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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract 3825: Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3825-3825
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3825-3825
    Abstract: With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas and 137 heritable tumor immune phenotype components (IP components), we identified and investigated 532 TIME-SNPs. Focusing on 77 variants that were relevant to cancer risk, survival, or treatment response, we explored their potential to reveal novel targets for immunotherapy. Many variants overlapped regions with histone marks indicating active transcription, and influenced gene activities in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs implicated genes such as LAIR1, TREX1, CTSS, CTSW and LILRB2 were differentially expressed between responders and non-responders to immune-checkpoint blockade (ICB) in preclinical studies. Of these, LILRB2 and LAIR1 have already been identified as putative targets for immunotherapy. Here we found that inhibition of CTSS led to better tumor control and survival in murine models, alone or in combination with anti-PD-1. Collectively we show that through an integrative approach, it is possible to link host genetics to TIME characteristics, informing novel biomarkers for cancer risk and target identification in immunotherapy. Citation Format: Meghana Pagadala, Victoria Wu, Eva Pérez-Guijarro, Hyo Kim, Andrea Castro, James Talwar, Cristian Gonzalez-Colin, Steven Cao, Benjamin J. Schmiedel, Timothy Sears, Shervin Goudarzi, Divya Kirani, Rany M. Salem, Gerald P. Morris, Olivier Harismendy, Sandip P. Patel, Jill P. Mesirov, Maurizio Zanetti, Chi-Ping Day, Chun C. Fan, Wesley K. Thompson, Glenn Merlino, J. Silvio Gutkind, Pandurangan Vijayanand, Hannah Carter. Germline modifiers of the tumor immune microenvironment reveal drivers of immunotherapy response [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 3825.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3825
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 1016: Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1016-1016
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1016-1016
    Abstract: Autophagy has been linked with melanoma, but no polymorphisms in autophagy related (ATG) genes have been investigated for association with melanoma prognostic indicators and survival. We examined 5 ATG gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped for five SNPs with a known or suspected impact on autophagic flux. While we did not identify an association with survival, a significant association was identified between the minor allele for an ATG16L polymorphism (rs2241880) and a decrease in Breslow thickness (p = 0.03), earlier tumor stage at diagnosis (OR 0.47, 95% CI 0.27-0.81, p = 0.02) and younger age at diagnosis (p = 0.02). In addition, two SNPs in ATG5 (rs2245214 and rs510432) were found to be significantly associated with increased tumor stage of melanoma (OR 1.84 95% CI 1.12-3.02, p = 0.05; OR 1.47 95% CI 1.11-1.94, p = 0.03). Finally, we identified inverse associations between the minor allele of rs2245214 and melanomas on the scalp or neck (OR 0.20, 95% CI 0.05-0.86, p = 0.03); rs1864182 (OR 0.42, 95% CI 0.21-0.88, p = 0.02) and brisk TILs, and rs510432 (OR 0.55 95% CI 0.34-0.87, p = 0.01) with non-brisk TILs, although they were not globally significant. In summary, our data suggests that ATG SNPs, while not associated with survival, may be associated with Breslow thickness, tumor stage, age at diagnosis, and aggressive histopathological factors. These associations could contribute to our current understanding of the significant role of autophagy in melanoma progression. Citation Format: Kirsten A. m. White, Li Luo, Todd A. Thompson, Salina Torres, Chien-An A. Hu, Nancy E. Thomas, Hoda Anton-Culver, Stephen B. Gruber, Lynn From, Klaus J. Busam, Irene Orlow, Peter A. Kanetsky, Lorraine D. Marrett, Richard P. Gallagher, Roberto Zanetti, Stefano Rosso, Terry Dwyer, Anne E. Cust, Allison Venn, Colin B. Begg, Marianne Berwick, Jenna Lillyquist. Variants in autophagy related genes and clinical characteristics in melanoma: a population-based study. [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 1016.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1016
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Characterization of ERG , AR and PTEN Gene Status in Circulating Tumor Cells from Patients with Castration-Resistant Prostate Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 7 ( 2009-04-01), p. 2912-2918
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 7 ( 2009-04-01), p. 2912-2918
    Abstract: Hormone-driven expression of the ERG oncogene after fusion with TMPRSS2 occurs in 30% to 70% of therapy-naive prostate cancers. Its relevance in castration-resistant prostate cancer (CRPC) remains controversial as ERG is not expressed in some TMPRSS2-ERG androgen-independent xenograft models. However, unlike these models, CRPC patients have an increasing prostate-specific antigen, indicating active androgen receptor signaling. Here, we collected blood every month from 89 patients (54 chemotherapy-naive patients and 35 docetaxel-treated patients) treated in phase I/phase II clinical trials of an orally available, highly specific CYP17 inhibitor, abiraterone acetate, that ablates the synthesis of androgens and estrogens that drive TMPRSS2-ERG fusions. We isolated circulating tumor cells (CTC) by anti–epithelial cell adhesion molecule immunomagnetic selection followed by cytokeratin and CD45 immunofluorescence and 4′,6-diamidino-2-phenylindole staining. We used multicolor fluorescence in situ hybridization to show that CRPC CTCs, metastases, and prostate tissue invariably had the same ERG gene status as therapy-naive tumors (n = 31). We then used quantitative reverse transcription–PCR to show that ERG expression was maintained in CRPC. We also observed homogeneity in ERG gene rearrangement status in CTCs (n = 48) in contrast to significant heterogeneity of AR copy number gain and PTEN loss, suggesting that rearrangement of ERG may be an earlier event in prostate carcinogenesis. We finally report a significant association between ERG rearrangements in therapy-naive tumors, CRPCs, and CTCs and magnitude of prostate-specific antigen decline (P = 0.007) in CRPC patients treated with abiraterone acetate. These data confirm that CTCs are malignant in origin and indicate that hormone-regulated expression of ERG persists in CRPC. [Cancer Res 2009;69(7):2912–8]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-3667
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 787: Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 787-787
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 787-787
    Abstract: Introduction: Tripartite Motif Containing 24 (TRIM24) is a PhD/Bromodomain containing steroid receptor co-activator that targets p53 for proteosomal degradation, transforms human mammary epithelial cells, and promotes treatment resistance in preclinical models. While bromodomain inhibitors and proteolysis targeting chimeras have been developed against TRIM24, the disease subtype it is most relevant to remains under explored. In this study, we characterize a uniquely annotated cohort of invasive ductal carcinomas for tumor expression of TRIM24 protein by immunohistochemistry (IHC) to assess its relationship with molecular and clinicopathological features. Methods: Tissue microarrays (TMAs) representing 198 tumors with 6 cores/tumor were obtained from the Tayside Biospecimen Repository and stained by IHC for TRIM24. TMAs were scored for nuclear and cytosolic intensity and the proportion of tumor cells with staining. These values were combined into Histo-scores (H-Scores) and averaged as a semi-quantitative metric for tumor TRIM24 expression. Statistical associations between TRIM24 H-Scores, clinicopathological annotations, and existing molecular profiles generated from the same TMA were determined using SciPy and SPSS. Results: TRIM24 has four distinct expression patterns in the 170 tumors with scorable cores on the TMA: nuclear (55), cytosolic (38), nuclear and cytosolic (35), and negative (42). Non-parametric analysis revealed associations between TRIM24 expression pattern and ER (χ2=21.3, p=0.000), PR (χ2=14.8, p=0.002), invasive grade (χ2=14.9, p=0.021), and TP53 mutation (χ2=9.55, p=0.023). No significant association was found with HER2 (χ2=1.51, p=0.68). Higher nuclear H-scores are observed in ER+ (p=0.0008) and PR+ (p=0.001) tumors. Higher cytosolic but not nuclear H-scores are observed in Grade 3 (p=0.003), triple negative (TNBC, p=0.004), and TP53 mutant (p=0.0289) cases. Kaplan-Meier analysis revealed high cytosolic (p=0.037) but not nuclear (p=0.601) H-scores associated with poor survival in ER- patients. No significant survival difference was found in ER+ patients stratified by nuclear (p=0.781) or cytosolic (p=0.683) H-scores. Similar analysis of TNBC was underpowered. TP53 mutant (p=0.142) but not TP53 wild type (p=0.378) disease with high cytosolic H-scores trend toward diminished survival. No such trend is observed in cases stratified by nuclear H-scores and TP53 status. Conclusions: TRIM24 is overexpressed in most human breast cancers. Nuclear expression is more common in ER+/PR+ tumors but does not stratify outcome. Cytosolic expression occurs in Grade 3, ER-, and TP53 mutant tumors and associates with poor clinical outcome in ER- disease. This suggests TRIM24 may be a more relevant drug target in ER-/PR- than luminal breast cancer and emphasizes the need for studies investigating the cytosolic functions of TRIM24 in ER-/PR- and TP53-mutant breast cancer. Citation Format: Lalit R. Patel, Jurgen Mitsch, Grazziela P. Figueredo, Philip Quinlan, Lee B. Jordan, Colin A. Purdie, Savitri Krishnamurthy, Michelle C. Barton, Alastair M. Thompson. Cytosolic TRIM24 characterizes an aggressive subset of ER- PR- and TP53 mutant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 787.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-787
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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