Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below ...Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,展开更多
Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is th...Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is the first report of simultaneously evaluating these two biomarkers in the same study.展开更多
B y comparing all gene-coding sequences in the genome between tumors and matched normal samples from clinically localized and castration-resistant （CR） prostate cancer patients, two groups of scien- tists have recen...B y comparing all gene-coding sequences in the genome between tumors and matched normal samples from clinically localized and castration-resistant （CR） prostate cancer patients, two groups of scien- tists have recently identified more than 5000 somatic mutations.展开更多
Current clinicopathologic indicators are insufficient to distinguish the small percentage of aggressive prostate cancer （PCa） from the vast majority of indolent disease at diagnosis, leading to overtreatment of PCa....Current clinicopathologic indicators are insufficient to distinguish the small percentage of aggressive prostate cancer （PCa） from the vast majority of indolent disease at diagnosis, leading to overtreatment of PCa. A recent study reported and confirmed a strong association of PCa-specific mortality with somatic DNA copy number alterations （CNAs） in primary pro- state tumors.展开更多
In western populations, prostate volume （PV） has been proven to be one of the strongest predictors of detecting prostate cancer （PCa） in biopsies. We performed this study in a biopsy cohort, to evaluate associatio...In western populations, prostate volume （PV） has been proven to be one of the strongest predictors of detecting prostate cancer （PCa） in biopsies. We performed this study in a biopsy cohort, to evaluate associations among the prostate volume, prostate-specific antigen （PSA） and PCa detection in the Chinese population. Between the years, 2007-13, 1486 men underwent prostate biopsy at Huashan Hospital, Fudan University, Shanghai, China. The study population was divided into two groups for analysis according to total PSA （tPSA） range （4 ng m1-1 〈tPSA 〈20 ng m1-1 and tPSA 〉20 ng ml-1）. PV, age, tPSA, digital rectal examination （DRE） and transrectal ultrasound （TRUS） results were also included in the analysis. Although the positive biopsy rates decreased in both tPSA range groups, the downtrend was more pronounced in the 4 ng ml-2 〈tPSA 〈20 ng m1-1 group; therefore, we focused on 853 men in this group with increasing PV. In multivariate logistic regression analysis, only DRE was found to be associated with PCa in four PV groups （P 〈 0.05） and tPSA did not show a good predictive ability when PV exceeded 50 ml （P 〉 0.05）. Further, it may suggest that with increasing PV, the cancer detection rate decreased in men with different tPSA, DRE and TRUS nodule statuses （all P values for trends were 〈0.001）. Our study indicates that in tPSA ranging from 4 to 20 ng ml-1, the use of PV ranges of 0-35 ml, 35-50 ml and 〉50 ml might be taken into consideration for the biopsy decision-making in the Chinese population.展开更多
The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in ...The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.展开更多
Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is...Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.展开更多
BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance...BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC,which sometimes becomes a point of discussion in clinical practice.Although these cancers demonstrate significant differences in their mutational landscape,several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers.CASE SUMMARY We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2(ERBB2)activating mutation on next-generation sequencing(NGS)-based genomic testing.One year later,a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis.The histological findings of the hepatic lesion were similar to those of the primary lesion.Additionally,using NGS panel testing,the hepatic lesion was found to have ERBB2 activating mutation,which is the identical mutation detected in the sequencing result of the primary site.ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA.Therefore,in the present case,we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence.Additionally,this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit.CONCLUSION This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.展开更多
Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signalin...Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we locus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes. CRKL. GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.展开更多
Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of ne...Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.展开更多
In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Ge...In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Gene co-expression clustering in scRNA-seq data presents certain challenges.We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately,and produce results that substantially limit biological expectations of co-expressed genes.Herein,we present single-cell Latent-variable Model(scLM),a gene coclustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context.Importantly,scLM can simultaneously cluster multiple single-cell datasets,i.e.,consensus clustering,enabling users to leverage single-cell data from multiple sources for novel comparative analysis.scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets.Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy.To illustrate the biological insights of scLM,we apply it to our in-house and public experimental scRNA-seq datasets.scLM identifies novel functional gene modules and refines cell states,which facilitates mechanism discovery and understanding of complex biosystems such as cancers.A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.展开更多
基金I thank for the contributions of study populations, data analysis and discussion to this paper from Drs S Lilly Zheng and lielin Sun from Wake Forest School of Medicine Dr Henrik Gronberg from Karolinska Institutet of Sweden+2 种基金 Mr Haitao Chen from School of Life Science, Fudan University, China Dr Qiang Ding, Ms Fang Liu and Xiaoling Lin from Fudan Institute of Urology, Fudan University, China Drs Yinghao Sun, Shangchen Ren and Zhensheng Zhang from Changhai Hospital, China and Dr Donna P Ankerst from Technical University Munich, Germany. This work was partially funded by the National Key Basic Research Program Grant 973 （No. 2012CB518301）, the Key Project of the National Natural Science Foundation of China （No. 81130047）, intramural grants from Fudan University and Huashan Hospital and the National Institutes of Health （No. NCI CA 129684）.
文摘Elevated serum prostate-specific antigen （PSA） level is the primaryindication for prostate biopsy for detection of prostate cancer （PCa） in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4-10 ng ml-1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score （GRS） derived from multiple PCa risk-associated single nucleotide polymorphisms （SNPs） have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However,
文摘Dear Editor We report here the performance of prostate cancer antigen 3 （PCA3） and genetic risk score （GRS） in predicting prostate cancer （PCa） from the prostate biopsy. To the best of our knowledge, this is the first report of simultaneously evaluating these two biomarkers in the same study.
文摘B y comparing all gene-coding sequences in the genome between tumors and matched normal samples from clinically localized and castration-resistant （CR） prostate cancer patients, two groups of scien- tists have recently identified more than 5000 somatic mutations.
文摘Current clinicopathologic indicators are insufficient to distinguish the small percentage of aggressive prostate cancer （PCa） from the vast majority of indolent disease at diagnosis, leading to overtreatment of PCa. A recent study reported and confirmed a strong association of PCa-specific mortality with somatic DNA copy number alterations （CNAs） in primary pro- state tumors.
文摘In western populations, prostate volume （PV） has been proven to be one of the strongest predictors of detecting prostate cancer （PCa） in biopsies. We performed this study in a biopsy cohort, to evaluate associations among the prostate volume, prostate-specific antigen （PSA） and PCa detection in the Chinese population. Between the years, 2007-13, 1486 men underwent prostate biopsy at Huashan Hospital, Fudan University, Shanghai, China. The study population was divided into two groups for analysis according to total PSA （tPSA） range （4 ng m1-1 〈tPSA 〈20 ng m1-1 and tPSA 〉20 ng ml-1）. PV, age, tPSA, digital rectal examination （DRE） and transrectal ultrasound （TRUS） results were also included in the analysis. Although the positive biopsy rates decreased in both tPSA range groups, the downtrend was more pronounced in the 4 ng ml-2 〈tPSA 〈20 ng m1-1 group; therefore, we focused on 853 men in this group with increasing PV. In multivariate logistic regression analysis, only DRE was found to be associated with PCa in four PV groups （P 〈 0.05） and tPSA did not show a good predictive ability when PV exceeded 50 ml （P 〉 0.05）. Further, it may suggest that with increasing PV, the cancer detection rate decreased in men with different tPSA, DRE and TRUS nodule statuses （all P values for trends were 〈0.001）. Our study indicates that in tPSA ranging from 4 to 20 ng ml-1, the use of PV ranges of 0-35 ml, 35-50 ml and 〉50 ml might be taken into consideration for the biopsy decision-making in the Chinese population.
基金We would like to thank all the study participants, urologists, and study coordinators for participating in the study. This work was partially funded by the National Key Basic Research Program Grant 973 （2012CB518301）, the Key Project of the National Natural Science Foundation of China （81130047）, National Natural Science Foundation of China （81202001, 81272835）, China Scholarship Council （CSC）, intramural grants from Fudan University and Huashan Hospital, and a research grant from Beckman Coulter, Inc.
文摘The [-2]proPSA （p2PSA） and its derivatives, the p2PSA-to-free PSA ratio （%p2PSA）, and the Prostate Health Index （PHI） have greatly improved discrimination between men with and without prostate cancer （PCa） in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination （DRE） and transrectal ultrasonography （TRUS） are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen （tPSA）, free PSA, and p2PSA. For each patient, the free-to-total PSA ratio （%fPSA）, PSA density （PSAD）, p2PSA-to-free PSA ratio （%p2PSA）, and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve （AUC） and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1. Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China.
基金This work was partially funded by the National Key Basic Research Program Grant 973 （No.2012CB518301） to JX, the Key Project of the National Natural Science Foundation of China （No.81130047） to IX, intramural grants from Fudan University ＇Thousand Talents Program＇ and Huashan Hospital to JX and the National Institutes of Health （No.NCI CA129684） to IX.
文摘Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.
文摘BACKGROUND Bile duct cancer constitutes gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICA),and extrahepatic cholangiocarcinoma(ECA).These three entities show morphological and immunohistochemical resemblance so that it is difficult to differentiate between primary ICA and liver metastasis of GBC,which sometimes becomes a point of discussion in clinical practice.Although these cancers demonstrate significant differences in their mutational landscape,several reports demonstrated shared genomic alteration in paired primary and metastatic site aids in distinguishing metastatic recurrence from second primary cancers.CASE SUMMARY We present a 73-year-old female patient who underwent curative resection for GBC harboring epidermal growth factor receptor 2(ERBB2)activating mutation on next-generation sequencing(NGS)-based genomic testing.One year later,a hepatic lesion was observed on follow-up imaging and she underwent surgical resection for a pathological diagnosis.The histological findings of the hepatic lesion were similar to those of the primary lesion.Additionally,using NGS panel testing,the hepatic lesion was found to have ERBB2 activating mutation,which is the identical mutation detected in the sequencing result of the primary site.ERBB2 activating mutation occurs more frequently in GBC than ICA and ECA.Therefore,in the present case,we think this molecular finding potentiated the diagnosis of the liver mass toward a metastatic recurrence.Additionally,this patient underwent HER2-targeted treatment with lapatinib in combination with capecitabin and obtained clinical benefit.CONCLUSION This case illustrated NGS panel usefulness in distinguishing GBC recurrence from second primary cancer and HER2-targeted agent efficacy on ERBB2 mutated GBC.
基金supported in part by grants from the U.S. NIH (U01 CA176058)the H.L. Snyder Medical Research Foundation and a HHMI Medical Student Fellowship
文摘Signal transduction pathways activated by receptor tyrosine kinases （RTK） play a critical role in many aspects of cell function. Adaptor proteins serve an important scaffolding function that facilitates key signaling transduction events downstream of RTKs. Recent work integrating both structural and functional genomic approaches has identified several adaptor proteins as new oncogenes. In this review, we locus on the discovery, structure and function, and therapeutic implication of three of these adaptor oncogenes. CRKL. GAB2, and FRS2. Each of the three genes is recurrently amplified in lung adenocarcinoma or ovarian cancer, and is essential to cancer cell lines that harbor such amplification. Overexpression of each gene is able to transform immortalized human cell lines in in vitro or in vivo models. These observations identify adaptor protein as a distinct class of oncogenes and potential therapeutic targets.
文摘Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.
基金the Cancer Genomics,Tumor Tissue Repository,and Bioinformatics Shared Resources under the NCI Cancer Center Support Grant to the Comprehensive Cancer Center of Wake Forest University Health Sciences,USA(Grant No.P30CA012197)。
文摘In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Gene co-expression clustering in scRNA-seq data presents certain challenges.We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately,and produce results that substantially limit biological expectations of co-expressed genes.Herein,we present single-cell Latent-variable Model(scLM),a gene coclustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context.Importantly,scLM can simultaneously cluster multiple single-cell datasets,i.e.,consensus clustering,enabling users to leverage single-cell data from multiple sources for novel comparative analysis.scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets.Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy.To illustrate the biological insights of scLM,we apply it to our in-house and public experimental scRNA-seq datasets.scLM identifies novel functional gene modules and refines cell states,which facilitates mechanism discovery and understanding of complex biosystems such as cancers.A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.
