BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-d...BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.展开更多
BACKGROUND Pulmonary mucoepidermoid carcinoma(PMEC)is a rare malignancy that arises from minor salivary glands within the tracheobronchial tree.The clear cell variant of PMEC is exceptionally uncommon and presents not...BACKGROUND Pulmonary mucoepidermoid carcinoma(PMEC)is a rare malignancy that arises from minor salivary glands within the tracheobronchial tree.The clear cell variant of PMEC is exceptionally uncommon and presents notable diagnostic challenges,primarily attributable to its morphological similarity to other tumors containing clear cells.CASE SUMMARY A 22-year-old male,formerly in good health,came in with a two-month duration of persistent cough and production of sputum.Subsequent imaging and bronchoscopy examinations revealed a 2 cm tumor in the distal left main bronchus,which resulted in complete atelectasis of the left lung.Further assessment via positron emission tomography/computed tomography scans and endoscopic biopsy confirmed the primary malignant nature of the tumor,charac-terized by clear cell morphology in most of the tumor cells.The patient underwent a left lower lobe sleeve resection accompanied by systematic mediastinal lymph node dissection.Molecular pathology analysis subsequently revealed a CRTC3-MAML2 gene fusion,leading to a definitive pathological diagnosis of the clear cell variant of PMEC,staged as T2N0M0.After surgery,the patient experienced a smooth recovery and exhibited no signs of recurrence during the one-and-a-half-year follow-up period.CONCLUSION This article describes an unusual case of a clear cell variant of PMEC characterized by the presence of a CRTC3-MAML2 gene fusion in a 22-year-old male.The patient underwent successful left lower lobe sleeve resection.This case underscores the distinctive challenges associated with diagnosing and treating this uncommon malignancy,underscoring the importance of precise diagnosis and personalized treatment strategies.展开更多
BACKGROUND Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death.In recent decades,increasing application of next-generation sequencing has enabled detecti...BACKGROUND Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death.In recent decades,increasing application of next-generation sequencing has enabled detection of molecular aberrations,including fusions.In cases where tissue is difficult to obtain,cell-free DNA(cfDNA)is used for detecting mutations to identify the molecular profile of cancer.Here,we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer.CASE SUMMARY A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel,but ascites was detected.The therapy was switched to nivolumab,but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020.Therapy was discontinued,and cfDNA nextgeneration sequencing was immediately evaluated.All genomic variants,including fusions,were analyzed from cfDNA.The following somatic alterations were detected from the patient’s cfDNA:an APC frameshift mutation(NM_000038.5:c.6579del,p.V2194fs)with variant allele frequency of 0.5%,an EGFR amplification with a copy number of 17.3,and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%.The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14.The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest thatEGFR-targeted therapies be tried in such future cases.CONCLUSIONThe expanded applications of the cfDNA assay may open a new horizon intreatment of patients with advanced gastric cancer.展开更多
Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served a...Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.展开更多
BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with...BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis.Herein,we report the successful treatment of relapsed acute promyelocytic leukemia(APL)in a patient on hemodialysis with ATO single agent and review the cases in literature.CASE SUMMARY A 46-year-old woman who has been on hemodialysis to chronic glomerulonephritis for 15 years visited our hospital for pancytopenia.She had been seen for pancytopenia 3 years ago and had been diagnosed with APL.She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy.She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago.Bone marrow biopsy and reverse transcriptase-polymerase chain reaction(RT-PCR)tests revealed a diagnosis of relapsed APL.Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO.Thus far,four consolidation therapies have been performed with the ATO single agent,and,to date,the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-αfusion gene as confirmed by RTPCR testing for two years.CONCLUSION This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.展开更多
BACKGROUND Fine-needle biopsy is an accurate and cost-efficient tool for the assessment of thyroid nodules.It includes two primary methods:Fine-needle capillary biopsy(FNCB)and fine-needle aspiration biopsy.Needle tra...BACKGROUND Fine-needle biopsy is an accurate and cost-efficient tool for the assessment of thyroid nodules.It includes two primary methods:Fine-needle capillary biopsy(FNCB)and fine-needle aspiration biopsy.Needle tract seeding(NTS)is a rare complication of thyroid fine-needle biopsy mainly caused by fine-needle aspiration biopsy rather than FNCB.Here,we present an extremely rare case of a papillary thyroid carcinoma(PTC)patient with FNCB-derived NTS.CASE SUMMARY We report a 32-year-old woman with PTC who showed subcutaneous NTS 1 year after FNCB and thyroidectomy.NTS was diagnosed based on clinical manifestations,biochemistry indices,and imaging(computed tomography and ultrasound).Pathological identification of PTC metastases consistent with the puncture path is the gold standard for diagnosis.Surgical resection was the main method used to treat the disease.After surgery,thyroid function tests and ultrasound scans were performed every 3-6 mo.To date,no evidence of tumor recurrence has been observed.CONCLUSION FNCB is a safe procedure as NTS is rare,and can be easily removed surgically with no recurrence.Accordingly,NTS should not limit the usefulness of FNCB.展开更多
BACKGROUND Chronic myeloid leukemia(CML)is a malignant hematologic malignancy that can progress to blast phase with a myeloid or lymphoid phenotype.Some patients with CML can also progress to blast crisis phase;howeve...BACKGROUND Chronic myeloid leukemia(CML)is a malignant hematologic malignancy that can progress to blast phase with a myeloid or lymphoid phenotype.Some patients with CML can also progress to blast crisis phase;however,the transformation of CML into Philadelphia-positive lymphoma is extremely rare.CASE SUMMARY We present a patient with CML who experienced a sudden transformation to anaplastic large-cell lymphoma(ALCL)after 7 mo of treatment with imatinib,during which she had achieved partial cytogenetic response as well as early molecular response.The patient noticed a mass in her left shoulder,the biopsy data of which were consistent with ALCL;moreover,her lymphoma cells exhibited BCR-ABL gene fusion.The patient was diagnosed with Philadelphia-positive ALCL that progressed from CML,and was thus treated with the second generation tyrosine kinase inhibitor nilotinib.Six months later,the mass had totally disappeared and the BCR-ABL fusion gene was undetectable in the peripheral blood.To our knowledge,this is the first patient known to have developed Philadelphia-positive ALCL transformed from CML.CONCLUSION Unexplained lymphadenopathy or an extramedullary mass in a patient with CML may warrant a biopsy and testing for BCR-ABL fusion.展开更多
Whole genome duplication(WGD) and tandem duplication(TD) are important modes of gene amplification and functional innovation, and they are common in plant genome evolution. We analyzed the genomes of three Solanaceae ...Whole genome duplication(WGD) and tandem duplication(TD) are important modes of gene amplification and functional innovation, and they are common in plant genome evolution. We analyzed the genomes of three Solanaceae species(Solanum lycopersicum, Capsicum annuum, and Petunia inflata), which share a common distant ancestor with Vitis vinifera, Theobroma cacao, and Coffea canephora but have undergone an extra whole genome triplication(WGT) event. The analysis was used to investigate the phenomenon of tandem gene evolution with(S. lycopersicum) or without WGT(V. vinifera). Among the tandem gene arrays in these genomes, we found that V. vinifera, which has not experienced the WGT event, retained relatively more and larger tandem duplicated gene(TDG) clusters than the Solanaceae species that experienced the WGT event. Larger TDG clusters tend to be derived from older TD events, so this indicates that continuous TDGs(absolute dosage) accumulated during long-term evolution. In addition, WGD and TD show a significant bias in the functional categories of the genes retained. WGD tends to retain dose-sensitive genes related to biological processes, including DNA-binding and transcription factor activity, while TD tends to retain genes involved in stress resistance. WGD and TD also provide more possibilities for gene functional innovation through gene fusion and fission. The TDG cluster containing the tomato fusarium wilt resistance gene I3 contains 15 genes, and one of these genes, Solyc07g055560, has undergone a fusion event after the duplication events. These data provide evidence that helps explain the new functionalization of TDGs in adapting to environmental changes.展开更多
With the development of deep sequencing and bioinformatics technology, a large number of products produced by abnormal RNA splicing, such as chimeric RNA and chimeric/fusion proteins, have been discovered. Natural chi...With the development of deep sequencing and bioinformatics technology, a large number of products produced by abnormal RNA splicing, such as chimeric RNA and chimeric/fusion proteins, have been discovered. Natural chimeric/fusion genes are new genes formed by natural fusion of two or more independent genes. Chimeric RNAs can be transcribed by natural chimeric genes, and can also be formed by cis-splicing or trans-splicing of two or more precursor mRNAs. Unlike fusion genes, the production of chimeric RNAs does not involve changes in the DNA level of chromosomes. At first, chimeric RNAs were found as tumor markers. With the deepening of research, researchers also found a large number of chimeric RNAs in normal tissues. From the perspective of biological function, chimeric RNAs can play a biological role in regulating the expression of corresponding maternal genes, translating into chimeric proteins, and forming long non-coding RNAs. The objective of the present study focused on the frontiers of chimeric RNA and reviewed its role in health and tumor study to reveal research progress of chimeric RNA and health and provide a new sight of relative disease treatment. The main conclusion of this review is that chimeric RNA may serve as a biomarker for specific tumor diagnose and treatment while its role in normal physiology needs to be revealed.展开更多
Secretory carcinoma (SC) is a malignant salivary gland tumor that has been first reported by Skalova et al. in 2010. Histologically, it shows solidity infiltrated with very small cystic cavities and cribriform and pap...Secretory carcinoma (SC) is a malignant salivary gland tumor that has been first reported by Skalova et al. in 2010. Histologically, it shows solidity infiltrated with very small cystic cavities and cribriform and papillary features and includes periodic acid-Schiff stain-positive, acid-fast secretions. The cells have oval nuclei, and vacuolated cytoplasm and foamy secretions are seen. Anaplasia is not strong and mitotic figures are rarely seen. These features closely resemble AciCC. Immunohistologically, it is thought to be positive for S-100 protein, vimentin, and mammaglobin and negative for DOG1. The presence of the ETV6-NTRK3 fusion gene is essential in diagnosing secretory carcinoma. In this report, we describe a case of SC in a 52-year-old woman. She was referred to our center because of a mass in left buccal mucosa. A soft and elastic submucosal mass measuring approximately 10 mm × 10 mm in size with a smooth surface was seen in the buccal mucosa in an area corresponding to the left mandibular canine to premolars. The imaging findings revealed that a high-intensity lesion was seen on T2-weighted images. Immunohistochemicalstaing for S-100 protein and vimentin were positive. Furthermore, genetic examination detected the presence of the ETV6-NTRK3 fusion gene. Based on these findings, the definitive diagnosis was secretory carcinoma.展开更多
Gene fusions are appreciated as ideal cancer biomarkers and therapeutic targets.Chimeric RNAs are traditionally thought to be products of gene fusions,and thus,also cancerspecific.Recent research has demonstrated that...Gene fusions are appreciated as ideal cancer biomarkers and therapeutic targets.Chimeric RNAs are traditionally thought to be products of gene fusions,and thus,also cancerspecific.Recent research has demonstrated that chimeric RNAs can be generated by intergenic splicing in the absence of gene fusion,and such chimeric RNAs are also found in normal physiology.These new findings challenge the traditional theory of chimeric RNAs exclusivity to cancer,and complicates use of chimeric RNAs in cancer detection.Here,we provide an overview of gene fusions and chimeric RNAs,and emphasize their differences.We note that gene fusions are able to generate chimeric RNAs in accordance with the central dogma of biology,and that chimeric RNAs may also be able to influence the generation of the gene fusions per the“horse before the cart”hypothesis.We further expand upon the“horse before the cart”hypothesis,summarizing current evidence in support of the theory and exploring its potential impact on the field.展开更多
Many gene fusions have been recognized as important diagnostic and/or prognostic markers in human malignancies.In recent years,novel gene fusions have been identified in cases without prior knowledge of the genetic ba...Many gene fusions have been recognized as important diagnostic and/or prognostic markers in human malignancies.In recent years,novel gene fusions have been identified in cases without prior knowledge of the genetic background.Accompanied by a powerful computational data analysis method,new genome-wide screening approaches were used to detect cryptic genomic aberrations.This review focused on advanced genome-wide screening approaches in fusion gene identification,such as microarray-based approaches,next-generation sequencing,and NanoString nCounter gene expression system.The fundamental rationale and strategy for fusion gene identification using each biotech platform are also discussed.展开更多
Integration of human papillomavirus(HPV)DNA into the human genome is a reputed key driver of cervical cancer.However,the effects of HPV integration on chromatin structural organization and gene expression are largely ...Integration of human papillomavirus(HPV)DNA into the human genome is a reputed key driver of cervical cancer.However,the effects of HPV integration on chromatin structural organization and gene expression are largely unknown.We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19.We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome,RNA,chromatin immunoprecipitation and high-throughput chromosome conformation capture(Hi-C)sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis.Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities,with correlation found between three-dimensional(3D)structural change and gene expression.Importantly,HPV integration divided one topologically associated domain(TAD)into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106,with a decrease in PEG3 expression and an increase in CCDC106 expression.This expression dysregulation was further confirmed using 10 samples from our cohort,which exhibited the same HPV-CCDC106 integration.In summary,we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling.Thus,this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.展开更多
Phylogenomic analysis of whole genome sequences of five benzylisoquinoline alkaloid(BIA)-producing species from the Ranunculales and Proteales orders of flowering plants revealed the sequence and timing of evolutionar...Phylogenomic analysis of whole genome sequences of five benzylisoquinoline alkaloid(BIA)-producing species from the Ranunculales and Proteales orders of flowering plants revealed the sequence and timing of evolutionary events leading to the diversification of these compounds.(S)-Reticuline is a pivotal intermediate in the synthesis of many BIAs and our analyses revealed parallel evolution between the two orders,which diverged122 million years ago(MYA).Berberine is present in species across the entire Ranunculales,and we found co-evolution of genes essential for production of the protoberberine class.The benzophenanthridine class,which includes the antimicrobial compound sanguinarine,is specific to the Papaveraceae family of Ranunculales,and biosynthetic genes emerged after the split with the Ranunculaceae family110 MYA but before the split of the three Papaveraceae species used in this study at77 MYA.The phthalideisoquinoline noscapine and morphinan class of BIAs are exclusive to the opium poppy lineage.Ks estimation of paralogous pairs indicates that morphine biosynthesis evolved more recently than 18 MYA in the Papaver genus.In the preceding 100 million years gene duplication,neofunctionalization and recruitment of additional enzyme classes,combined with gene clustering,gene fusion,and gene amplification,resulted in emergence of medicinally valuable BIAs including morphine and noscapine.展开更多
The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of t...The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of the oncogenic kinase,whereas only a few of RET point mutations found in human cancers are known oncogenic drivers.Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors(TKIs)with RET inhibitor activity.These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations.Recently,two potent and selective RET TKIs,pralsetinib(BLU-667)and selpercatinib(LOXO-292),were developed.High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials,demonstrating the RET dependence in human cancers harboring these RET lesions.Pralsetinib and selpercatinib were effective in inhibiting RETV804L/M gatekeeper mutants.However,adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RETG810 residue have been found,pointing to the need for the development of the next-generation of RET TKIs.展开更多
R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway.Among the R-spondin family,RSPO2 has emanated as a novel regulator of Wnt signa...R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway.Among the R-spondin family,RSPO2 has emanated as a novel regulator of Wnt signaling,which has now been acknowledged in numerous in vitro and in vivo studies.Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer.Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks.Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types,particularly CRC.As a critical regulator of the Wnt pathway,it modulates several phenotypes of cells,such as cell proliferation,invasion,migration,and cancer stem cell properties.Recently,RSPO mutations,gene rearrangements,fusions,copy number alterations,and altered gene expression have also been identified in a variety of cancers,including CRC.In this review,we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC.In addition to the compelling physiological and biological roles in cellular fate and regulation,we propose that RSPO2 would be valuable as a potential biomarker for prognostic,diagnostic,and therapeutic use in CRC.展开更多
文摘BACKGROUND Approximately half of all new cases of gastric cancer(GC)and related deaths occur in China.More than 80%of patients with GC are diagnosed at an advanced stage,which results in poor prognosis.Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful,new drugs are still needed for the treatment of GC.Notably,several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors,including GC,such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers.However,gene fusions involving targetable genes have not been well characterized in Chinese patients with GC.AIM To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC.METHODS We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC.Clinicopathological characteristics were obtained from their medical records.Genetic alterations,such as single nucleotide variants,indels,amplifications,and gene fusions,were identified using a targeted sequencing panel containing 825 genes.Fusions were validated by fluorescence in situ hybridization(FISH)using break-apart probes.The microsatellite instability(MSI)status was evaluated using MSIsensor from the targeted sequencing panel data.Tumor mutational burden(TMB)was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region.Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC.RESULTS We found that 1.68%(16/954)of patients harbored 20 fusion events involving targetable genes.RARA fusions(n=5)were the most common,followed by FGFR2,BRAF,MET,FGFR3,RET,ALK,EGFR,NTRK2,and NRG1 fusions.Two of the RARA fusions,EML4-ALK(E6:E20)and EGFRSEPTIN14(E7:E10),have been identified in other tumors but not in GC.Surprisingly,18 gene fusion events were previously not reported in any cancer types.Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes,such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA-and ligand-binding domains of RARA.Consistent with the results of detection using the targeted sequencing fusion panel,the results of FISH(fluorescence in situ hybridization)confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09,respectively.Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification(P=0.02);however,there were no significant differences between fusion-positive and fusion-negative patients in age,sex,MSI status,and TMB.CONCLUSION We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68%of patients with GC harbor potential targetable gene fusions,which were enriched in patients with ERBB2 amplification.Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.
基金Hunan Provincial Natural Science Foundation of China,No.2022JJ40246The Hunan Cancer Hospital Climb Plan,No.2021NSFC-B005.
文摘BACKGROUND Pulmonary mucoepidermoid carcinoma(PMEC)is a rare malignancy that arises from minor salivary glands within the tracheobronchial tree.The clear cell variant of PMEC is exceptionally uncommon and presents notable diagnostic challenges,primarily attributable to its morphological similarity to other tumors containing clear cells.CASE SUMMARY A 22-year-old male,formerly in good health,came in with a two-month duration of persistent cough and production of sputum.Subsequent imaging and bronchoscopy examinations revealed a 2 cm tumor in the distal left main bronchus,which resulted in complete atelectasis of the left lung.Further assessment via positron emission tomography/computed tomography scans and endoscopic biopsy confirmed the primary malignant nature of the tumor,charac-terized by clear cell morphology in most of the tumor cells.The patient underwent a left lower lobe sleeve resection accompanied by systematic mediastinal lymph node dissection.Molecular pathology analysis subsequently revealed a CRTC3-MAML2 gene fusion,leading to a definitive pathological diagnosis of the clear cell variant of PMEC,staged as T2N0M0.After surgery,the patient experienced a smooth recovery and exhibited no signs of recurrence during the one-and-a-half-year follow-up period.CONCLUSION This article describes an unusual case of a clear cell variant of PMEC characterized by the presence of a CRTC3-MAML2 gene fusion in a 22-year-old male.The patient underwent successful left lower lobe sleeve resection.This case underscores the distinctive challenges associated with diagnosing and treating this uncommon malignancy,underscoring the importance of precise diagnosis and personalized treatment strategies.
文摘BACKGROUND Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death.In recent decades,increasing application of next-generation sequencing has enabled detection of molecular aberrations,including fusions.In cases where tissue is difficult to obtain,cell-free DNA(cfDNA)is used for detecting mutations to identify the molecular profile of cancer.Here,we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer.CASE SUMMARY A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel,but ascites was detected.The therapy was switched to nivolumab,but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020.Therapy was discontinued,and cfDNA nextgeneration sequencing was immediately evaluated.All genomic variants,including fusions,were analyzed from cfDNA.The following somatic alterations were detected from the patient’s cfDNA:an APC frameshift mutation(NM_000038.5:c.6579del,p.V2194fs)with variant allele frequency of 0.5%,an EGFR amplification with a copy number of 17.3,and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%.The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14.The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest thatEGFR-targeted therapies be tried in such future cases.CONCLUSIONThe expanded applications of the cfDNA assay may open a new horizon intreatment of patients with advanced gastric cancer.
文摘Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.
基金Supported by Research fund from Chosun University,2020.
文摘BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis.Herein,we report the successful treatment of relapsed acute promyelocytic leukemia(APL)in a patient on hemodialysis with ATO single agent and review the cases in literature.CASE SUMMARY A 46-year-old woman who has been on hemodialysis to chronic glomerulonephritis for 15 years visited our hospital for pancytopenia.She had been seen for pancytopenia 3 years ago and had been diagnosed with APL.She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy.She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago.Bone marrow biopsy and reverse transcriptase-polymerase chain reaction(RT-PCR)tests revealed a diagnosis of relapsed APL.Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO.Thus far,four consolidation therapies have been performed with the ATO single agent,and,to date,the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-αfusion gene as confirmed by RTPCR testing for two years.CONCLUSION This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.
文摘BACKGROUND Fine-needle biopsy is an accurate and cost-efficient tool for the assessment of thyroid nodules.It includes two primary methods:Fine-needle capillary biopsy(FNCB)and fine-needle aspiration biopsy.Needle tract seeding(NTS)is a rare complication of thyroid fine-needle biopsy mainly caused by fine-needle aspiration biopsy rather than FNCB.Here,we present an extremely rare case of a papillary thyroid carcinoma(PTC)patient with FNCB-derived NTS.CASE SUMMARY We report a 32-year-old woman with PTC who showed subcutaneous NTS 1 year after FNCB and thyroidectomy.NTS was diagnosed based on clinical manifestations,biochemistry indices,and imaging(computed tomography and ultrasound).Pathological identification of PTC metastases consistent with the puncture path is the gold standard for diagnosis.Surgical resection was the main method used to treat the disease.After surgery,thyroid function tests and ultrasound scans were performed every 3-6 mo.To date,no evidence of tumor recurrence has been observed.CONCLUSION FNCB is a safe procedure as NTS is rare,and can be easily removed surgically with no recurrence.Accordingly,NTS should not limit the usefulness of FNCB.
基金Supported by the Jiangxi“5511”Science and Technology Innovation Talent Project,No.20171BCB18003。
文摘BACKGROUND Chronic myeloid leukemia(CML)is a malignant hematologic malignancy that can progress to blast phase with a myeloid or lymphoid phenotype.Some patients with CML can also progress to blast crisis phase;however,the transformation of CML into Philadelphia-positive lymphoma is extremely rare.CASE SUMMARY We present a patient with CML who experienced a sudden transformation to anaplastic large-cell lymphoma(ALCL)after 7 mo of treatment with imatinib,during which she had achieved partial cytogenetic response as well as early molecular response.The patient noticed a mass in her left shoulder,the biopsy data of which were consistent with ALCL;moreover,her lymphoma cells exhibited BCR-ABL gene fusion.The patient was diagnosed with Philadelphia-positive ALCL that progressed from CML,and was thus treated with the second generation tyrosine kinase inhibitor nilotinib.Six months later,the mass had totally disappeared and the BCR-ABL fusion gene was undetectable in the peripheral blood.To our knowledge,this is the first patient known to have developed Philadelphia-positive ALCL transformed from CML.CONCLUSION Unexplained lymphadenopathy or an extramedullary mass in a patient with CML may warrant a biopsy and testing for BCR-ABL fusion.
基金supported by the National Natural Science Foundation of China(NSFC,31972411 and 31722048)the Program for Scientific and Technological Innovative Talents in Universities of Henan Province,China(20HASTIT035)+1 种基金the Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciencesthe Key Laboratory of Biology and Genetic Improvement of Horticultural Crops,Ministry of Agriculture and Rural Affairs,China。
文摘Whole genome duplication(WGD) and tandem duplication(TD) are important modes of gene amplification and functional innovation, and they are common in plant genome evolution. We analyzed the genomes of three Solanaceae species(Solanum lycopersicum, Capsicum annuum, and Petunia inflata), which share a common distant ancestor with Vitis vinifera, Theobroma cacao, and Coffea canephora but have undergone an extra whole genome triplication(WGT) event. The analysis was used to investigate the phenomenon of tandem gene evolution with(S. lycopersicum) or without WGT(V. vinifera). Among the tandem gene arrays in these genomes, we found that V. vinifera, which has not experienced the WGT event, retained relatively more and larger tandem duplicated gene(TDG) clusters than the Solanaceae species that experienced the WGT event. Larger TDG clusters tend to be derived from older TD events, so this indicates that continuous TDGs(absolute dosage) accumulated during long-term evolution. In addition, WGD and TD show a significant bias in the functional categories of the genes retained. WGD tends to retain dose-sensitive genes related to biological processes, including DNA-binding and transcription factor activity, while TD tends to retain genes involved in stress resistance. WGD and TD also provide more possibilities for gene functional innovation through gene fusion and fission. The TDG cluster containing the tomato fusarium wilt resistance gene I3 contains 15 genes, and one of these genes, Solyc07g055560, has undergone a fusion event after the duplication events. These data provide evidence that helps explain the new functionalization of TDGs in adapting to environmental changes.
文摘With the development of deep sequencing and bioinformatics technology, a large number of products produced by abnormal RNA splicing, such as chimeric RNA and chimeric/fusion proteins, have been discovered. Natural chimeric/fusion genes are new genes formed by natural fusion of two or more independent genes. Chimeric RNAs can be transcribed by natural chimeric genes, and can also be formed by cis-splicing or trans-splicing of two or more precursor mRNAs. Unlike fusion genes, the production of chimeric RNAs does not involve changes in the DNA level of chromosomes. At first, chimeric RNAs were found as tumor markers. With the deepening of research, researchers also found a large number of chimeric RNAs in normal tissues. From the perspective of biological function, chimeric RNAs can play a biological role in regulating the expression of corresponding maternal genes, translating into chimeric proteins, and forming long non-coding RNAs. The objective of the present study focused on the frontiers of chimeric RNA and reviewed its role in health and tumor study to reveal research progress of chimeric RNA and health and provide a new sight of relative disease treatment. The main conclusion of this review is that chimeric RNA may serve as a biomarker for specific tumor diagnose and treatment while its role in normal physiology needs to be revealed.
文摘Secretory carcinoma (SC) is a malignant salivary gland tumor that has been first reported by Skalova et al. in 2010. Histologically, it shows solidity infiltrated with very small cystic cavities and cribriform and papillary features and includes periodic acid-Schiff stain-positive, acid-fast secretions. The cells have oval nuclei, and vacuolated cytoplasm and foamy secretions are seen. Anaplasia is not strong and mitotic figures are rarely seen. These features closely resemble AciCC. Immunohistologically, it is thought to be positive for S-100 protein, vimentin, and mammaglobin and negative for DOG1. The presence of the ETV6-NTRK3 fusion gene is essential in diagnosing secretory carcinoma. In this report, we describe a case of SC in a 52-year-old woman. She was referred to our center because of a mass in left buccal mucosa. A soft and elastic submucosal mass measuring approximately 10 mm × 10 mm in size with a smooth surface was seen in the buccal mucosa in an area corresponding to the left mandibular canine to premolars. The imaging findings revealed that a high-intensity lesion was seen on T2-weighted images. Immunohistochemicalstaing for S-100 protein and vimentin were positive. Furthermore, genetic examination detected the presence of the ETV6-NTRK3 fusion gene. Based on these findings, the definitive diagnosis was secretory carcinoma.
基金Hao Wu was supported by China Scholarship Council(CSC,No.201706370109).We thank Emily Lin for her help in creating the figure.We thank Justin Elfman for his help with English editing.
文摘Gene fusions are appreciated as ideal cancer biomarkers and therapeutic targets.Chimeric RNAs are traditionally thought to be products of gene fusions,and thus,also cancerspecific.Recent research has demonstrated that chimeric RNAs can be generated by intergenic splicing in the absence of gene fusion,and such chimeric RNAs are also found in normal physiology.These new findings challenge the traditional theory of chimeric RNAs exclusivity to cancer,and complicates use of chimeric RNAs in cancer detection.Here,we provide an overview of gene fusions and chimeric RNAs,and emphasize their differences.We note that gene fusions are able to generate chimeric RNAs in accordance with the central dogma of biology,and that chimeric RNAs may also be able to influence the generation of the gene fusions per the“horse before the cart”hypothesis.We further expand upon the“horse before the cart”hypothesis,summarizing current evidence in support of the theory and exploring its potential impact on the field.
文摘Many gene fusions have been recognized as important diagnostic and/or prognostic markers in human malignancies.In recent years,novel gene fusions have been identified in cases without prior knowledge of the genetic background.Accompanied by a powerful computational data analysis method,new genome-wide screening approaches were used to detect cryptic genomic aberrations.This review focused on advanced genome-wide screening approaches in fusion gene identification,such as microarray-based approaches,next-generation sequencing,and NanoString nCounter gene expression system.The fundamental rationale and strategy for fusion gene identification using each biotech platform are also discussed.
基金supported by the National Natural Science Foundation of China(81630060 to P.W.,31771402 to G.L.,81830074 and 81772786 to H.W.,81572569 to G.C.,and 81772775 to J.W.)National Science and Technology Major Project(2019YFC1005202 and 2019YFC1005201 to K.L.,and 2018ZX10301402-002 to Q.G.)the research-oriented clinician funding program of Tongji Medical College,Huazhong University of Science and Technology for P.W
文摘Integration of human papillomavirus(HPV)DNA into the human genome is a reputed key driver of cervical cancer.However,the effects of HPV integration on chromatin structural organization and gene expression are largely unknown.We studied a cohort of 61 samples and identified an integration hot spot in the CCDC106 gene on chromosome 19.We then selected fresh cancer tissue that contained the unique integration loci at CCDC106 with no HPV episomal DNA and performed whole-genome,RNA,chromatin immunoprecipitation and high-throughput chromosome conformation capture(Hi-C)sequencing to identify the mechanisms of HPV integration in cervical carcinogenesis.Molecular analyses indicated that chromosome 19 exhibited significant genomic variation and differential expression densities,with correlation found between three-dimensional(3D)structural change and gene expression.Importantly,HPV integration divided one topologically associated domain(TAD)into two smaller TADs and hijacked an enhancer from PEG3 to CCDC106,with a decrease in PEG3 expression and an increase in CCDC106 expression.This expression dysregulation was further confirmed using 10 samples from our cohort,which exhibited the same HPV-CCDC106 integration.In summary,we found that HPV-CCDC106 integration altered local chromosome architecture and hijacked an enhancer via 3D genome structure remodeling.Thus,this study provides insight into the 3D structural mechanism underlying HPV integration in cervical carcinogenesis.
基金I.A.G.received support from the Biotechnology and Biological Sciences Research Council,United Kingdom(grant BB/K018809/1)and the Gar-field Weston Foundation,United Kingdom.
文摘Phylogenomic analysis of whole genome sequences of five benzylisoquinoline alkaloid(BIA)-producing species from the Ranunculales and Proteales orders of flowering plants revealed the sequence and timing of evolutionary events leading to the diversification of these compounds.(S)-Reticuline is a pivotal intermediate in the synthesis of many BIAs and our analyses revealed parallel evolution between the two orders,which diverged122 million years ago(MYA).Berberine is present in species across the entire Ranunculales,and we found co-evolution of genes essential for production of the protoberberine class.The benzophenanthridine class,which includes the antimicrobial compound sanguinarine,is specific to the Papaveraceae family of Ranunculales,and biosynthetic genes emerged after the split with the Ranunculaceae family110 MYA but before the split of the three Papaveraceae species used in this study at77 MYA.The phthalideisoquinoline noscapine and morphinan class of BIAs are exclusive to the opium poppy lineage.Ks estimation of paralogous pairs indicates that morphine biosynthesis evolved more recently than 18 MYA in the Papaver genus.In the preceding 100 million years gene duplication,neofunctionalization and recruitment of additional enzyme classes,combined with gene clustering,gene fusion,and gene amplification,resulted in emergence of medicinally valuable BIAs including morphine and noscapine.
文摘The rearranged during transfection(RET)gene encodes a protein tyrosine kinase.RET alterations by point mutations and gene fusions were found in diverse cancers.RET fusions allow abnormal expression and activation of the oncogenic kinase,whereas only a few of RET point mutations found in human cancers are known oncogenic drivers.Earlier studies of RET-targeted therapy utilized multi-targeted protein tyrosine kinase inhibitors(TKIs)with RET inhibitor activity.These multi-targeted TKIs often led to high-grade adverse events and were subject to resistance caused by the gatekeeper mutations.Recently,two potent and selective RET TKIs,pralsetinib(BLU-667)and selpercatinib(LOXO-292),were developed.High response rates to these selective RET inhibitors across multiple forms of RET alterations in different types of cancers were observed in clinical trials,demonstrating the RET dependence in human cancers harboring these RET lesions.Pralsetinib and selpercatinib were effective in inhibiting RETV804L/M gatekeeper mutants.However,adaptive mutations that cause resistance to pralsetinib or selpercatinib at the solvent front RETG810 residue have been found,pointing to the need for the development of the next-generation of RET TKIs.
文摘R-spondins are secretory proteins localized in the endoplasmic reticulum and Golgi bodies and are processed through the secretory pathway.Among the R-spondin family,RSPO2 has emanated as a novel regulator of Wnt signaling,which has now been acknowledged in numerous in vitro and in vivo studies.Cancer is an abnormal growth of cells that proliferates and spreads uncontrollably due to the accumulation of genetic and epigenetic factors that constitutively activate Wnt signaling in various types of cancer.Colorectal cancer (CRC) begins when cells in the colon and rectum follow an indefinite pattern of division due to aberrant Wnt activation as one of the key hallmarks.Decades-long progress in research on R-spondins has demonstrated their oncogenic function in distinct cancer types,particularly CRC.As a critical regulator of the Wnt pathway,it modulates several phenotypes of cells,such as cell proliferation,invasion,migration,and cancer stem cell properties.Recently,RSPO mutations,gene rearrangements,fusions,copy number alterations,and altered gene expression have also been identified in a variety of cancers,including CRC.In this review,we addressed the recent updates regarding the recurrently altered R-spondins with special emphasis on the RSPO2 gene and its involvement in potentiating Wnt signaling in CRC.In addition to the compelling physiological and biological roles in cellular fate and regulation,we propose that RSPO2 would be valuable as a potential biomarker for prognostic,diagnostic,and therapeutic use in CRC.
