Ankit Patel’s research while affiliated with Roswell Park Comprehensive Cancer Center and other places
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Although the value of tumor-infiltrating lymphocytes is well known, the clinical relevance of an increased immune response, specifically in breast cancer, has not been investigated across large cohorts of patients using computational algorithms. Our hypothesis stated that an enhanced immune response is associated with an improvement in outcomes. To quantify the immune response, we utilized the allograft rejection score correlated with cytolytic activity and with all the other Hallmark immune-related gene sets. The score reflected the amount of infiltrating immune cells that correlated with the immune checkpoint molecule expressions, including CD4+ and CD8+ T cells, T helper type 1 (Th1) and type 2 (Th2) cells, M1 macrophages, B cells, and plasmacytoid dendritic cells (pDC). A high score was associated with high levels of intratumor heterogeneity, homologous recombination defects, mutation rate, histological grade, advanced stage, and lymph node metastasis. Breast malignancy with a high score enriched immune-related gene sets and pro-cancer-related gene sets, including epithelial–mesenchymal transition and KRAS pathway, in ER-positive/HER2-negative and triple-negative breast cancer (TNBC) groups. TNBC had the highest score compared to other subtypes, and was associated with better survival. In conclusion, we found that breast cancer with a high immune response is associated with aggressive cancer biology, but with better survival in TNBC.
INTRODUCTION: Homologous recombination deficiency (HRD) is involved in breast cancer carcinogenesis, however, activation of DNA repair in cancer cells may promote its survival and progression. RAD51 plays an essential role in homologous recombination with BRCA2. Recently, RAD51 has been highlighted to play a role in resistance to DNA-damaging chemotherapy or PARP inhibitors. We hypothesized that RAD51 as a prognostic and predictive biomarker of drug sensitivity in breast cancer.
MATERIALS AND METHODS: Total of 4500 primary breast cancer patients from three independent cohorts were examined. High and low expression of RAD51 were divided by median RNA expression. Response to treatments were assessed in total of 3000 patients across 11 independent cohorts of breast cancer patients that received neoadjuvant chemotherapy.
RESULTS: RAD51 was upregulated in cancer compared to normal tissues in the TCGA cohort and was positively correlated with HRD. Cancer with high RAD51 group enriched DNA repair gene set in gene set enrichment analysis (GSEA) in all cohorts and had high expression of HRD-related genes including BRCA1 and BRCA2. Histological grade and Ki67 expression were positively correlated with RAD51, and all cancer proliferation gene sets from Hallmark (E2F target, G2M checkpoint, Myc Targets v1 and v2, and Mitotic Spindle) were strongly enriched in the high RAD51 expression breast cancer in all cohorts. In TCGA, tumor mutation burden and neoantigen were also higher in tumor with high RAD51 expression, but RAD51 expression was not elevated in BRCA1 or BRCA2 mutant tumors. Cytolytic activity score, a marker of cancer immunity, was elevated high RAD51 group in two cohorts, and the immune cell fraction calculated by the xCell algorithm showed increase in immune cell infiltration, including CD4 memory T cells, Th1 cells, M1 macrophages and activated dendritic cells, in all cohorts, suggesting a certain level of activation of cancer immunity in this RAD51 high breast cancer group. However, contrary to previous reports, RAD51 expression in breast cancer cell lines did not show any association between sensitivity to chemotherapy or PARP inhibitors. Neither for the breast cancer NAC cohort, RAD51 expression was not increased in the residual burden group, but conversely increase in RAD51expression was observed in pathological complete response group in some cohorts. Surprisingly, RAD51 was significantly associated with worse overall survival in all three large cohorts included in this analysis, and with worse disease-specific survival in two cohorts.
CONCLUSIONS: RAD51 expression was significantly associated with worse survival, but did not with treatment-responsive, suggesting its usefulness as prognostic, but not predictive, biomarker.
Citation Format: Rongrong Wu, Ankit Patel, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Li Yan, Takashi Ishikawa, Kazuaki Takabe. High RAD51 gene expression is associated with aggressive biology and with poor survival in breast cancer [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 812.
Purpose
Estrogen signals play an important role in the phenotype of estrogen receptor-positive breast cancer. However, comprehensive analyses of the effect of responsiveness to estrogen signals on the tumor microenvironment and survival in large cohorts of primary breast cancer patients have been lacking. We aimed to test the hypothesis that estrogen reactivity affects gene expression and immune cell infiltration profiles in the tumor microenvironment and survival.
Methods
A total of 3,098 breast cancer cases were analyzed: 1,904 from the Molecular Taxonomy of Breast Cancer (METABRIC) cohort, 1,082 from The Cancer Genome Atlas (TCGA) cohort, and 112 from the Hokkaido University Hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing the scores of ESTROGEN_RESPONSE_EARLY and ESTROGEN_RESPONSE_LATE in Gene Set Variation Analysis.
Results
Breast cancer with high estrogen reactivity was related to Myc targets, metabolism-related signaling, cell stress response, TGF-beta signaling, androgen response, and MTORC1 signaling gene sets in the tumor microenvironment. Low estrogen reactivity was related to immune-related proteins, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, KRAS signaling, cell cycle-related gene sets, and EMT. In addition, breast cancer with high levels of estrogen reactivity had low immune cytolytic activity and low levels of immunostimulatory cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle. Patients with high estrogen reactivity were also associated with a better prognosis.
Conclusion
We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression, as well as survival.
Purpose
Although the DNA repair mechanism is important in preventing carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients.
Methods
A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. The median value was used to divide each cohort into high and low RAD51 expression groups.
Results
High RAD51 expression enriched the DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all significantly associated with the high RAD51 BC group. RAD51 expression was positively correlated with Homologous Recombination Deficiency, as well as both mutational burden and neoantigens that accompanied a higher infiltration of immune cells. Primary BC with lymph node metastases was associated with high expression of RAD51 in two cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in three independent cohorts.
Conclusion
RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer.
Purpose: Although DNA repair mechanism is a key to prevent carcinogenesis, its activation in established cancer cells may support their proliferation and aggravate cancer progression. RAD51 cooperates with BRCA2 and is essential in the homologous recombination of DNA repair. To this end, we hypothesized that RAD51 gene expression is associated with cancer cell proliferation and poor prognosis of breast cancer (BC) patients.
Methods: A total of 8515 primary BC patients with transcriptome and clinical data from 17 independent cohorts were analyzed. Median was used to divide each cohort into high and low RAD51 expression groups.
Results: High RAD51 expression enriched DNA repair gene set and was correlated with DNA repair-related genes. Nottingham histological grade, Ki67 expression and cell proliferation-related gene sets (E2F Targets, G2M Checkpoint and Myc Targets) were all significantly associated with the high RAD51 BC. RAD51 expression was positively correlated with Homologous Recombination Deficiency, as well as both mutation burden and neoantigen that accompanied with higher infiltration of immune cells. Primary BC with lymph node metastases were associated with high expression of RAD51 in 2 cohorts. There was no strong correlation between RAD51 expression and drug sensitivity in cell lines, and RAD51 expression was lower after the neoadjuvant chemotherapy compared to before the treatment. High RAD51 BC was associated with poor prognosis consistently in 3 independent cohorts.
Conclusion: RAD51 gene expression is associated with aggressive cancer biology, cancer cell proliferation, and poor survival in breast cancer.
Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.
BACKGROUND: Pancreatic cancer is one of the most aggressive cancers with a 5-year survival of less than 10%. Surgery is the only cure for pancreatic cancer but the majority of patients present with metastatic disease at the time of diagnosis. Systemic chemotherapy remains the primary treatment option. Given the insidious clinical presentation and poor treatment response, there is an urgent need to discover a predictive biomarker for appropriate patient selection. We hypothesized that the 4-gene score, which reflects tumor cell proliferation, is both a prognostic and predictive biomarker for pancreatic cancer.
METHODS: The 4-gene score is derived from tumor expression of DOK4, HCCS, PGF, and SHCBP1 genes, which were identified based on differential mRNA expression analysis of a human breast cell line, its metastatic variant cells, and clinical outcome data of breast cancer patient cohorts, as previously reported. A total of 954 pancreatic cancer patients were analyzed for both discovery and validation of the 4-gene score from publicly available datasets to investigate the relationship between the score with clinical features such as metastasis, cancer aggressiveness, immune cell infiltration, patient survival, and resectability.
RESULTS: We found that the 4-gene score correlation in pancreatic cancer was higher than in breast cancer cohorts, specifically in clinically aggressive parameters such as pathological grade and MKI67 expression. Also, the score in metastatic tumor cohorts was higher than in primary cancer cohorts (p < 0.001). These findings were mirrored in gene set analysis, in which the score high tumors enriched cell proliferation-related gene sets such as E2F targets, G2M checkpoint, MYC targets v1 and v2, mitotic spindle, and metastasis-related gene sets in three cohorts (TCGA, GSE62452, and GSE57495). A high score was associated with increased mutation rates in KRAS and CDKN2A genes (p = 0.006 and 0.044) in the TCGA cohort, as well as enhancement of KRAS, CDKN2A, p53, TGF-β, and E2F pathways in three cohorts. Furthermore, a high score tumor had less infiltration of CD8⁺ T cells but was associated with high cytolytic activity and IFN-γ scores, which reflect overall cancer immunity. The high score was correlated with the level of drug sensitivity area under the curve of Sorafenib (r = 0.648) in primary cancer, Paclitaxel (r = 0.624) and Doxorubicin (r = 0.575) in metastatic cancer. Finally, a high 4-gene score was significantly associated with worse clinical outcomes in three cohorts (p = 0.044, 0.048, and 0.022), a low rate of R0 resection (p = 0.013), and worse survival after R1/2 resection (p = 0.027).
CONCLUSION: The 4-gene score identified poor survival in pancreatic cancer and has potential as a predictive biomarker for R0 resection and treatment response in metastatic pancreatic cancer. Evaluating the degree of the 4-gene score could be a valuable potential prognostic tool.
Citation Format: Masanori Oshi, Lan Le, Yoshihisa Tokumaru, Ankit Patel, Ryusei Matsuyama, Itaru Endo, Li Yan, Matthew H.G. Katz, Kazuaki Takabe. A novel 4-gene score predict patient survival as well as pathologically complete (R0) resection in pancreatic 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 404.
Background: Estrogen signals play an important role in the phenotype of estrogen receptor positive breast cancer (BC). However, comprehensive analyses of the effect of estrogen signals on the tumor microenvironment (TME) and treatment response in large cohorts of primary BC patients have been lacking. We aimed to test the hypothesis that estrogen reactivity effects gene expression and immune cell infiltration profiles in the TME and relates to response to chemotherapy (CT) and endocrine therapy (ET).
Methods: A total of 3091 BC cases were analyzed; 1075 from TCGA cohort, 1904 from METABRIC cohort, and 112 from Hokkaido University hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing estrogen response genes.
Results: BC with high estrogen reactivity was related to Myc targets, Metabolism-related signaling, cell stress response, TGF-beta signaling, androgen response, and MTORC1 signaling gene sets in the TME. Low estrogen reactivity was related to immune-related proteins, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, KRAS signaling, cell cycle related gene sets, and EMT. In addition, BC with high levels of estrogen reactivity had low immune cytolytic activity, low levels of immunostimulatory cells, and high levels of immunosuppressive cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle (CIC). Patients with high estrogen reactivity were also associated with a better prognosis. Regarding the effect of estrogen reactivity on treatment, patients who were treated with ET and CT but relapsed (BC with CT rec) were related with higher levels of E2F targets and G2M checkpoint, but lower levels of immunosuppressive M2 macrophages or Tregs cells. In addition, the TME in CT rec had higher levels of CIC regulators.
Conclusions: We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression within the TME, as well as the treatment effect of CT given in addition to ET.
Given the severe side effects of the treatments and poor survival, prognostic and predictive biomarkers to guide management of pancreatic cancer are in critical need. We hypothesized that cell proliferation-related pathways are associated with drug response and survival in pancreatic cancer. Six Hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis were evaluated in 3 independent cohorts- TCGA-PAAD (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). G2M and E2F, as well as Mitotic and p53 pathway correlated highly with other gene sets. All pathways were significantly correlated with MKI67 expression and its proliferation score, but none with cytolytic activity and the rate of pathologically complete resection (R0). All pathways were significantly associated with high alteration and expression of KRAS gene except for MYC v1. G2M, E2F, and p53 pathway were significantly associated with high alteration of TP53 gene. Interestingly, different pathways correlated with the AUC of different cancer therapeutics, such as Gemcitabine (Mitotic: r = 0.706 [P = 0.01]), Paclitaxel (MYC v2: r = -0.636 [P < 0.05]), Apatinib (Mitotic: r = -0.556 [P = 0.03]), Palbociclib (E2F: r = 0.675 [P < 0.01]), and Sorafenib (G2M: r = -0.593 [P = 0.03]). Among all six pathways, only G2M was consistently associated with worse patient survival in all three cohorts. In conclusion, each cell proliferation-related pathway was predictive of a unique agent, and the G2M score alone predicts survival in pancreatic cancer.
... 16,17 Thus, targeted modulation of mitochondrial metabolism appears to be a potential tumor therapy. 18,19 Meanwhile, immune factors play a major role in breast cancer development, 20 and NDUFAF6 can promote PD-L1 expression by inhibiting the NRF2 signaling pathway to respond to the immune response. 21 In this research, we evaluated the levels of the mitochondria-related gene NDUFAF6 in breast cancer tissues and its association with prognosis. ...
... We also saw a decrease in the OXIDATIVE_PHOSPHORYLATION gene set, which is related to mitochondrial function, as well as a decrease in INTERFERON_ALPHA_RESPONSE, INTERFERON_ GAMMA_RESPONSE, and ALLOGRAFT_REJECTION, which are related to immune response (Fig. 3A). Interestingly, we observed a reduction in the ESTROGEN_ RESPONSE_LATE gene set: it has been reported that the value of this pathway correlates with estrogen reactivity [18], suggesting that a decrease in estrogen reactivity occurs in the C1orf50-high patient group. Furthermore, the Gene Set Variation Analysis (GSVA) confirmed a similar trend to the GSEA results, as well as a stronger association with transforming growth factor (TGF) beta signaling (adjusted p = 2.48e-04) in the C1orf50-high group (Fig. 3B). ...
... Previous research has indicated that RAD51 135G > C genetic polymorphism may be associated with an increased risk of breast cancer by modulating the transcriptional activity and expression levels of the RAD51 gene 7,8 . While differential expression of RAD51 family members and their prognostic implications in breast cancer have been documented 6,9 , their clinical-pathological characteristics and prognostic significance remain uncertain. To date, no meta-analysis has systematically examined the relationship between RAD51 family genes expression and breast cancer. ...
... Additionally, mtDNA copy number variations and mutations lead to impairments in OXPHOS-mediated ATP production [110]. Nevertheless, many cancer cells have competent OXPHOS activity that can produce ATP, even though the glycolytic phenotype in cancer cells was thought to be caused by defective mitochondrial OXPHOS [111][112][113][114]. Moreover, the unfolded protein response (UPR) and worsening of mitochondrial dysfunction can be caused by mtDNA mutation and deletion. ...
... 49 The finding that the overexpression of these cell proliferation-related genes is associated with a better drug response is consistent with previous studies. 50,51 Specifically, Chawla et al showed that highly proliferative tumor cells tend to be more sensitive to TMZ in prostate cancer because rapidly dividing cells are actively going through the cell cycle and TMZ induces double-strand breaks in the post-treatment cell cycle. 52 The 3 cell cycle-related pathways, E2F targets, G2M checkpoint, and MYC targets, together with the UV response, have been identified in our previous study 19 on the GSE232173 cohort in both patient-derived cell cultures and matching patient tumor tissues. ...
... org/ gsea/ index. jsp) was used for the GSEA [26], following the same approach as described in our previous reports [16,[27][28][29]. The enrichment of Hallmark gene sets was compared in the BRCA1 gene expression of high and low expression groups. ...
... The xCell 20 algorithm calculates and generates able cell type enrichment scores based on the association between expression pro les and features. The ESTIMATE and xCell algorithms have been applied to lung adenocarcinoma 21,22 , colon cancer 23,24 , and adrenal cortical cancer 25,26 . The multiple cancer applications illustrate the strong applicability of both algorithms. ...
... As previously detailed, we used the xCell algorithm to assess the correlation between myogenesis high and low groups and the infiltration of stromal and immune cells in the tumor microenvironment (TME) [26][27][28][29][30]. In their evaluation of the TCGA cohort, Thorsson et al. [31] offered supplementary scores, including indel and single-nucleotide variant (SNV) neoantigens, copy number alteration (CNA), silent and non-silent mutations, homologous recombination defects (HRD), intratumor heterogeneity, and proliferation score. ...