ORCID Profile
0000-0003-2197-7083
Current Organisation
Deep Genomics
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474205
Abstract: Scatter plot depicting principal component analysis of the top 25% most variable genes across the integrated cohort of resectable and advanced PDACs before (left) and after (right) batch correction.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520703.V1
Abstract: Supplemental Table S5 lists EGA accession numbers for each s le included in the study.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479606.V1
Abstract: Supplemental Tables and Figures
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474184.V1
Abstract: Supplemental Figures and Tables
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474199.V1
Abstract: Box plots depicting tumor content levels across the metabolic subgroups in each PDAC cohort.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489305
Abstract: Figure S1. hENT1 expression by modified Moffitt subtypes Figure S2. OS in GnP cohort stratified by hENT1 and modified Moffitt Classifier
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474205.V1
Abstract: Scatter plot depicting principal component analysis of the top 25% most variable genes across the integrated cohort of resectable and advanced PDACs before (left) and after (right) batch correction.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474190
Abstract: Heatmap showing median gene expression levels (z-score) of genes involved in various pathways related to cellular metabolism. For each gene, within each of the four metabolic subgroups, expression values were assessed for significant deviation from zero using Wilcoxon signed rank test (mu = 0).
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520697
Abstract: Supplemental Table S2 lists all genes differentially expressed in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 12-10-2022
DOI: 10.1158/1078-0432.CCR-22-2576
Abstract: Modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) remain standard first-line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC. COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal χ2 statistic. 253 patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median overall survival (OS) was 10.0 months in hENT1high versus 7.9 months in hENT1low (P = 0.02). In patients receiving mFFX, there was no difference in overall response rate (ORR 35% vs. 28%, P = 0.56) or median OS (10.6 vs. 10.5 months, P = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1high compared with hENT1low tumors (43% vs. 21%, P = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1high versus 6.7 months hENT1low (P & 0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction P = 0.002). In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530256
Abstract: AbstractPurpose: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood. Experimental Design: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor s les. Patient s les were stratified into EOPC (age of onset ≤55 years i n /i = 117), intermediate (age of onset 55–70 years i n /i = 264), and average (age of onset ≥70 years i n /i = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups. Results: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in i CDKN2A /i ( i P /i = 0.0017), and were more likely to achieve biallelic mutation of i CDKN2A /i through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset ( i P /i = 1.5e-4). Transcription factor forkhead box protein C2 ( i FOXC2 /i ) was significantly upregulated in EOPC tumors ( i P /i = 0.032). Genes significantly correlated with i FOXC2 /i in PDAC s les were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included i VIM /i ( i P /i = 1.8e-8), i CDH11 /i ( i P /i = 6.5e-5), and i CDH2 /i ( i P /i = 2.4e-2). Conclusions: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient s les highlights a distinctive pattern of biallelic i CDKN2A /i mutation in EOPC tumors. Increased expression of i FOXC2 /i in EOPC, with the correlation between i FOXC2 /i and EMT pathways, represents novel molecular characteristics of EOPC. i See related commentary by Lou, p. 8 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474193.V1
Abstract: Kaplan-Meier curve demonstrating the differences in the time to relapse in resectable PDAC. Data for ICGC PACA-CA cohort with available relapse data are shown (N=118).
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474193
Abstract: Kaplan-Meier curve demonstrating the differences in the time to relapse in resectable PDAC. Data for ICGC PACA-CA cohort with available relapse data are shown (N=118).
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520709.V1
Abstract: Supplemental Table S3 lists gene sets significantly enriched among genes up-regulated in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474196
Abstract: Heatmap showing results of consensus clustering (k=2) based on expression of genes associated with normal (n=20) and active (n=22) stroma in PDAC (Moffitt et al., 2015). Robust clusters of normal (n=167) and active (n=158) stroma s les were identified. Lower heatmap shows expression values (z-score) of each gene within each s le. Metabolic subgroup is overlaid as the bottom-most track. There was no significant enrichment of any of the metabolic subgroups among the s les in active or normal stroma clusters.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6542730.V1
Abstract: Abstract Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene i TET2 /i . Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520697.V1
Abstract: Supplemental Table S2 lists all genes differentially expressed in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474199
Abstract: Box plots depicting tumor content levels across the metabolic subgroups in each PDAC cohort.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6528713.V1
Abstract: AbstractPurpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test i P /i = 0.018) and metastatic settings (log-rank test i P /i = 0.027). Patients with cholesterogenic tumors had the longest median survival. i KRAS /i and i MYC /i - lified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test i P /i = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers i MPC1 /i and i MPC2 /i . Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles. i See related commentary by Mehla and Singh, p. 6 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530256.V1
Abstract: AbstractPurpose: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood. Experimental Design: We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor s les. Patient s les were stratified into EOPC (age of onset ≤55 years i n /i = 117), intermediate (age of onset 55–70 years i n /i = 264), and average (age of onset ≥70 years i n /i = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups. Results: EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in i CDKN2A /i ( i P /i = 0.0017), and were more likely to achieve biallelic mutation of i CDKN2A /i through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset ( i P /i = 1.5e-4). Transcription factor forkhead box protein C2 ( i FOXC2 /i ) was significantly upregulated in EOPC tumors ( i P /i = 0.032). Genes significantly correlated with i FOXC2 /i in PDAC s les were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included i VIM /i ( i P /i = 1.8e-8), i CDH11 /i ( i P /i = 6.5e-5), and i CDH2 /i ( i P /i = 2.4e-2). Conclusions: Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient s les highlights a distinctive pattern of biallelic i CDKN2A /i mutation in EOPC tumors. Increased expression of i FOXC2 /i in EOPC, with the correlation between i FOXC2 /i and EMT pathways, represents novel molecular characteristics of EOPC. i See related commentary by Lou, p. 8 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22479606
Abstract: Supplemental Tables and Figures
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489305.V1
Abstract: Figure S1. hENT1 expression by modified Moffitt subtypes Figure S2. OS in GnP cohort stratified by hENT1 and modified Moffitt Classifier
Publisher: American Association for Cancer Research (AACR)
Date: 09-2020
DOI: 10.1158/1535-7163.MCT-20-0094
Abstract: Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520709
Abstract: Supplemental Table S3 lists gene sets significantly enriched among genes up-regulated in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 2020
DOI: 10.1158/1078-0432.CCR-19-1543
Abstract: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC- lified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles. See related commentary by Mehla and Singh, p. 6
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520703
Abstract: Supplemental Table S5 lists EGA accession numbers for each s le included in the study.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532926.V1
Abstract: AbstractPurpose: Modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) remain standard first-line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC. Experimental Design: COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal i χ /i sup /sup statistic. Results: patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median overall survival (OS) was 10.0 months in hENT1 sup high /sup versus 7.9 months in hENT1 sup low /sup ( i P /i = 0.02). In patients receiving mFFX, there was no difference in overall response rate (ORR 35% vs. 28%, i P /i = 0.56) or median OS (10.6 vs. 10.5 months, i P /i = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1 sup high /sup compared with hENT1 sup low /sup tumors (43% vs. 21%, i P /i = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1 sup high /sup versus 6.7 months hENT1 sup low /sup ( i P /i 0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction i P /i = 0.002). Conclusions: In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520706.V1
Abstract: Supplemental Table S4 lists gene sets significantly enriched among genes down-regulated in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520706
Abstract: Supplemental Table S4 lists gene sets significantly enriched among genes down-regulated in VMP s les.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520700
Abstract: Supplemental Table S1 lists clinical characteristics for the study cohort. Figure S1 depicts results of batch correction. Figures S2 and S3 show comparisons between ERV levels and tumor content. Figure S4 shows ERV levels across different biopsy sites.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22520700.V1
Abstract: Supplemental Table S1 lists clinical characteristics for the study cohort. Figure S1 depicts results of batch correction. Figures S2 and S3 show comparisons between ERV levels and tumor content. Figure S4 shows ERV levels across different biopsy sites.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6542730
Abstract: Abstract Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. Although expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic, and clinical data across an integrated cohort of 199 patients with metastatic breast, colorectal, and pancreatic ductal adenocarcinoma tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene i TET2 /i . Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation, and immunogenicity. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474196.V1
Abstract: Heatmap showing results of consensus clustering (k=2) based on expression of genes associated with normal (n=20) and active (n=22) stroma in PDAC (Moffitt et al., 2015). Robust clusters of normal (n=167) and active (n=158) stroma s les were identified. Lower heatmap shows expression values (z-score) of each gene within each s le. Metabolic subgroup is overlaid as the bottom-most track. There was no significant enrichment of any of the metabolic subgroups among the s les in active or normal stroma clusters.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529866
Abstract: AbstractPurpose: RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each s le, and results were tested for subtype call consistency and association with survival. Results: Basal-like and classical subtype calls were concordant in 88% of patient s les, and survival outcomes were significantly different ( i P /i 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression ( i P /i 0.0001) and mutant i KRAS /i allelic imbalance ( i P /i 0.001). Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529866.V1
Abstract: AbstractPurpose: RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. Experimental Design: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each s le, and results were tested for subtype call consistency and association with survival. Results: Basal-like and classical subtype calls were concordant in 88% of patient s les, and survival outcomes were significantly different ( i P /i 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression ( i P /i 0.0001) and mutant i KRAS /i allelic imbalance ( i P /i 0.001). Conclusions: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice. /
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/1078-0432.CCR-20-1042
Abstract: With the rising incidence of early-onset pancreatic cancer (EOPC), molecular characteristics that distinguish early-onset pancreatic ductal adenocarcinoma (PDAC) tumors from those arising at a later age are not well understood. We performed bioinformatic analysis of genomic and transcriptomic data generated from 269 advanced (metastatic or locally advanced) and 277 resectable PDAC tumor s les. Patient s les were stratified into EOPC (age of onset ≤55 years n = 117), intermediate (age of onset 55–70 years n = 264), and average (age of onset ≥70 years n = 165) groups. Frequency of somatic mutations affecting genes commonly implicated in PDAC, as well as gene expression patterns, were compared between EOPC and all other groups. EOPC tumors showed significantly lower frequency of somatic single-nucleotide variant (SNV)/insertions/deletions (indel) in CDKN2A (P = 0.0017), and were more likely to achieve biallelic mutation of CDKN2A through homozygous copy loss as opposed to heterozygous copy loss coupled with a loss-of-function SNV/indel mutation, the latter of which was more common for tumors with later ages of onset (P = 1.5e-4). Transcription factor forkhead box protein C2 (FOXC2) was significantly upregulated in EOPC tumors (P = 0.032). Genes significantly correlated with FOXC2 in PDAC s les were enriched for gene sets related to epithelial-to-mesenchymal transition (EMT) and included VIM (P = 1.8e-8), CDH11 (P = 6.5e-5), and CDH2 (P = 2.4e-2). Our comprehensive analysis of sequencing data generated from a large cohort of PDAC patient s les highlights a distinctive pattern of biallelic CDKN2A mutation in EOPC tumors. Increased expression of FOXC2 in EOPC, with the correlation between FOXC2 and EMT pathways, represents novel molecular characteristics of EOPC. See related commentary by Lou, p. 8
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474184
Abstract: Supplemental Figures and Tables
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474190.V1
Abstract: Heatmap showing median gene expression levels (z-score) of genes involved in various pathways related to cellular metabolism. For each gene, within each of the four metabolic subgroups, expression values were assessed for significant deviation from zero using Wilcoxon signed rank test (mu = 0).
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478148.V1
Abstract: Supplementary Figures S1-7
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6528713
Abstract: AbstractPurpose: Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. Experimental Design: We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). Results: On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test i P /i = 0.018) and metastatic settings (log-rank test i P /i = 0.027). Patients with cholesterogenic tumors had the longest median survival. i KRAS /i and i MYC /i - lified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test i P /i = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers i MPC1 /i and i MPC2 /i . Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. Conclusions: Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles. i See related commentary by Mehla and Singh, p. 6 /i /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478148
Abstract: Supplementary Figures S1-7
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532926
Abstract: AbstractPurpose: Modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) remain standard first-line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC. Experimental Design: COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal i χ /i sup /sup statistic. Results: patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median overall survival (OS) was 10.0 months in hENT1 sup high /sup versus 7.9 months in hENT1 sup low /sup ( i P /i = 0.02). In patients receiving mFFX, there was no difference in overall response rate (ORR 35% vs. 28%, i P /i = 0.56) or median OS (10.6 vs. 10.5 months, i P /i = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1 sup high /sup compared with hENT1 sup low /sup tumors (43% vs. 21%, i P /i = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1 sup high /sup versus 6.7 months hENT1 sup low /sup ( i P /i 0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction i P /i = 0.002). Conclusions: In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474187
Abstract: Boxplots demonstrating expression values (z-score) for genes involved in amino acid catabolism (n=64), nucleotide metabolism (n=272) or the pentose phosphate pathway (n=100). P values were calculated using multiple pairwise Wilcoxon rank sum tests (two-tailed), and were subjected to Benjamini-Hochberg multiple test correction.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474187.V1
Abstract: Boxplots demonstrating expression values (z-score) for genes involved in amino acid catabolism (n=64), nucleotide metabolism (n=272) or the pentose phosphate pathway (n=100). P values were calculated using multiple pairwise Wilcoxon rank sum tests (two-tailed), and were subjected to Benjamini-Hochberg multiple test correction.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474202.V1
Abstract: Bar plot depicting the proportion of glycolytic and cholesterogenic genes in each of the three consensus clusters in different cancer types.
Publisher: American Association for Cancer Research (AACR)
Date: 08-2019
DOI: 10.1158/1078-0432.CCR-19-0191
Abstract: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion–positive pancreatic ductal adenocarcinoma is not fully understood. Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion–positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib. See related commentary by Aguirre, p. 4589
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/1078-0432.CCR-20-2831
Abstract: RNA-sequencing–based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. “Classical” and “basal-like” PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each s le, and results were tested for subtype call consistency and association with survival. Basal-like and classical subtype calls were concordant in 88% of patient s les, and survival outcomes were significantly different (P & 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P & 0.0001) and mutant KRAS allelic imbalance (P & 0.001). Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22474202
Abstract: Bar plot depicting the proportion of glycolytic and cholesterogenic genes in each of the three consensus clusters in different cancer types.
No related grants have been discovered for Rob Denroche.