Transcriptomic and proteomic intra-tumor heterogeneity of colorectal cancer varies depending on tumor location within the colorectum

Background Intra-tumor heterogeneity (ITH) of colorectal cancer (CRC) complicates molecular tumor classification, such as transcriptional subtyping. Differences in cellular states, biopsy cell composition, and tumor microenvironment may all lead to ITH. Here we analyze ITH at the transcriptomic and proteomic levels to ascertain whether subtype discordance between multiregional biopsies reflects relevant biological ITH or lack of classifier robustness. Further, we study the impact of tumor location on ITH. Methods Multiregional biopsies from stage II and III CRC tumors were analyzed by RNA sequencing (41 biopsies, 14 tumors) and multiplex immune protein analysis (89 biopsies, 29 tumors). CRC subtyping was performed using consensus molecular subtypes (CMS), CRC intrinsic subtypes (CRIS), and TUMOR types. ITH-scores and network maps were defined to determine the origin of heterogeneity. A validation cohort was used with one biopsy per tumor (162 tumors). Results Overall, inter-tumor transcriptional variation exceeded ITH, and subtyping calls were frequently concordant between multiregional biopsies. Still, some tumors had high transcriptional ITH and were classified discordantly. Subtyping of proximal MSS tumors were discordant for 50% of the tumors, this ITH was related to differences in the microenvironment. Subtyping of distal MSS tumors were less discordant, here the ITH was more cancer-cell related. The subtype discordancy reflected actual molecular ITH within the tumors. The relevance of the subtypes was reflected at protein level where several inflammation markers were significantly increased in immune related transcriptional subtypes, which was verified in an independent cohort (Wilcoxon rank sum test; p<0.05). Unsupervised hierarchical clustering of the protein data identified large ITH at protein level; as the multiregional biopsies clustered together for only 9 out of 29 tumors. Conclusion Our transcriptomic and proteomic analyses show that the tumor location along the colorectum influence the ITH of CRC, which again influence the concordance of subtyping.

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Clinical Impact of Primary Tumor Location in Metastatic Colorectal Cancer Patients Under Later-Line Regorafenib or Trifluridine/Tipiracil Treatment

Frontiers in Oncology ◽

10.3389/fonc.2021.688709 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hiromichi Nakajima ◽

Shota Fukuoka ◽

Toshiki Masuishi ◽

Atsuo Takashima ◽

Yosuke Kumekawa ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Predictive Factor ◽

Primary Tumor ◽

Group Performance ◽

Univariate Analysis ◽

Tumor Location ◽

Clinical Impact ◽

Primary Tumor Location ◽

The Impact

BackgroundPrimary tumor location (PTL) is an important prognostic and predictive factor in the first-line treatment of metastatic colorectal cancer (mCRC). Although regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) have been introduced recently, the clinical impact of PTL in these treatments is not well understood.Materials and MethodsWe retrospectively evaluated patients with mCRC who were registered in a multicenter observational study (the REGOTAS study). The main inclusion criteria were Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, angiogenesis inhibitors, anti-epidermal growth factor receptor therapy (if RAS wild-type), and no prior use of REG and FTD/TPI. The impact of PTL on overall survival (OS) was evaluated using Cox proportional hazard models based on baseline characteristics.ResultsA total of 550 patients (223 patients in the REG group and 327 patients in the FTD/TPI group) were included in this study, with 122 patients with right-sided tumors and 428 patients with left-sided tumors. Although the right-sided patients had significantly shorter OS compared with the left-sided patients by univariate analysis (p = 0.041), a multivariate analysis revealed that PTL was not an independent prognostic factor (hazard ratio, 0.95; p = 0.64). In a subgroup analysis, the OS was comparable between the REG and FTD/TPI groups regardless of PTL (p for interactions = 0.60).ConclusionsIn the present study, PTL is not a prognostic and predictive factor in patients with mCRC under later-line REG or FTD/TPI therapy.

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Relationship between primary tumor location and prognosis in metastatic colorectal cancer patients treated with irinotecan/5-FU/leucovorin (FOLFIRI).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.557 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 557-557 ◽

Cited By ~ 1

Author(s):

Qianqian Yu ◽

Hong Qiu ◽

Mingsheng Zhang ◽

Xianglin Yuan

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Median Survival ◽

Survival Probability ◽

Primary Tumor ◽

Statistical Significance ◽

Tumor Location ◽

First Line ◽

Primary Tumor Location ◽

The Impact

557 Background: Clinical trials including CALGB/SWOG 80405 and FIRE-3 reveal differences in overall survival (OS) for metastatic colorectal cancer (mCRC) patients treated with targeted therapy based on primary tumor location. We assessed the impact of tumor location on prognosis in a prospective series of patients with mCRC received FOLFIRI in first-line therapy. Methods: Patients treated with FOLFIRI were consecutively recruited between November 2010 and December 2014. Follow-up information was updated in February 2016 when 77.3% of the patients were deceased. We defined the right-sided colon = cecum to transverse colon, left-sided colon = splenic flexure to sigmoid descending colon, rectum = rectosigmoid plus rectal cancer, respectively. We measured median survival using Kaplan-Meier plots and 2-year survival probability using life tables. Associations between tumor locations and treatment outcomes were estimated using a Cox proportional hazards model. Age and gender were included in adjusted Cox models to estimate the hazard ratio (HR) for death of rectal and left-sided tumors relative to right-sided tumors. Results: Right-sided cancer had a shorter median survival (13.5 vs. 20.4 months) and worse 2-year survival probability (28% vs. 39%) than left-sided and rectal cancers, however the difference was of no statistical significance no matter in unadjusted (HR = 1.002, 95% CI 0.635-1.581) or adjusted models (HR = 1.037, 95% CI 0.657-1.639). Conclusions: mCRC patients with right-sided colon got comparative survival benefit from FOLFIRI in first-line treatment to the left-sided colon and rectum. This result needs to be validated in studies with larger sample size. Clinical trial information: NCT01282658.

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The Impact of Extramural Venous Invasion in Colorectal Cancer: A Detailed Analysis Based on Tumor Location and Evaluation Methods

International Journal of Surgical Pathology ◽

10.1177/1066896919874493 ◽

2019 ◽

Vol 28 (2) ◽

pp. 120-127

Author(s):

Young-Min Shin ◽

Jung-Soo Pyo ◽

Mee Ja Park

Keyword(s):

Colorectal Cancer ◽

Subgroup Analysis ◽

Meta Analysis ◽

Survival Rates ◽

Venous Invasion ◽

Tumor Location ◽

Evaluation Methods ◽

Hazard Ratio ◽

Significant Difference ◽

The Impact

This study aimed to elucidate the prognostic implications of extramural venous invasion (EMVI) in colorectal cancer (CRC) through a meta-analysis. Eighteen eligible studies were included in this meta-analysis. Data on the prevalence of EMVI and the correlation between EMVI and survival were collected from these studies. In addition, a subgroup analysis was conducted based on tumor location and evaluation methods. The estimated prevalence of EMVI was 28.3% (95% confidence interval [CI] = 23.1% to 34.0%) in patients with CRC. The estimated prevalence of EMVI in patients with colon cancer and rectal cancer was 23.0% (95% CI = 17.6% to 29.6%) and 35.7% (95% CI = 22.3% to 51.6%), respectively. Based on the evaluation method, the estimated prevalence of EMVI were 28.3% (95% CI = 23.2% to 34.1%) and 27.3% (95% CI = 8.4% to 60.6%) in pathologic and radiologic examinations, respectively. The correlation of EMVI with worse overall and disease-free survival rates was significant (hazard ratio = 1.773, 95% CI = 1.483-2.120, and hazard ratio = 2.059, 95% CI = 1.683-2.520, respectively). However, in the subgroup analysis with radiologic examination, there was no significant difference in survival rates between patients with and without EMVI. Our study showed that EMVI was frequently detected in 28.3% of patients with CRC and was correlated to worse survival. The detection of EMVI can be useful for predicting the prognosis of patients with CRC.

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The Impact of Primary Tumor Location in Synchronous Metastatic Colorectal Cancer: Differences in Metastatic Sites and Survival

Annals of Surgical Oncology ◽

10.1245/s10434-019-08100-5 ◽

2019 ◽

Vol 27 (5) ◽

pp. 1580-1588 ◽

Cited By ~ 5

Author(s):

Nelleke P. M. Brouwer ◽

Dave E. W. van der Kruijssen ◽

Niek Hugen ◽

Ignace H. J. T. de Hingh ◽

Iris D. Nagtegaal ◽

...

Keyword(s):

Colorectal Cancer ◽

Rectal Cancer ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Primary Tumor ◽

Relative Survival ◽

Tumor Location ◽

Primary Tumor Location ◽

Metastatic Sites ◽

The Impact

Abstract Purpose We explored differences in survival between primary tumor locations, hereby focusing on the role of metastatic sites in synchronous metastatic colorectal cancer (mCRC). Methods Data for patients diagnosed with synchronous mCRC between 1989 and 2014 were retrieved from the Netherlands Cancer registry. Relative survival and relative excess risks (RER) were analyzed by primary tumor location (right colon (RCC), left colon (LCC), and rectum). Metastatic sites were reported per primary tumor location. Survival was analyzed for metastatic sites combined and for single metastatic sites. Results In total, 36,297 patients were included in this study. Metastatic sites differed significantly between primary tumor locations, with liver-only metastases in 43%, 54%, and 52% of RCC, LCC, and rectal cancer patients respectively (p < 0.001). Peritoneal metastases were most prevalent in RCC patients (33%), and lung metastases were most prevalent in rectal cancer patients (28%). Regardless of the location of metastases, patients with RCC had a worse survival compared with LCC (RER 0.81, 95% CI 0.78–0.83) and rectal cancer (RER 0.73, 95% CI 0.71–0.76). The survival disadvantage for RCC remained present, even in cases with metastasectomy for liver-only disease (LCC: RER 0.66, 95% CI 0.57–0.76; rectal cancer: RER 0.84, 95% CI 0.66–1.06). Conclusions This study showed significant differences in relative survival between primary tumor locations in synchronous mCRC, which can only be partially explained by distinct metastatic sites. Our findings support the concept that RCC, LCC and rectal cancer should be considered distinct entities in synchronous mCRC.

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Tumor Heterogeneity and Consequences for Bladder Cancer Treatment

Cancers ◽

10.3390/cancers13215297 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5297

Author(s):

Etienne Lavallee ◽

John P. Sfakianos ◽

David J. Mulholland

Keyword(s):

Bladder Cancer ◽

Stress Responses ◽

Tumor Heterogeneity ◽

Immune Cell ◽

De Novo ◽

Epithelial Tumor ◽

Cancer Management ◽

Impact On Treatment ◽

Tumor Types ◽

The Impact

Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations—whether de novo or newly acquired—closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response.

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A retrospective cohort study evaluating the safety and efficacy of TAS-102 in patients with metastatic colorectal cancer (HGCSG1503): Analysis of tumor location.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.802 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 802-802

Author(s):

Kohei Ogawa ◽

Satoshi Yuki ◽

Yasuyuki Kawamoto ◽

Masataka Yagisawa ◽

Kazuaki Harada ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Primary Tumor ◽

Patient Characteristics ◽

Tumor Location ◽

Recent Analysis ◽

Safety And Efficacy ◽

Primary Tumor Location ◽

Significant Difference ◽

The Impact

802 Background: Recent analysis from some clinical trials showed that primary tumor location in patients with metastatic colorectal cancer (mCRC) correlates with different outcome. The J003 trial and RECOURSE trial revealed the safety and efficacy of TAS-102 for patients with metastatic colorectal cancer (mCRC). In March 2014, TAS-102 was approved in Japan. However, the impact of primary tumor location in mCRC treated TAS-102 is unclear. Methods: We retrospectively analyzed the clinical data of 411 patients who received TAS-102 in the multi-institutional retrospective study (HGCSG1503). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR). To compare with right-sided tumor (RT : Cecum to Transverse colon) and left-sided tumor (LT : Descending colon to Rectum), Fisher’s exact test was used in terms of patient characteristics, AE, RR/DCR, and Log-rank test was used in terms of TTF, PFS and OS. Results: Patients with RT and LT were 137 and 274, respectively. The patient’ characteristics between RT and LT were generally balanced except for Gender (Male ; 45.3% in RT, 56.9% in LT ; p = 0.028), Age (Median ; 68.0y in RT, 66.0y in LT ; p = 0.007), Liver metastasis (70.8% in RT, 57.7% in LT ; p = 0.010), Peritoneal metastasis (47.4% in RT, 24.5% in LT ; p < 0.001), and KRAS exon2 status (wild ; 40.5% in RT, 59.0% in LT ; p = 0.001). The AEs between RT and LT were also generally balanced except for Platelet count decreased (≥Grade 3 ; 8.8% in RT, 2.9% in LT ; p = 0.014). RR/DCR were 0/30.9% in the RT and 0.8/40.3% in the LT (p = 1.000/0.088). Median TTF was 2.2 months in the RT and 2.1 months in the LT (HR 0.962, p = 0.712). Median PFS was 2.2 months in the RT and 2.2 months in the LT (HR 1.024, p = 0.826). Median OS was 7.3 months in the RT and 7.3 months in the LT (HR 1.114, p = 0.327). Conclusions: As a result of this analysis, efficacy was no significant difference between RT and LT for patients who were administered TAS-102 in the real-world clinical practice. This analysis suggested TAS-102 benefits mCRC patients regardless of primary tumor location. Clinical trial information: 000020551.

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Impact of race on incidence and survival from colorectal cancer in young adults in the United States.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.62 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 62-62

Author(s):

Dhruvika Mukhija ◽

Sajan Nagpal

Keyword(s):

Colorectal Cancer ◽

Older Adults ◽

Young Adults ◽

American Indian ◽

Alaska Native ◽

The United States ◽

Tumor Location ◽

Asian Pacific ◽

The Impact ◽

White Patients

62 Background: Multiple studies have reported an increasing incidence of colorectal cancer (CRC) in young( < 45 years)adults.However, the impact of race on the incidence, tumor location and survival in adults < 45 years with CRC has not been explored. Methods: Using Surveillance,Epidemiology and End Results database,we identified patients with CRC and abstracted data on patient demographics,tumor location and survival between 1973-2014, and compared these variables in patients 18-44 years with those > 45 years. Cases where CRC was not the first/only malignancy were excluded.Categorical variables were compared using the Chi-square test and overall survival was analyzed using Kaplan-Meier method. Results: Overall, 453,019 patients were included (27, 352 < 45,and 425,667 >45 years). 81.7% among those > 45 years were caucasian, as compared to 74.3% < 45 years of age. Among those < 45, 14.3% were black, 10.3% were Asian/Pacific Islander (API) and 1.1% were American Indian/Alaska Native (compared to 10.1%, 7.5% and 0.6% respective in adults > 45) (p < 0.0001*) (Table). 73.1% of those < 45 had left sided disease (descending, sigmoid colon and rectum) as compared to 60.1% in those > 45 (p < 0.0001*).Survival was poorer for non-white patients (black, API and AI) (94 months, 95%CI 90-100) as compared to white patients (153 months, 95%CI 145-161) overall, and individually for the < 45 and >45 years subgroups as well. Conclusions: Racial distribution in patients with CRC differs significantly among patients < 45 as compared to older adults,with incidence in young American Indian/Alaska Natives approaching 2 times that of older adults,and 1.5 times in young Blacks and Asian/Pacific Islanders.Non-white races have poorer survival across all age groups.With rates of CRC rising sharply in young adults, underlying reasons for these differences require further investigation to better channelize efforts for education and screening. [Table: see text]

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NIMG-50. DOES THE PRESENCE OF GADOLINIUM AFFECT T2 –WEIGHTED IMAGES OF GLIOMA?: IMPLICATIONS FOR MRI PROTOCOL STANDARDIZATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.719 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi172-vi172

Author(s):

Pamela Jackson ◽

Yuxiang Zhou ◽

Joseph Hoxworth ◽

Kristin Swanson ◽

Leland Hu

Keyword(s):

Post Contrast ◽

Normal Appearing White Matter ◽

Signal Decay ◽

Wilcoxon Rank Sum Test ◽

Mri Protocol ◽

Magnetic Resonance Imaging Mri ◽

Tumor Types ◽

Protocol Standardization ◽

The Impact ◽

T2 Weighted Images

Abstract There have been increasing efforts to standardize MRI scanning protocols for both routine and clinical trial imaging of glioma. The recent BTIP guidelines propose acquisition of T2-weighted images after gadiolinium (Gd) based contrast injection and before post-contrast 3D T1-weighted (T1W) images to control timing of images after contrast administration. While Gd-contrast shortens T1W signal and appears hyperintense on magnetic resonance imaging (MRI), Gd-contrast also shortens T2W signal, which could result in unintended alternations in T2W signal intensities. This has potential implications for model-based approaches for GBM diagnosis and the differential diagnosis of other tumor types (e.g., lymphoma) that rely on T2W signal characteristics. To our knowledge, no neuroimaging studies have formally evaluated the impact of Gd contrast on T2W imaging. We acquired multi-echo T2 sequences (TE=14, 28, 41, 55, 69 ms) both prior to and after the administration of Gd for 5 patients suspected of having a brain tumor. Quantitative T2 maps were created by fitting the signal decay to a signal exponential with the Levenburg-Marqurdt algorithm. Percent difference maps were calculated to compare the quantitative T2 changes between the pre- and post-Gd T2 maps. Additionally, we performed a Wilcoxon Rank-Sum test comparing T2 values within regions of interest (ROIs) representing the tumor and normal appearing white matter (NAWM). Significant differences between the T2 values in the tumor and NAWM ROIs were seen for 4 and 3 of the patients, respectively (all p-values < 0.01). Our initial data suggests that the administration of Gd contrast may affect T2 values in both the tumor and NAWM, which could impact quantitative image-based models and diagnoses in glioma. We are currently replicating these preliminary results in an expanded cohort.

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The effect of primary tumor location on second- or later-line treatment with anti-EGFR antibodies in patients with metastatic colorectal cancer: A single-center cohort study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3541 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3541-3541

Author(s):

Anita Archwamety ◽

Naravat Poungvarin ◽

Charuwan Akewanlop ◽

Krittiya Korphaisarn

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Treatment Outcomes ◽

Primary Tumor ◽

Single Agent ◽

Tumor Location ◽

Rank Test ◽

Line Treatment ◽

Primary Tumor Location ◽

The Impact

3541 Background: The guideline recommends anti-EGFR monoclonal antibodies (anti-EGFR Ab) as first-line treatment only for patients with left-sided RAS wild type (RASwt) metastatic colorectal cancer (mCRC). However, there are no recommendations on tumor sidedness in subsequent lines. This study aimed to evaluate the effect of primary tumor location on second- or later-line treatment outcomes in patients with KRASwt mCRC. Methods: Medical records of patients diagnosed with mCRC at Siriraj Hospital between 2008 and 2019 were retrospectively reviewed. Patients with KRASwt who received anti-EGFR Ab in second- or later-line treatment were included. The impact of tumor sidedness on progression-free survival (PFS) was determined using the Kaplan-Meier method and compared using the log-rank test. Results: Of 671 patients who had data on KRAS analysis, 396 patients (59%) had KRASwt. Of these, 210 patients received anti-EGFR Ab in second- or later-line treatment. Twenty-nine percent of patients (60 out of 210) had extended RAS analysis. Thirty patients (14%) had right-sided tumors, while 180 patients (86%) had left-sided tumors. Sixty-nine percent of patients (146 of 210) were treated in the third line, while 19% and 12% were treated in the second and the fourth line, respectively. Single-agent irinotecan was the most commonly used chemotherapy backbone (92%). Patients with right-sided tumors had non-significantly inferior PFS compared with patients with left-sided tumors (median PFS was 4.7 months, 95% CI 0.8–8.7 vs. 6 months, 95% CI 4.6–7.3; p = 0.55). Subgroup analysis on the impact of primary tumor location showed no difference in PFS when stratified by treatment lines. Conclusions: This study demonstrated that tumor sidedness has no impact on treatment outcomes in patients treated with anti-EGFR Ab in second- or later-line treatment. Therefore, there is not enough evidence to use tumor sidedness for treatment selection in these settings. A multi-center retrospective study is ongoing.

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Prognostic Significance of GRINA in Colorectal Cancer

10.21203/rs.3.rs-707758/v1 ◽

2021 ◽

Author(s):

Ying Cui ◽

Yibing Bai ◽

Jiani Yang ◽

Yuanfei Yao ◽

Qingwei Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Regression Analysis ◽

Clinical Outcomes ◽

Functional Enrichment ◽

Th2 Cells ◽

Cox Regression Analysis ◽

Immune Infiltration ◽

Wilcoxon Rank Sum Test ◽

The Impact

Abstract Background: Glutamate Receptor, Ionotropic, N-Methyl D-Aspartate-Associated Protein 1 (GRINA), also named TMBIM3, has been deemed to have oncogenic activities in gastric cancer. However, the role and molecular mechanisms of GRINA in colorectal cancer (CRC) remain largely unknown. We evaluated its prognostic value in CRC by an integrated bioinformatics analysis and experimental verification. Methods: Patients with CRC were derived from TCGA and GTEx databases. We first confirmed the expression profiles of GRINA in human cancers and compared GRINA expression between CRC and normal colorectal tissues by Wilcoxon rank sum test and Wilcoxon signed rank test. χ2 test and logistic regression analysis was used for correlation analysis, and Wilcoxon rank sum test or Kruskal-Wallis rank sum was performed to evaluate the connection between GRINA expression and clinical features. Furthermore, Kaplan-Meier’s analysis and Cox regression analysis were used to assess the correlation between GRINA expression and clinical outcomes. Colony formation and wound-healing assays were performed to observe the impact of GRINA on cell proliferation and motility. GO annotation, PPI network and GSEA were utilized to explore the underlying function of GRINA. Finally, we analyzed the correlation of GRINA in CRC with immune infiltration levels by ssGSEA.Results: We found that GRINA expression was upregulated in diverse human cancer types and especially in CRC. Higher GRINA expression was closely related to unfavorable clinicopathologic features and clinical outcomes. GRINA overexpression promotes CRC proliferation and migration in vitro. Functional enrichment analyses suggested that GRINA is involved in the most significant terms including anion transmembrane transport, cell proliferation related pathways, metabolic pathways and DNA damage and repair related pathways. GRINA expression was most positively correlated with NK CD56dim cells and negatively associated with Th2 cells through analyzing GRINA expression and immune infiltration.Conclusion: GRINA may be a potential prognostic biomarker and therapeutic target in CRC. Moreover, GRINA might accelerate CRC development and EMT by regulating the crosstalk of WNT and MYC signaling which contribute to the unfavorite survival rate and adverse immune infiltration in CRC patients.

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