Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix

Objective Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma(CSCC).Methods Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy.RNA Sequencing was performed to analyze neoantigen expression.Results Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs.Missense mutations were the most frequent types of somatic mutation in the coding sequence regions.Mutational signature analysis detected signature 2,signature 6,and signature 7 in CSCC samples.PIK3CA,FBXW7,and BICRA were identified as potential driver genes,with BICRA as a newly reported gene.Genomic variation profiling identified 4,960 potential neoantigens,of which 114 were listed in two neoantigen-related databases.Conclusion The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

Targeting HER2 genomic alterations in non-small cell lung cancer

Oncogenic mutations and amplifications in the erythroblastic oncogene B(ERBB2),or human epidermal growth factor receptor 2(HER2),have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer(NSCLC).Each genomic alteration occurs in 2-4%of NSCLC by next generation sequencing and is asso-ciated with constitutive HER2 activation.The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular domain.Unlike in breast and gastric cancer,HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted agents.High HER2 protein overexpression by immunohistochemistry(3+)only occurs in 2-4%of NSCLC.Until now HER2-targeted agents(such as afatinib and ado-trastuzumab emtansine)only demonstrate modest clinical activity in patients with HER2-mutant NSCLC.Retrospective studies show concern for inferior clinical benefit of immune checkpoint inhibitors in HER2-mutated NSCLC.Therefore,platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this pa-tient population.In May 2020 trastuzumab deruxtecan(T-DXd)received the U.S.Food and Drug Administration breakthrough therapy designation for HER2-mutant metastatic NSCLC,and was added as an option for HER2-mutant NSCLC to the NCCN guidelines V1.2021.A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring HER2 exon 20 mutations was just opened for enrollment in September 2020.In this review,we highlight the current knowledge and perspectives on targeting-HER2 genomic alterations in NSCLC.

Genomic alterations and precise medicine of esophageal squamous cell carcinoma

Human cancer is a complex disease caused by the interaction of multiple genes and environmental factors.It is known that environmental factors such as smoking,drinking,and food carcinogens are implicated in the development of certain types of cancer including esophageal squamous cell carcinoma(ESCC).However,only a small portion of exposed individuals finally developed cancer,indicating that genetic makeup also plays an important role in the tumorigenesis.Genome-wide association studies(GWAS)have found numerous susceptible genes or loci for cancers,providing new ideas and directions for precision prevention and treatment of cancers.With the advances in the field of next-generation sequencing(NGS),the genomic landscapes of many types of human cancer have comprehensively been characterized.Here,we review the progresses of GWAS and NGS in revealing genomic variations of ESCC,one of the most common cancers in China,and discuss the potential applications of these results in precision medicine of ESCC.

Genetic alterations and tumor mutation burden predict chemosensitivity of pancreatic cancer: a retrospective study

Background:Chemotherapy stands as a recommended approach for all stages of pancreatic cancer.However,its efficacy stratification remains obscure.Genomic sequencing is extensively applied across diverse diseases.This study aims to explore the potential genomic markers in relation to the decision-making of chemotherapy.Methods:A total of 140 patients with pancreatic cancer were categorized into chemotherapy-first group and adjuvant chemo-therapy group.The genomic alterations were detected from the next-generation sequencing using surgical or fine-needle-biopsy specimens.Chemotherapy response was defined according to objective response based on the RECIST criteria(version 1.1).Results:In the chemotherapy-first group,the patients who harbored higher tumor mutation burden(TMB)levels had significant shorter progress-free survival(PFS)than that with low TMB levels(hazard ratio[HR]=30.362,P=.002).No independent risk factors were found to be correlated with chemoresistance in patients receiving chemotherapy at first(all P>.05).In the adjuvant chemotherapy group,the increased carbohydrate antigen 125(CA125)level of more than 35 U/mL potentially elucidated a shorter period of DFS(HR=3.695,P=.020).Conclusion:Our study indicated that a high level of TMB may predict earlier tumor progression in pancreatic cancer patients received chemotherapy at first.The elevation of CA125 presents itself as a predictive indicator for postoperative chemotherapy patients’tumor recurrence,whereas gene mutations remain unrelated to this phenomenon.

Genomic characterization and risk stratification of esophageal squamous dysplasia

Objectives:The majority of esophageal squamous dysplasia(ESD)patients progress slowly,while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment.However,the molecular mechanisms underlying these clinical observations are still largely unknown.Methods:By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma(ESCC)patients,we demonstrated lower somatic mutation and copy number alteration(CNA)burden in ESD compared with ESCC.Results:Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression.Furthermore,we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD.Conclusions:These findings largely expanded our understanding of ESD genetics and tumorigenesis,which possessed promising significance for improving early diagnosis,reducing overtreatment,and identifying high-risk ESD patients.

Defect of SLC38A3 promotes epithelial-mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma

Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.

Novel chromosomal alterations detected in primary nasopharyngeal carcinoma by comparative genomic hybridization

Objective To gain a better understanding of genetic changes in Cantonese nasopharyngeal carcinoma (NPC) Methods Comparative genomic hybridization (CGH) was performed on 17 primary nasopharyngeal carcinomas Results A novel copy number gain an chromosome 4q and loss of chromosome 1p were found at a high frequency (>50%) Conclusions Current analysis revealed a comprehensive profile of the chromosomal regions showing gain of chromosomes 4q, 12q, and 1q as well as loss of chromosomes 1p, 3p, 11q, 14q, 15q, 13q, Xq, 9q, 10p, 10q, and 16q Frequently altered loci may encode oncogenes or tumor suppressor genes involved in the development of primary NPC

Genomic predictors for treatment of late stage prostate cancer

In spite of the development of new treatments for late stage prostate cancer, significant challenges persist to match individuals with effective targeted therapies. Genomic classification using high-throughput sequencing technologies has the potential to achieve this goal and make precision medicine a reality in the management of men with castrate-resistant prostate cancer. This chapter reviews some of the most recent studies that have resulted in significant progress in determining the landscape of somatic genomic alterations in this cohort and, more importantly, have provided clinically actionable information that could guide treatment decisions. This chapter reviews the current understanding of common alterations such as alterations of the androgen receptor and PTEN pathway, as well as ETS gene fusions and the growing importance of PARP inhibition. It also reviews recent studies that characterize the evolution to neuroendocrine tumors, which is becoming an increasingly important clinical problem. Finally, this chapter reviews recent innovative studies that characterize the compelling evolutionary history of lethal prostate cancer evidenced by polyclonal seeding and interclonal cooperation between metastasis and the importance of tumor clone dynamics measured serially in response to treatment. The genomic landscape of late stage prostate cancer is becoming better defined, and the prospect for assigning clinically actionable data to inform rationale treatment for individuals with this disease is becoming a reality.

Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma:New opportunities towards molecularly targeted therapy

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis.Esophageal squamous cell carcinoma(ESCC)and esophageal adenocarcinoma(EAC)are two major subtypes of esophageal cancer.ESCC predominantly affects African and Asian populations,which is closely related to chronic smoking and alcohol consumption.EAC typically arises in Barrett’s esophagus with a predilection for Western countries.While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer,molecularly targeted therapy is still at the early stages.With the development of large-scale next-generation sequencing,various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied.Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer.In this review,we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer.Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

Targeted deep sequencing reveals the genetic heterogeneity in well-differentiated pancreatic neuroendocrine tumors with liver metastasis

Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor,but the genetic alterations in the metastatic cases remain relatively unclear,which we aimed to study.Methods:Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.We performed deep sequencing on the exome of 341 tumor-related genes,and compared the differences of genetic alterations between the metastatic and the non-metastatic cases,as well as between the primary and the paired liver metastatic tumors.Results:Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis.A total of 2,471 somatic variants were identified,75.5%of which were considered as low-abundance.NOTCH1 was the most frequently mutated gene,altered in 26(53.1%)pancreatic neuroendocrine tumor samples from 18(62.1%)patients.Compared with the non-metastatic pancreatic neuroendocrine tumors,the metastatic cases were discovered with more single nucleotide variants and copy number variations,indicating the increased genomic instability.In addition,among the paired metastatic cases,the primary and the metastatic lesions shared limited mutated genes.Conclusions:Through the targeted deep sequencing,we identified the intratumor,intraindividual,and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients,particularly in the metastatic cases,bringing potential challenges for the current biopsy strategies in guiding clinical treatments.