DNA profiling is an established method for cancer treatment selection,while RNA profiling remains investigational.We explored associations between DNA and RNA alterations and between the number of genes with altered e...DNA profiling is an established method for cancer treatment selection,while RNA profiling remains investigational.We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival(OS)using patient data from IMPACT2(NCT02152254),a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types.Molecular profiling,including DNA next-generation sequencing,was performed on all 829 patients in the IMPACT2 study.RNA profiling was performed by Tempus for 253 of 829 patients.We evaluated the concordance between DNA and RNA profiling,analyzed OS in 217 treated patients with RNA profiling,and assessed PD-L1 status and number of genes with altered expression.Fifty patients exhibited 58 concordant events,i.e.,genomic and expression alteration(s)in the same gene,including 38 copy number events,and 41 patients had statistically significant concordance.We identified 123 gene pairs with significant associations between genomic and expression alterations(p<0.05),including TP53 alterations with VEGFA overexpression.The median OS for patients with 0-2,3-5,and≥6 genes with altered expression was 9.8,11.9,and 6.7 months,respectively(p=0.03).These results underscore RNA profiling’s potential actionability,and altered expression in≥6 genes was associated with shorter OS.Significant concordance of TP53 alterations with VEGFA overexpression may partially explain tumor response to bevacizumab in TP53-mutant patients.展开更多
Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,...Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based chemotherapy.Survival benefit with second-line treatment is unknown.Thus,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of value.Methods:Comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients.Clinical data were collected using an IRB approved protocol from a single-center in US and from China.Results:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per patient.The most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US patients.NFE2L2 mutations were present in 6.5%of Chinese patients and not observed in the US cohort.Interestingly,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases.Out of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).Conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options.The identification of high TMB,ERBB2,CDKN2A/B,PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.展开更多
基金supported in part by Mr.and Mrs.Steven McKenzie’s EndowmentKatherine Russell Dixie’s Distinguished Professorship Endowment+1 种基金donor funds from Jamie’s Hope and Mrs.and Mr.James Ritter for Dr.Tsimberidou’s Personalized Medicine Programin part also supported by the National Institutes of Health/National Cancer Institute award number P30 CA016672(University of Texas MD Anderson Cancer Center).
文摘DNA profiling is an established method for cancer treatment selection,while RNA profiling remains investigational.We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival(OS)using patient data from IMPACT2(NCT02152254),a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types.Molecular profiling,including DNA next-generation sequencing,was performed on all 829 patients in the IMPACT2 study.RNA profiling was performed by Tempus for 253 of 829 patients.We evaluated the concordance between DNA and RNA profiling,analyzed OS in 217 treated patients with RNA profiling,and assessed PD-L1 status and number of genes with altered expression.Fifty patients exhibited 58 concordant events,i.e.,genomic and expression alteration(s)in the same gene,including 38 copy number events,and 41 patients had statistically significant concordance.We identified 123 gene pairs with significant associations between genomic and expression alterations(p<0.05),including TP53 alterations with VEGFA overexpression.The median OS for patients with 0-2,3-5,and≥6 genes with altered expression was 9.8,11.9,and 6.7 months,respectively(p=0.03).These results underscore RNA profiling’s potential actionability,and altered expression in≥6 genes was associated with shorter OS.Significant concordance of TP53 alterations with VEGFA overexpression may partially explain tumor response to bevacizumab in TP53-mutant patients.
文摘Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based chemotherapy.Survival benefit with second-line treatment is unknown.Thus,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of value.Methods:Comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients.Clinical data were collected using an IRB approved protocol from a single-center in US and from China.Results:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per patient.The most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US patients.NFE2L2 mutations were present in 6.5%of Chinese patients and not observed in the US cohort.Interestingly,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases.Out of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).Conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options.The identification of high TMB,ERBB2,CDKN2A/B,PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.
