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  • 1
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    Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 11 ( 2021-06-01), p. 3134-3143
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 11 ( 2021-06-01), p. 3134-3143
    Abstract: Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P & lt; 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. Significance: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-3267
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
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    The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 20 ( 2014-10-15), p. 5808-5818
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 20 ( 2014-10-15), p. 5808-5818
    Abstract: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-1531
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
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    Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 18 ( 2020-09-15), p. 4004-4013
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 18 ( 2020-09-15), p. 4004-4013
    Abstract: Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at P values & lt; 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10−6, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC (P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease (P = 0.22) and primary sclerosing cholangitis (P = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. Significance: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-0447
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Genetic Mechanisms of Immune Evasion in Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 6 ( 2018-06-01), p. 730-749
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 6 ( 2018-06-01), p. 730-749
    Abstract: To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-1327
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract 998: Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukemia (B-ALL): A report from the children's oncology group (COG) - Target - St. Jude Pediatric Cancer Genome Project
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 998-998
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 998-998
    Abstract: Tumor clonal heterogeneity has been demonstrated in several cancers; however, the rise and fall of subclones under therapy have not been well characterized. To gain insight into the subclonal population architecture of pediatric B-ALL, we analyzed somatic lesions including sequence mutations, structural alterations and DNA copy number abnormalities derived from high coverage (200X) exome sequencing, whole-genome sequencing and SNP arrays of diagnosis (Dx)-remission-relapse DNA from 20 patients (median 7 yrs, range 2 to 19) treated on recent COG B-ALL trials. Cases were selected for analysis based upon occurrence of an early bone marrow relapse (median 19.2 months, range 3.8 to 35.7), which is associated with poor survival. We identified a high frequency of mutations in B-cell development (80%, e.g. PAX5, IKZF1, TCF3, BTG1, TOX, and EBF1 ), RAS signaling (65%, e.g. NRAS, KRAS, PTPN11 and FLT3), TP53 (60%, e.g. CDKN2A, TP53 and RB1), kinase signaling (25%, e.g. JAK2, CRLF2 and SH2B3) and chromatin remodeling (60%, e.g. WHSC1, MLL2, CREBBP, ARID2 and SETD2) pathways. Somatic lesions in these pathways were mostly retained (68%) between Dx and relapse. In contrast, mutations in the purine metabolism genes NT5C2 (45%) and NT5CB1 (15%) were relapse-specific. We constructed clonal lineage of somatic lesions for 15 cases based on subclonal population fractions estimated by a binomial mixture model that adjusts for sequence coverage of mutant alleles. The subclone number (median 3, range 1-5) at Dx was comparable to that at relapse (median=3, range 2-4). Notably, 6 Dx samples were observed with multiple subclones harboring distinct driver mutations in the same oncogene (e.g. NRAS, KRAS and JAK2). In almost all cases only one subclone from Dx arose to be the predominant clone present at relapse. Moreover, the mutation burden in an emergent subclone was comparable to those eradicated by therapy (P=0.43, Wilcoxon rank sum). In 80% of cases, the predominant clone at relapse originated from the smallest Dx subclone; in 45% of those cases, mutant allele present in relapse was detectable in remission DNA (∼0.1%) obtained at the end of the 1st month of therapy. Clonal lineage shows that the earliest acquired mutations at relapse are NT5C2 (n=5), NRAS (n=3), USH2A (n=3), WHSC1 (n=2), TP53 (n=2), IKZF1 (n=1) and CREBBP (n=1). Our study is the first that analyzes the genetic composition and population architecture of subclones that rise or fall after B-ALL therapy. The majority of the “rising” subclones are oligoclonal at Dx, which may explain acquisition of mutations such as those found in NT5C2 to confer growth advantage in relapse. Additional studies of patients who were cured of B-ALL are needed to determine if the presence of mutant clone at end induction might help to predict risk and tempo of relapse. Citation Format: Xiaotu Ma, Mignon L. Loh, Michael Rusch, Michael Edmonson, Richard C. Harvey, David A. Wheeler, Oliver A. Hampton, John Easton, Donald Yergeau, Bhavin Vadodaria, Gang Wu, William L. Carroll, I-Ming Chen, Daniela S. Gerhard, Julie M. Gastier-Foster, Mary V. Relling, Malcolm A. Smith, Meenakshi Devidas, Jaime M. Guidry Auvil, James R. Downing, Cheryl L. Willman, Charles G. Mullighan, Stephen P. Hunger, Jinghui Zhang. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukemia (B-ALL): A report from the children's oncology group (COG) - Target - St. Jude Pediatric Cancer Genome Project. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2014-998
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-998
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 6
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    Abstract LB-180: The genetic landscape of Wilms tumor
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-180-LB-180
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. LB-180-LB-180
    Abstract: Introduction: The National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative seeks to characterize the genomes of high-risk pediatric tumors to identify therapeutic targets. The High-Risk Renal Tumor TARGET initiative includes the analysis of pre-therapy favorable histology Wilms Tumors (FHWT) that relapsed and tumors with diffuse anaplasia (unfavorable histology; DAWT). These two tumor subsets have survival rates of approximately 50% and 60%, respectively. Experimental procedures: Genomic sequencing (whole genome [WGS] or exome [WXS] ), global copy number analysis, and global gene expression analysis were performed on a discovery set of 117 (78 FHWT, 39 DAWT) pre-therapy high-risk WTs treated on National Wilms Tumor Study-5 (NWTS-5). To determine the frequency of recurrent variants, targeted sequencing (Illumina HiSeq2500) was performed on a validation set of pre-therapy tumor DNA from a case-cohort of all FHWT treated on NWTS-5 (531 FHWT) and all available 118 DAWT treated on NWTS-5 (these groups include tumors from the discovery set). Results: WGS and WXS revealed an average of 21.74 ± 22.6 high-quality variants per DAWT (range, 3-131) and 13.8 ± 10.9 per FHWT (range 2-58). Genes previously reported to be recurrently mutated in WT were mutated at the following frequencies in the validation set: WTX (6%), CTNNB1 (15%), WT1 (7.5%), DROSHA (11%), DGCR8 (4.5%), XPO5 (2%), SIX1/2 (7%), and MLLT1 (3%). In addition, mutations were identified in three genes that impact the NMYC pathway, which is known to be involved in renal development. These include MYCN P44L/H (4%), MAX R60Q (2%), and novel mutations in NONO (2%); these mutations were mutually exclusive. Novel mutations in BCOR, a transcriptional corepressor that regulates both gene expression during development and chromatin modification, were found in 3% of validation set tumors. Analysis of global gene expression revealed significant up-regulation of genes associated with kidney development, extracellular matrix organization, and epithelial tube development in BCOR-mutant tumors compared with precursor lesions (5 hyperplastic perilobar nephrogenic rests). TP53 mutations were identified in 48% of DAWTs and 1% of FHWTs. The above data do not include copy number changes, which were recurrently detected in WT1, WTX, NMYC, and TP53. Conclusions: Through the TARGET initiative, we have identified several novel, potential driver mutations that occur in WT and have not been reported in other pediatric tumors. The majority of these genes are known to function in processes critical to early development and/or specifically in renal development. Many of these mutations are accompanied by Wnt activating mutations or 11p15 biallelic expression. However, approximately 50% of WTs lack clear driver mutations. Future studies will need to focus on elucidating epigenetic alterations in these tumors as well as genetic changes outside of protein-coding regions. Citation Format: Samantha L. Gadd, Amy L. Walz, Ariadne HAG Ooms, Vicki Huff, Daniela S. Gerhard, Malcolm A. Smith, Jaime M. Guidry Auvil, Leandro Hermida, Tanja Davidsen, Patee Gesuwan, Daoud Meerzaman, Yussanne Ma, Marco A. Marra, Jeffrey S. Dome, Charles G. Mullighan, David A. Wheeler, Oliver A. Hampton, Julie M. Gastier-Foster, Nicole Ross, Elizabeth J. Perlman. The genetic landscape of Wilms tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-180.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-LB-180
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
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    Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Discovery Vol. 11, No. 12 ( 2021-12-01), p. 3008-3027
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 11, No. 12 ( 2021-12-01), p. 3008-3027
    Abstract: Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor–normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. Significance: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-20-1631
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children's Oncology Group
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 22 ( 2016-11-15), p. 5582-5591
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 22 ( 2016-11-15), p. 5582-5591
    Abstract: Purpose: To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs). Experimental Design: All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs. Results: Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry. Conclusions: These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582–91. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-0985
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Abstract LB176: Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network identifies microenvironment features as drivers of metastasis
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB176-LB176
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB176-LB176
    Abstract: Background: Metastatic breast cancer (MBC) patients often have short survival, and successful treatment represents one of the most challenging aspects of cancer care. This poor prognosis is likely multifactorial, including increased clonal heterogeneity, drug resistance mechanisms, and alterations of the tumor microenvironment. Methods: The primary data source was multi-platform data coming from the AURORA US Project that includes RNAseq, DNAseq, and DNA methylation arrays, which assayed 55 MBC patients representing 51 primary cancers and 102 linked metastatic specimens. In addition, RNA sequencing data from two other datasets of primary tumor-metastasis pairs were also used (i.e. UNC Tumor Donation Program/RAP dataset (24 primary and 74 metastasis specimens), and the GEICAM/2009-03 ConvertHER trial dataset (102 primaries and 102 metastatic pairs)). In total, this combined RNAseq dataset contained 177 primary tumors and 278 metastases, including 28 liver, 18 lung, 12 brain, and 24 lymph node metastases. We used these data to address two pressing questions, namely: 1) do gene expression features vary in primary tumors vs metastases according to PAM50 expression subtype, and 2) do gene expression features vary according to site of metastasis. Results: Using the AURORA multi-platform data, we determined that 17% of metastatic tumors (mainly TNBC/Basal-like) showed reduced expression of HLA-A that was associated with DNA methylation and/or focal DNA deletions near the HLA-A locus; these methylated tumors also showed concomitant lower immune cell infiltrates. Reduced expression of HLA-A gene and immune cell infiltrates were also validated at the RNA level in RAP dataset. Next, RNA expression differences were examined using the combined data set and varied according to tumor subtype. ER+/Luminal metastases had lower fibroblast and endothelial cell content, while triple negative (TNBC)/Basal-like metastases showed a dramatic decrease in T cell and B cell signatures/features. Comparative analyses between primary and site-specific metastasis (i.e., primary vs liver metastasis) or between sites of metastases (i.e., liver vs lung metastasis) revealed that both liver and brain, on average, had low immune cell features regardless of the primary tumor phenotype. Even within the same patient, we detected low immune cell features in brain and liver metastases compared to lung and lymph node metastases. Lastly, liver metastases showed a gain of Luminal B/HER2E gene expression features and MYC targets, and brain TNBC metastasis showed a gain of cell differentiation/Luminal-related gene signatures. Conclusions: These findings could have direct implications for the treatment of MBC patients with immune-based therapies and suggest new therapeutic avenues depending upon the tumor metastasis phenotype, and site of metastasis. Citation Format: Susana Garcia Recio, Toshinori Hinoue, Gregory L. Wheeler, Benjamin J. Kelly, Justin M. Balko, Katherine A. Hoadley, Peter W. Laird, Elaine R. Mardis, Charles M. Perou. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network identifies microenvironment features as drivers of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB176.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB176
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract 642: Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 642-642
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 642-642
    Abstract: Clinical genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. In the Genomes for Kids study (NCT02530658) we used a three-platform sequencing approach, including whole genome (WGS), whole exome (WES) and RNA sequencing, to examine tumor and paired germline genomes from prospectively identified children with cancer. The goal of the study was to assess the potential of comprehensive next generation sequencing to elucidate the molecular mechanisms underlying tumor formation and investigate the potential of this information to influence clinical decision-making.The cohort, with a median age of 6 yrs, range 0 - 26 yrs, included 301 patients with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type or stage. Patients with hematologic malignancies accounted for 41% of cases, 31% had CNS tumors, and 28% had other non-CNS solid tumors. This cohort also included 18 patients with very rare tumor types, defined here as occurring in less than 2 cases per million person per year.Two hundred fifty three patients (84%) had sufficient tumor for three-platform sequencing and all 301 had adequate paired germline samples. Following analysis, 86% of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer predisposing (18%) variants. The inclusion of WGS enabled detection of oncogenic gene fusions, as well as 22 cases in which oncogenes were activated through enhancer hijacking, a particularly frequent occurrence in hematologic malignancies. In addition, WGS effectively detected clinically relevant small intragenic deletions (15% of tumors) and a variety of mutational signatures, which were not detectable through analysis of whole exome data. Evaluation of 56 pathogenic germline variants in the context of paired tumor sequence data helped establish the disease relevance of several genes that are not typically associated with the cancer type in question, providing critical insights on a case-by-case basis. Examples include a pathogenic germline variant in MUTYH in a patient with retinoblastoma whose tumor exhibited a mutation signature associated with reactive oxygen species indicative of loss of MUTYH function; and conversely, a likely pathogenic variant in PMS2 in a rare brain cancer, which did not exhibit a mutation signature associated with microsatellite instability. This study successfully demonstrated the power of this three-platform approach to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. As a result of these findings, we have incorporated this three-platform approach into our routine real-time clinical service at St. Jude Children's Hospital. Citation Format: David A. Wheeler, Scott Newman, Joy Nakitandwe, Chimene A. Kesserwan, Elizabeth M. Azzato, Michael C. Rusch, Sheila Shurtleff, Armita Bahrami, Brent Orr, Jeffery M. Klco, Dale J. Hedges, Kayla V. Hamilton, Scott G. Foy, Michael N. Edmonson, Andrew Thrasher, Jiali Gu, Lynn W. Harrison, Lu Wang, Roya Mostafavi, Manish Kubal, Jamie Maciaszek, Michael Clay, Annastasia Ouma, Antonina Silkov, Yanling Liu, Zhaojie Zhang, Yu Liu, Samuel W. Brady, Xin Zhou, Mark Wilkinson, Delaram Rahbarinia, Jay Knight, Jian Wang, Charles G. Mullighan, Rose B. McGee, Emily A. Quinn, Elsie L. Gerhardt, Leslie M. Taylor, Regina Nuccio, Jessica M. Valdez, Stacy J. Hines-Dowell, Alberto Pappo, Giles Robinson, Liza-Marie Johnson, Ching-Hon Pui, David W. Ellison, James R. Downing, Jinghui Zhang, Kim E. Nichols. Genomes for Kids: Comprehensive DNA and RNA sequencing defining the scope of actionable mutations in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 642.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-642
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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