was used for this meta-analysis. RESULTS: Four publications including five studies were identified. It was found that the CDH1 -160C/A polymorphism was significantly associated with breast cancer risk in the dominant model (CA + AA vs. CC: OR = 1.207, 95 % CI = 1.031-1.412, P = 0.019). CONCLUSIONS: Our meta-analysis demonstrated that the -160C/A polymorphism in the CDH1 gene might contribute to breast cancer susceptibility. Further investigations using a much larger sample including different ethnicities are still needed to verify this association.

Sirtuin 1 Activator SRT1720 Protects Against Lung Injury via Reduction of Type II Alveolar Epithelial Cells Apoptosis in Emphysema.

In chronic obstructive pulmonary disease (COPD), two major pathological changes that occur are the loss of alveolar structure and airspace enlargement. Type II alveolar epithelial cells (AECII) play a vital role in maintaining alveolar homeostasis and lung tissue repair. Sirtuin 1 (SIRT1), a NAD(+)-dependent histone deacetylase, regulates many pathophysiological processes including inflammation, apoptosis, cellular senescence and stress resistance. The main aim of this study was to investigate whether SRT1720, a pharmacological SIRT1 activator, could protect against AECII apoptosis in rats with emphysema caused by cigarette smoke exposure and intratracheal lipopolysaccharide instillation in vivo. During the induction of emphysema in rats, administration of SRT1720 improved lung function including airway resistance and pulmonary dynamic compliance. SRT1720 treatment up-regulated the levels of surfactant protein (SP)A, SPC, SIRT1 and forkhead box O 3, increased SIRT1 activity, down-regulated the level of p53 and inhibited AECII apoptosis. Lung injury caused by emphysema was alleviated after SRT1720 treatment. SRT1720 could protect against AECII apoptosis in rats with emphysema and thus could be used in COPD treatment.

Expression of galectin-1 in carcinoma-associated fibroblasts promotes gastric cancer cell invasion through upregulation of integrin ß1.

Increased expression of galectin-1 (Gal-1) in carcinoma-associated fibroblasts (CAFs) has been reported to correlate with progression and prognosis in many cancers. However, rarely have reports sought to determine whether high Gal-1 expression in CAFs in gastric cancer is involved in the tumor process, and the specific mechanism by which it promotes the evolution of gastric cancer is still unknown. In this study, we cultured gastric cancer CAFs, which showed strong expression of Gal-1, and established a co-culture system of CAFs with gastric cancer cells. Specific siRNA and in vitro migration and invasion assays were used to explore the effects of the interaction between Gal-1 expression of CAFs and gastric cancer cells on cell migration and invasion. We found that the overexpression of Gal-1 in CAFs enhanced gastric cancer cell migration and invasion, and these stimulatory effects could be blocked by specific siRNA which reduced the Gal-1 expression level. A set of cancer invasion-associated genes were then chosen to identify the possible mechanism of Gal-1-induced cell invasion. Among these genes, integrin ß1 expression in cancer cells was considered to be associated with Gal-1 expression. Pre-blocking of the integrin ß1 expression in gastric cancer cells with siRNA could interrupt the invasion-promoting effect of CAFs with high Gal-1 expression. Furthermore, immunohistochemical assay confirmed a positive correlation between Gal-1 and integrin ß1 expression. Our results showed that high expression of Gal-1 in CAFs might facilitate gastric cancer cell migration and invasion by upregulating integrin ß1 expression in gastric cancer.

Therapeutic effects of amniotic fluid-derived mesenchymal stromal cells on lung injury in rats with emphysema.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), two major pathological changes that occur are the loss of alveolar structure and airspace enlargement. To treat COPD, it is crucial to repair damaged lung tissue and regenerate the lost alveoli. Type II alveolar epithelial cells (AECII) play a vital role in maintaining lung tissue repair, and amniotic fluid-derived mesenchymal stromal cells (AFMSCs) possess the characteristics of regular mesenchymal stromal cells. However, it remains untested whether transplantation of rat AFMSCs (rAFMSCs) might alleviate lung injury caused by emphysema by increasing the expression of surfactant protein (SP)A and SPC and inhibiting AECII apoptosis. METHODS: We analyzed the phenotypic characteristics, differentiation potential, and karyotype of rAFMSCs, which were isolated from pregnant Sprague-Dawley rats. Moreover, we examined the lung morphology and the expression levels of SPA and SPC in rats with emphysema after cigarette-smoke exposure and intratracheal lipopolysaccharide instillation and rAFMSC transplantation. The ability of rAFMSCs to differentiate was measured, and the apoptosis of AECII was evaluated. RESULTS: In rAFMSCs, the surface antigens CD29, CD44, CD73, CD90, CD105, and CD166 were expressed, but CD14, CD19, CD34, and CD45 were not detected; rAFMSCs also strongly expressed the mRNA of octamer-binding transcription factor 4, and the cells could be induced to differentiate into adipocytes and osteocytes. Furthermore, rAFMSC treatment up-regulated the levels of SPA, SPC, and thyroid transcription factor 1 and inhibited AECII apoptosis, and rAFMSCs appeared to be capable of differentiating into AECII-like cells. Lung injury caused by emphysema was alleviated after rAFMSC treatment. CONCLUSIONS: rAFMSCs might differentiate into AECII-like cells or induce local regeneration of the lung alveolar epithelium in vivo after transplantation and thus could be used in COPD treatment and lung regenerative therapy.

Up-regulated miR-199a-5p in gastric cancer functions as an oncogene and targets klotho.

BACKGROUND: Recent studies have shown that miR-199a-5p plays opposite roles in cancer initiation and progression of different cancer types, acting as oncogene for some cancer types but as tumor suppressor gene for others. However, the role and molecular mechanism of miR-199a-5p in gastric cancer are largely unknown. METHODS: In this study, miR-199a-5p expression level in gastric cancer was first analyzed by qPCRand then validated in 103 gastric cancer patients by in situ hybridization (ISH). Gastric cancer cell lines were transfected with miR-199a-5p inhibitor and mimic, and underwent in vitro transwell assays. Target genes (klotho) were identified using Luciferase reporter assay. Immunohistochemical staining was also used to investigate on how miR-199a-5p regulates the tumour-suppressive effects of klotho in gastric cancer. RESULTS: In our present study, we found that miR-199a-5p level was significantly increased in gastric cancer tissues compared to paired normal tissues. We observed that miR-199a-5p could promote migration and invasion of gastric cancer cells. In situ hybridization of miR-199a-5p also confirmed that higher miR-199a-5p expression level was associated with increased likelihood of lymph node metastasis and later TNM stage. Luciferase reporter assay and immunohistochemistry revealed that klotho might be the downstream target of miR-199a-5p. CONCLUSIONS: Our present study suggests that miR-199a-5p acts as an oncogene in gastric cancer and functions by targeting klotho.

Abnormal expression of miR-301a in gastric cancer associated with progression and poor prognosis.

BACKGROUND AND OBJECTIVES: miR-301a is significantly overexpressed in many cancers. However, its expression and biological role in gastric cancer remain poorly understood. We investigated microRNA-301a (miR-301a) expression in gastric cancer and determined its effects on cancer cell behavior and its clinical significance in the development and progression of gastric cancer. METHODS: We determined miR-301a expression in gastric tumors and gastric cancer cell lines by reverse transcription-polymerase chain reaction. The effects of miR-301a on cell clone formation, migration, and invasion of HGC-27 and SGC-7901 cells were detected following transfection of an miR-301a inhibitor. miR-301a expression in a 304-tissue gastric cancer microarray was determined by in situ hybridization and its role in progression and prognosis was analyzed. RESULTS: miR-301a was upregulated in gastric tumor tissues and cell lines. Down-regulation of miR-301a significantly inhibited cell clone formation, migration, and invasion of HGC-27and SGC-7901 cells. Overexpression of miR-301a in primary gastric cancer tissues was associated with tumor size, invasion depth, lymph node metastasis, and TNM stage. CONCLUSIONS: miR-301a overexpression correlated with TNM stage and prognosis, suggesting that miR-301a is involved in cellular clone formation, migration, and invasion in vitro and may play an important role in the clinical progression and prognosis of gastric cancer.

GP73 is down-regulated in gastric cancer and associated with tumor differentiation.

BACKGROUND: Golgi protein 73 (GP73) is a type II Golgi transmembrane protein. It is over-expressed in several cancers, including hepatocellular carcinomas, bile duct carcinomas, lung cancer and prostate cancer. However, there are few reports of GP73 in gastric cancer. This study is aimed at investigating the expression of GP73 and its relationship with clinical pathological characters in gastric cancer. METHODS: GP73 mRNA level was determined by quantitative real-time RT-PCR in 41 pairs of matched gastric tumorous tissues and adjacent non-tumorous mucosal tissues. Western blotting was also performed to detect the GP73 protein level. GP73 protein expression was analyzed by immunohistochemistry in 52 clinically characterized gastric cancer patients and 10 non-tumorous gastric mucosal tissue controls. RESULTS: The mRNA and protein level of GP73 were significantly down-regulated in gastric tumorous tissues compared with the non-tumorous mucosal tissues. In non-tumorous mucosa, strong diffuse cytoplasmic staining can be seen in cells located at the surface of the glandular and foveolar compartment; while in tumorous tissues, the staining was much weaker or even absent, and mainly in a semi-granular dot-like staining pattern. The expression level of GP73 protein was associated with patients' gender and tumor differentiation. CONCLUSIONS: GP73 was normally expressed in non-tumorous gastric mucosa and down-regulated in gastric cancer. Its expression in gastric cancer was correlated with tumor differentiation.

[Timing and efficacy of surgical intervention for severe acute pancreatitis].

OBJECTIVE: To explore the indications, timing and approaches of surgical interventions for severe acute pancreatitis (SAP). METHODS: A retrospective study was performed for 115 hospitalized SAP patients from 2007 to 2013. RESULTS: Among them, 62 underwent surgery and another 53 were treated conservatively. The curative and mortality rates of surgical intervention and non-operation groups were 87.1%vs 84.9% (P > 0.05) and 9.68% vs 9.43% (P > 0.05) respectively. Twenty-five patients received early surgical intervention (<2 week) and another 37 delayed surgical intervention. The interval from diagnosis to surgical intervention of two groups were 7.5 ± 3.3 and 23.9 ± 8.5 days respectively. The mortality rates of early and delayed surgical groups were 16.0% and 5.4% respectively (P > 0.05). CONCLUSIONS: Individualized comprehensive therapy should be offered in the treatment of SAP. Timing of surgery for those with pancreatic necrosis and infection should be delayed to 3-4 weeks later until their general conditions permit.

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late-onset cancers.

BACKGROUND: Pathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer-associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late-onset cancer types has not been comprehensively evaluated to date. METHODS: A total of 131 young cancer patients (1-29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late-onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head-neck cancer. Cancer PGVs were identified and analyzed. based on NGS-based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity. RESULTS: Twenty-three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all-age patients, was revealed. CONCLUSION: This study demonstrates the high prevalence of PGVs in young cancer patients with the common late-onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head-neck cancer.

Molecular characterization of genomic breakpoints of ALK rearrangements in non-small cell lung cancer.

ALK rearrangement is called the 'diamond mutation' in non-small cell lung cancer (NSCLC). Accurately identifying patients who are candidates for ALK inhibitors is a key step in making clinical treatment decisions. In this study, a total of 783 ALK rearrangement-positive NSCLC cases were identified by DNA-based next-generation sequencing (NGS), including 731 patients with EML4-ALK and 52 patients with other ALK rearrangements. Diverse genomic breakpoints of ALK rearrangements were identified. Approximately 94.4% (739/783) of the cases carried ALK rearrangements with genomic breakpoints in the introns of ALK and its partner genes, and 2.8% (21/739) of these cases resulted in frameshift transcripts of ALK. Meanwhile, 5.6% (44/783) of the ALK rearrangement-positive cases had breakpoints in the exons that would be expected to result in abnormal transcripts. RNA-based NGS was performed to analyse the aberrant fusions at the transcript level. Some of these rearranged DNAs were not transcribed, and the others were fixed by some mechanisms so that the fusion kinase proteins could be expressed. Altogether, these findings emphasize that, when using DNA-based NGS, functional RNA fusions should be confirmed in cases with uncommon/frameshift rearrangement by RNA-based assays.

Microribonucleic acids and gastric cancer.

Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Microribonucleic acids (miR) are a recently-described class of genes encoding small non-coding RNA molecules, which primarily act by downregulating the translation of target mRNA. It has become apparent that miR are also key factors in cancer, playing both oncogenic and tumor-suppressing roles in gastric cancer. Recent studies have shown that a substantial number of miR show differential expression in gastric cancer tissues, and they are turning out to be just like any other regulatory gene. In this connection, miR dysregulation are reported to be associated with incidence, early diagnosis and prognosis of gastric cancer. Therefore, investigation of the biological aspects of miR dysregulation might help us better understand the pathogenesis of gastric cancer and promote the development of miR-directed therapeutics against this deadly disease. The aim of the present review was to describe the mechanisms of several known miR, summarize recent studies on oncogenic miR (e.g. miR-21, miR-106a and miR-17), tumor suppressor miR (e.g. miR-101, miR-181, miR-449, miR-486, let-7a) and controversial roles of miR (e.g. miR-107, miR-126) for gastric cancer. In addition, their potential clinical applications and prospects in gastric cancer, such as biomarkers and clinical therapy tools, are also briefly discussed.

REG4 contributes to the invasiveness of pancreatic cancer by upregulating MMP-7 and MMP-9.

Recent studies have shown that overexpression of regenerating gene family member 4 (REG4) is associated with the initiation and progression of pancreatic cancer. In our study, we explored the role of REG4 in the invasion of pancreatic cancer. Real-time PCR and Western blot analysis were used to determine REG4 expression in pancreatic cancer cell lines. An MTT assay was carried out to test the effect of REG4 on the growth of pancreatic cancer cells. The involvement of REG4 in cancer cell invasion was examined by Transwell invasion assay. Two MMPs, MMP-7 and MMP-9, were identified from a pool of candidate genes as being related to REG4-induced cell invasion by PCR and Western blotting. Immunohistochemistry was used to confirm the correlation between REG4 and the two MMPs. High expression of REG4 was found in BXPC-3 cells and its culture media. But in PANC-1 and ASPC-1 cell lines, REG4 expression levels were very low, and no detectable protein was found in the culture medium. The MTT and Transwell invasion assays showed that recombinant REG4 protein and BXPC-3 conditioned media significantly promoted the proliferation and invasiveness of pancreatic cancer cells. It was also shown that MMP-7 and MMP-9 are upregulated by REG4 induction using real-time PCR and Western blotting analysis. Immunohistochemical study further verified this result. In conclusion, REG4 promotes not only growth but also in vitro invasiveness of pancreatic cancer cells by upregulating MMP-7 and MMP-9.

The role of NLRP3 inflammasome in digestive system malignancy.

Digestive system malignancies, the most common types of cancer and a major cause of death in the worldwide, are generally characterized by high morbidity, insidious symptoms and poor prognosis. NLRP3 inflammasome, the most studied inflammasome member, is considered to be crucial in tumorigenesis. In this paper, we reviewed its pro-tumorigenic and anti-tumorigenic properties in different types of digestive system malignancy depending on the types of cells, tissues and organs involved, which would provide promising avenue for exploring new anti-cancer therapies.

PBRM1 presents a potential prognostic marker and therapeutic target in duodenal papillary carcinoma.

BACKGROUND: Due to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided. METHODS: Whole-exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA-seq, ATAC-seq and in vitro cell function experiments were performed to confirm the underlying mechanisms. RESULTS: We described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1-inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial-to-mesenchymal transition via the PBRM1-c-JUN-VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c-JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU-80 cells was sensitive to radiation, which may be due to the suppression of c-JUN by irradiation. CONCLUSIONS: Our findings define a novel molecular subgroup of PBRM1-inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.

Genomic and Transcriptional Profiling of Chinese Melanoma Patients Enhanced Potentially Druggable Targets: A Multicenter Study.

BACKGROUND: In contrast to Caucasian melanoma, which has been extensively studied, there are few studies on melanoma in Asian populations. Sporadic studies reported that only 40% of Asian melanoma patients could be druggable, which was much lower than that in Caucasians. More studies are required to refine this conclusion. METHODS: Chinese melanoma patients (n = 469) were sequentially sequenced by DNA-NGS and RNA-NGS. The genomic alterations were determined, and potentially actionable targets were investigated. RESULTS: Patients with potential druggable targets were identified in 75% of Chinese melanoma patients by DNA-NGS based on OncoKB, which was much higher than in a previous Asian study. NRG1 fusions were first identified in melanoma. In addition, up to 11.7% (7/60) of patients in the undruggable group could be recognized as actionable by including RNA-NGS analysis. By comparing the fusion detection rate between DNA-NGS and RNA-NGS, all available samples after DNA-NGS detection were further verified by RNA-NGS. The use of RNA-NGS enhanced the proportion of druggable fusions from 2.56% to 17.27%. In total, the use of RNA-NGS increased the druggable proportion from 75% to 78%. CONCLUSIONS: In this study, we systemically analyzed the actionable landscape of melanoma in the largest Asian cohort. In addition, we first demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more patients with melanoma.