Microbiome diversity in African American, European American, and Egyptian colorectal cancer patients.

Purpose: Although there is an established role for microbiome dysbiosis in the pathobiology of colorectal cancer (CRC), CRC patients of various race/ethnicities demonstrate distinct clinical behaviors. Thus, we investigated microbiome dysbiosis in Egyptian, African American (AA), and European American (EA) CRC patients. Patients and methods: CRCs and their corresponding normal tissues from Egyptian (n = 17) patients of the Alexandria University Hospital, Egypt, and tissues from AA (n = 18) and EA (n = 19) patients at the University of Alabama at Birmingham were collected. DNA was isolated from frozen tissues, and the microbiome composition was analyzed by 16S rRNA sequencing. Differential microbial abundance, diversity, and metabolic pathways were identified using linear discriminant analysis (LDA) effect size analyses. Additionally, we compared these profiles with our previously published microbiome data derived from Kenyan CRC patients. Results: Differential microbiome analysis of CRCs across all racial/ethnic groups showed dysbiosis. There were high abundances of Herbaspirillum and Staphylococcus in CRCs of Egyptians, Leptotrichia in CRCs of AAs, Flexspiria and Streptococcus in CRCs of EAs, and Akkermansia muciniphila and Prevotella nigrescens in CRCs of Kenyans (LDA score >4, adj. p-value <0.05). Functional analyses showed distinct microbial metabolic pathways in CRCs compared to normal tissues within the racial/ethnic groups. Egyptian CRCs, compared to normal tissues, showed lower l-methionine biosynthesis and higher galactose degradation pathways. Conclusions: Our findings showed altered mucosa-associated microbiome profiles of CRCs and their metabolic pathways across racial/ethnic groups. These findings provide a basis for future studies to link racial/ethnic microbiome differences with distinct clinical behaviors in CRC.

BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis.

Because survival of patients with metastatic colorectal cancer remain poor, there is an urgent need to identify potential novel druggable targets that are associated with colorectal cancer progression. One such target, basic leucine zipper and W2 domains 2 (BZW2), is involved in regulation of protein translation, and its overexpression is associated with human malignancy. Thus, we investigated the expression and regulation of BZW2, assessed its role in activation of WNT/ß-catenin signaling, identified its downstream molecules, and demonstrated its involvement in metastasis of colorectal cancer. In human colorectal cancers, high mRNA and protein expression levels of BZW2 were associated with tumor progression. BZW2-knockdown reduced malignant phenotypes, including cell proliferation, invasion, and spheroid and colony formation. BZW2-knockdown also reduced tumor growth and metastasis; conversely, transfection of BZW2 into BZW2 low-expressing colorectal cancer cells promoted malignant features, including tumor growth and metastasis. BZW2 expression was coordinately regulated by microRNA-98, c-Myc, and histone methyltransferase enhancer of zeste homolog 2 (EZH2). RNA sequencing analyses of colorectal cancer cells modulated for BZW2 identified P4HA1 and the long noncoding RNAs, MALAT1 and NEAT1, as its downstream targets. Further, BZW2 activated the Wnt/ß-catenin signaling pathway in colorectal cancers expressing wild-type ß-catenin. In sum, our study suggests the possibility of targeting BZW2 expression by inhibiting EZH2 and/or c-Myc. IMPLICATIONS: FDA-approved small-molecule inhibitors of EZH2 can indirectly target BZW2 and because BZW2 functions as an oncogene, these inhibitors could serve as therapeutic agents for colorectal cancer.

Immunophenotypic profiles and prognosis for colorectal mucinous adenocarcinomas are dependent on anatomic location.

BACKGROUND: The prognostic value of mucinous adenocarcinomas (MCAs, exhibiting >50% extracellular mucin) of the colorectum, in relation to their anatomic location is not well studied. MATERIALS AND METHODS: We compared MCAs (n = 175) with non-MCAs (NMCAs, n = 1015) and the cancer-specific survival rates were evaluated, based on their anatomic site, by univariate Kaplan-Meier and multivariate Cox methods. Subsets of these tumors were immunostained for MUC1, MUC2, Bcl-2, and p53. RESULTS: MCAs were more commonly found in the right colon, were of high-grade, and were more prevalent in younger patients (<40 years). They exhibited strong expression of MUC2 and Bcl-2 and showed less p53 nuclear staining. In contrast, most NMCAs were low-grade with high expression of MUC1. MCAs of the rectum were associated with poorer outcomes relative to NMCAs (HR 1.85, CI 95% 1.15-2.97), even though the distributions of advanced-stage tumors were similar. CONCLUSION: Late-stage disease and age were poor independent prognostic indicators of cancer-specific deaths across all tumor locations. In summary, rectal MCAs have a poor prognosis.

Molecular characterization of visible low-grade dysplastic lesions in patients with inflammatory bowel disease.

We studied pathogenic gene mutations and tumor mutation burden (TMB) in visible low-grade dysplastic lesions in patients with inflammatory bowel disease (IBD). The dysplastic lesions with histologically normal mucosa in the background (group 1) were compared with dysplastic lesions occurring either in a background of chronic active colitis (group 2) or associated with synchronous carcinomas regardless of the status of the background mucosa (group 3). The TMB in group 3 was consistently higher in comparison to the group 1 and group 2 lesions, although the difference was not statistically significant. There also seem to be different mutation profiles between the groups, indicating different pathways of tumor pathogenesis. More frequent APC mutations were seen in group 1 as compared to other groups and TP53 mutations were seen in groups 2 and 3, but none in group 1. Molecular characterization could potentially be used as an ancillary prognostic marker in challenging cases to guide the further management of IBD patients with visible dysplastic lesions.

A signature of Prevotella copri and Faecalibacterium prausnitzii depletion, and a link with bacterial glutamate degradation in the Kenyan colorectal cancer patients.

Background: Colorectal cancer (CRC) is the fifth most diagnosed cancer in Sub-Saharan Africa. In Kenya, CRC incidence rates tripled from 1997 to 2017. In the Moi Teaching and Referral Hospital, Moi University, there has been an increase in CRC cases, notably for younger patients. A suggested pathobiology for this increase is gut microbiome dysbiosis. Since, for the Kenyan CRC patient population, microbiome studies are rare, there is a need for a better understanding of how microbiome dysbiosis influences CRC epidemiology in Kenya. In this single-center study, the focus was on profiling the gut microbiome of Kenyan CRC patients and healthy volunteers and evaluating associations between microbiome profiles and the age of CRC patients. Methods: The gut mucosa-associated microbiome of 18 CRC patients and 18 healthy controls were determined by 16S rRNA sequencing and analyzed for alpha and beta diversity, differential abundance, and microbial metabolic profiling. Results: Alpha diversity metrics showed no significant differences, but beta diversity metrics showed dissimilarities in the microbial communities between CRC patients and healthy controls. The most underrepresented species in the CRC group were Prevotella copri (P. copri) and Faecalibacterium prausnitzii (F. prausnitzii), although Bacteroides fragilis (B. fragilis) and Prevotella nigrescens were overrepresented (linear discriminant analysis, LDA score >2, P<0.05). Also, for CRC patients, significant metagenomic functional alterations were evident in microbial glutamate metabolic pathways (L-glutamate degradation VIII was enriched, and L-glutamate and L-glutamine biosynthesis were diminished) (P<0.05, log2 Fold Change >1). Moreover, the microbiome composition was different for patients under 40 years of age compared to older patients (LDA score >2, P<0.05). Conclusions: Microbiome and microbial metabolic profiles of CRC patients are different from those of healthy individuals. CRC microbiome dysbiosis, particularly P. copri and F. prausnitzii depletion and glutamate metabolic alterations, are evident in Kenyan CRC patients.

Age-Dependent Heterogeneity of Lymph Node Metastases and Survival Identified by Analysis of a National Breast Cancer Registry.

Background: For several cancers, including those of the breast, young age at diagnosis is associated with an adverse prognosis. Although this effect is often attributed to heritable mutations such as BRCA1/2, the relationship between pathologic features, young age of onset, and prognosis for breast cancer remains unclear. In the present study, we highlight links between age of onset and lymph node metastasis (NM) in US women with breast cancer. Methods: Case listings from Surveillance, Epidemiology, and End Result (SEER) 18 registry data for women with breast cancer, which include information on race, were used. NM and its associated outcomes were evaluated for a subset of women with receptor subtype information and then compared against a larger, pre-subtype validation set of data from the same registry. Age of diagnosis was a 5-category variable; under 40 years, 40-49 years, 50-59 years, 60-69 years and 70+ years. Univariate and adjusted multivariate survival models were applied to both sets of data. Results: As determined with adjusted logistic regression models, women under 40 years old at diagnosis had 1.55 times the odds of NM as women 60-69 years of age. The odds of NM for (HR = hormone receptor) HR+/HER2+, HR-/HER2+, and triple-negative breast cancer subtypes were significantly lower than those for HR+/HER2-. In subtype-stratified adjusted models, age of diagnosis had a consistent trend of decreasing odds of NM by age category, most noticeable for HR+ subtypes of luminal A and B. Univariate 5-year survival by age was worst for women under 40 years, with NM attributable for 49% of the hazard of death from cancer in adjusted multivariate models. Conclusions: Lymph node metastasis is age-dependent, yet not all molecular subtypes are clearly affected by this relationship. For <40-yr-old women, NM is a major cause for shorter survival. When stratified by subtype, the strongest associations were in HR+ groups, suggesting a possible hormonal connection between young age of breast cancer onset and NM.

Meta-analysis of the robustness of COVID-19 diagnostic kit performance during the early pandemic.

BACKGROUND: Accurate detection of SARS-CoV-2 is necessary to mitigate the COVID-19 pandemic. However, the test reagents and assay platforms are varied and may not be sufficiently robust to diagnose COVID-19. METHODS: We reviewed 85 studies (21 530 patients), published from five regions of the world, to highlight issues involved in the diagnosis of COVID-19 in the early phase of the pandemic. All relevant articles, published up to 31 May 2020, in PubMed, BioRiXv, MedRiXv and Google Scholar, were included. We evaluated the qualitative (9749 patients) and quantitative (10 355 patients) performance of RT-PCR and serologic diagnostic tests for real-world samples, and assessed the concordance (5538 patients) between test performance in meta-analyses. Synthesis of results was done using random effects modelling and bias was evaluated according to QUADAS-2 guidelines. RESULTS: The RT-PCR tests exhibited heterogeneity in the primers and reagents used. Of 1957 positive RT-PCR COVID-19 participants, 1585 had positive serum antibody (IgM±IgG) tests (sensitivity 0.81, 95% CI 0.66 to 0.90). While 3509 of 3581 participants RT-PCR negative for COVID-19 were found negative by serology testing (specificity 0.98, 95% CI 0.94 to 0.99). The chemiluminescent immunoassay exhibited the highest sensitivity, followed by ELISA and lateral flow immunoassays. Serology tests had higher sensitivity and specificity for laboratory approval than for real-world reporting data. DISCUSSION: The robustness of the assays/platforms is influenced by variability in sampling and reagents. Serological testing complements and may minimise false negative RT-PCR results. Lack of standardised assay protocols in the early phase of pandemic might have contributed to the spread of COVID-19.

DCZ0415, a small-molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/ß-catenin pathway in colorectal cancer.

Thyroid receptor-interacting protein 13 (TRIP13), a protein of the AAA-ATPase family, is upregulated in various human cancers, including colorectal cancer (CRC). This study focused on the inhibition of TRIP13-induced CRC progression and signalling by DCZ0415, a small molecule targeting TRIP13. It demonstrated potent antitumour activity in TRIP13-deregulated cancer cell lines, regardless of their p53, KRAS, BRAF, epidermal growth factor receptor or microsatellite instability status. The treatment of CRC cells with DCZ0415 resulted in decreased cell proliferation, induced cell cycle arrest in the G2-M phase and increased apoptosis. DCZ0415 diminished xenograft tumour growth and metastasis of CRC in immunocompromised mice. DCZ0415 reduced expression of fibroblast growth factor receptor 4 (FGFR4), signal transducer and activator of transcription 3 (STAT3), and proteins associated with the epithelial-mesenchymal transition and nuclear factor kappa B (NF-κB) pathways in cells and xenografts exhibiting high expression of TRIP13. Additionally, DCZ0415 decreased cyclin D1, ß-catenin and T-cell factor 1, leading to the inactivation of the Wnt/ß-catenin pathway. In a syngeneic CRC model, DCZ0415 treatment induced an immune response by decreasing PD1 and CTLA4 levels and increasing granzyme B, perforin and interferon gamma. In sum, DCZ04145 inhibits the TRIP13-FGFR4-STAT3 axis, inactivates NF-κB and Wnt/ß-catenin signalling, activates antitumour immune response and reduces the progression and metastasis of CRC. This study provides a rationale to evaluate DCZ0415 clinically for the treatment of a subset of CRCs that exhibit dysregulated TRIP13 and FGFR4.

Immunophenotype-associated gene signature in ductal breast tumors varies by receptor subtype, but the expression of individual signature genes remains consistent.

BACKGROUND: In silico deconvolution of invasive immune cell infiltration in bulk breast tumors helps characterize immunophenotype, expands treatment options, and influences survival endpoints. In this study, we identify the differential expression (DE) of the LM22 signature to classify immune-rich and -poor breast tumors and evaluate immune infiltration by receptor subtype and lymph node metastasis. METHODS: Using publicly available data, we applied the CIBERSORT algorithm to estimate immune cells infiltrating the tumor into immune-rich and immune-poor groups. We then tested the association of receptor subtype and nodal status with immune-rich/poor phenotype. We used DE to test individual signature genes and over-representation analysis for related pathways. RESULTS: CCL19 and CXCL9 expression differed between rich/poor signature groups regardless of subtype. Overexpression of CHI3L2 and FES was observed in triple negative breast cancers (TNBCs) relative to other subtypes in immune-rich tumors. Non-signature genes, LYZ, C1QB, CORO1A, EVI2B, GBP1, PSMB9, and CD52 were consistently overexpressed in immune-rich tumors, and SCUBE2 and GRIA2 were associated with immune-poor tumors. Immune-rich tumors had significant upregulation of genes/pathways while none were identified in immune-poor tumors. CONCLUSIONS: Overall, the proportion of immune-rich/poor tumors differed by subtype; however, a subset of 10 LM22 genes that marked immune-rich status remained the same across subtype. Non-LM22 genes differentially expressed between the phenotypes suggest that the biologic processes responsible for immune-poor phenotype are not yet well characterized.

Comparative analysis of triple-negative breast cancer transcriptomics of Kenyan, African American and Caucasian Women.

PURPOSE: Triple-negative breast cancer (TNBC) patients of various ethnic groups often have discrete clinical presentations and outcomes. Women of African descent have a disproportionately higher chance of developing TNBCs. The aim of the current study was to establish the transcriptome of TNBCs from Kenyan (KE) women of Bantu origin and compare it to those TNBCs of African-Americans (AA) and Caucasians (CA) for identifying KE TNBC-specific molecular determinants of cancer progression and potential biomarkers of clinical outcomes. PATIENTS AND METHODS: Pathology-confirmed TNBC tissues from Kenyan women of Bantu origin (n = 15) and age and stage range matched AA (n = 19) and CA (n = 23) TNBCs of patients from Alabama were included in this study. RNA was isolated from paraffin-embedded tissues, and expression was analyzed by RNA sequencing. RESULTS: At clinical presentation, young KE TNBC patients have tumors of higher stages. Differential expression analysis identified 160 up-regulated and 178 down-regulated genes in KE TNBCs compared to AA and CA TNBCs. Validation analyses of the TCGA breast cancer data identified 45 KE TNBC-specific genes that are involved in the apoptosis (ACTC1, ERCC6 and CD14), cell proliferation (UHRF2, KDM4C, UHMK1, KCNH5, KRT18, CSF1R and S100A13), and Wnt signaling (BCL9L) pathways. CONCLUSIONS: In this study, we identified biomarkers that are specific for KE TNBC patients of Bantu origin. Further study with a larger sample size of matched tumors could confirm our findings. If biologically confirmed, these molecular determinants could have clinical and biological implications and serve as targets for development of personalized therapeutics for KE TNBC patients.

Meta-Analysis of Robustness of COVID-19 Diagnostic Kits During Early Pandemic.

BACKGROUND: Accurate detection of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is necessary to mitigate the coronavirus disease-19 (COVID-19) pandemic. However, the test reagents and assay platforms are varied and may not be sufficiently robust to diagnose COVID-19. METHODS: We reviewed 85 studies (21,530 patients), published from five regions of the world, to highlight issues involved in the diagnosis of COVID-19 in the early phase of the pandemic, following the standards outlined in the PRISMA statement. All relevant articles, published up to May 31, 2020, in PubMed, BioRiXv, MedRiXv, and Google Scholar, were included. We evaluated the qualitative (9749 patients) and quantitative (10,355 patients) performance of RT-PCR and serologic diagnostic tests for real-world samples, and assessed the concordance (5,538 patients) between methods in meta-analyses. RESULTS: The RT-PCR tests exhibited heterogeneity in the primers and reagents used. Of 1,957 positive RT-PCR COVID-19 participants, 1,585 had positive serum antibody (IgM +/- IgG) tests (sensitivity 0.81, 95%CI 0.66-.90). While 3,509 of 3581 participants RT-PCR negative for COVID-19 were found negative by serology testing (specificity 0.98, 95%CI 0.94-0.99). The chemiluminescent immunoassay exhibited the highest sensitivity, followed by ELISA and lateral flow immunoassays. Serology tests had higher sensitivity and specificity for laboratory-approval than for real-world reporting data. CONCLUSIONS: The robustness of the assays/platforms is influenced by variability in sampling and reagents. Serological testing complements and may minimize false negative RT-PCR results. Lack of standardized assay protocols in the early phase of pandemic might have contributed to the spread of COVID-19.

Obesity-Associated Myeloid-Derived Suppressor Cells Promote Apoptosis of Tumor-Infiltrating CD8 T Cells and Immunotherapy Resistance in Breast Cancer.

Nearly 70% of adults in the US are currently overweight or obese. Despite such high prevalence, the impact of obesity on antitumor immunity and immunotherapy outcomes remains incompletely understood, particularly in patients with breast cancer. Here, we addressed these gaps in knowledge using two murine models of breast cancer combined with diet-induced obesity. We report that obesity increases CXCL1 concentrations in the mammary tumor microenvironment, driving CXCR2-mediated chemotaxis and accumulation of granulocytic myeloid-derived suppressor cells (G-MDSCs) expressing Fas ligand (FasL). Obesity simultaneously promotes hyperactivation of CD8 tumor-infiltrating lymphocytes (TILs), as evidenced by increased expression of CD44, PD-1, Ki-67, IFNγ, and the death receptor Fas. Accordingly, G-MDSCs induce Fas/FasL-mediated apoptosis of CD8 T cells ex vivo and in vivo. These changes promote immunotherapy resistance in obese mice. Disruption of CXCR2-mediated G-MDSC chemotaxis in obese mice is sufficient to limit intratumoral G-MDSC accumulation and improve immunotherapy outcomes. The translational relevance of our findings is demonstrated by transcriptomic analyses of human breast tumor tissues, which reveal positive associations between CXCL1 expression and body mass index, poor survival, and a MDSC gene signature. Further, this MDSC gene signature is positively associated with FASLG expression. Thus, we have identified a pathway wherein obesity leads to increased intratumoral CXCL1 concentrations, which promotes CXCR2-mediated accumulation of FasL+ G-MDSCs, resulting in heightened CD8 TIL apoptosis and immunotherapy resistance. Disruption of this pathway may improve immunotherapy outcomes in patients with breast cancer and obesity.

TRIP13 promotes metastasis of colorectal cancer regardless of p53 and microsatellite instability status.

Overexpression of TRIP13, a member of the AAA-ATPase family, is linked with various cancers, but its role in metastasis is unknown in colorectal cancer (CRC). In the current study, we investigated the role TRIP13 in experimental metastasis and its involvement in regulation of WNT/ß-catenin and EGFR signaling pathways. Evaluation of formalin-fixed paraffin-embedded (FFPE) and frozen tissues of adenomas and CRCs, along with their corresponding normal samples, showed that TRIP13 was gradually increased in its phenotypic expression from adenoma to carcinoma and that its overexpression in CRCs was independent of patient's gender, age, race/ethnicity, pathologic stage, and p53 and microsatellite instability (MSI) status. Moreover, liver metastases of CRCs showed TRIP13 overexpression as compared to matched adjacent liver tissues, indicating the biological relevance of TRIP13 in CRC progression and metastasis. TRIP13 knockdown impeded colony formation, invasion, motility, and spheroid-forming capacity of CRC cells irrespective of their p53 and MSI status. Furthermore, xenograft studies demonstrated high expression of TRIP13 contributed to tumor growth and metastasis. Depletion of TRIP13 in CRC cells decreased metastasis and it was independent of the p53 and MSI status. Furthermore, TRIP13 interacted with a tyrosine kinase, FGFR4; this interaction could be essential for activation of the EGFR-AKT pathway. In addition, we demonstrated the involvement of TRIP13 in the Wnt signaling pathway and in the epithelial-mesenchymal transition. Cell-based assays revealed that miR-192 and PNPT1 regulate TRIP13 expression in CRC. Additionally, RNA sequencing of CRC cells with TRIP13 knockdown identified COL6A3, TREM2, SHC3, and KLK7 as downstream targets that may have functional relevance in TRIP13-mediated tumor growth and metastasis. In summary, our results demonstrated that TRIP13 promotes tumor growth and metastasis regardless of p53 and MSI status, and indicated that it is a target for therapy of CRC.

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer.

The identification of colorectal cancer (CRC) molecular targets is needed for the development of drugs that improve patient survival. We investigated the functional role of phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a de novo purine biosynthetic enzyme involved in DNA synthesis, in CRC progression and metastasis by using cell and animal models. Its clinical utility was assessed in human CRC samples. The expression of PAICS was regulated by miR-128 and transcriptionally activated by Myc in CRC cells. Increased expression of PAICS was involved in proliferation, migration, growth, and invasion of CRC cells irrespective of the p53 and microsatellite status. In mice, the depletion of PAICS in CRC cells led to reduced tumor growth and metastatic cell dissemination to the liver, lungs, and bone. Positron emission tomography imaging showed significantly reduced metastatic lesions in stable PAICS knockdown CRC cells. In cells with PAICS knockdown, there was upregulation of the epithelial mesenchymal transition marker, E-cadherin, and bromodomain inhibitor, JQ1, can target its increased expression by blocking Myc. PAICS was overexpressed in 70% of CRCs, and was associated with poor 5-year survival independent of the pathologic stage, patient's race, gender, and age. Overall, the findings point to the usefulness of PAICS targeting in the treatment of aggressive colorectal cancer.

Targeting P4HA1 with a Small Molecule Inhibitor in a Colorectal Cancer PDX Model.

Deposition, remodeling, and signaling of the extracellular matrix facilitate tumor growth and metastasis. Here, we demonstrated that an enzyme, collagen prolyl 4-hydroxylase, alpha polypeptide I (P4HA1), which is involved in collagen synthesis and deposition, had elevated expression in colorectal cancers (CRCs) as compared to normal colonic tissues. The expression of P4HA1 in CRCs was independent of patient's age, race/ethnicity, gender, pathologic stage and grade, tumor location, and microsatellite instability (MSI) and p53 status. By modulating P4HA1 with shRNA, there was a reduction in malignant phenotypes of CRCs, including cell proliferation, colony formation, invasion, migration, and tumor growth, in mice regardless of their p53 and MSI status. Immunoblot analysis of excised xenograft tumors developed from cells with silenced PH4HA1 showed low levels of proliferating cell nuclear antigen. Further, in CRC mouse models, silencing of P4HA1 in HT29 cells resulted in less metastasis to liver and bone. P4HA1 expression was regulated by miR-124, and inhibition of cell growth was noted for CRC cells treated with miR-124. Furthermore, low levels of the transcriptional repressor EZH2 reduced P4HA1 expression in CRC cells. Inhibition of P4HA1 with the small molecule inhibitor diethyl-pythiDC decreased AGO2 and MMP1, which are P4HA1 target molecules, and reduced the malignant phenotypes of CRC cells. Treatment of CRC patient-derived xenografts that exhibit high expression of P4HA1 with diethyl-pythiDC resulted in tumor regression. Thus, the present study shows that P4HA1 contributes to CRC progression and metastasis and that targeting of P4HA1 with diethyl-pythiDC could be an effective therapeutic strategy for aggressive CRCs.

Gain of function in somatic TP53 mutations is associated with immune-rich breast tumors and changes in tumor-associated macrophages.

BACKGROUND: Somatic mutations in TP53 are present in 20%-30% of all breast tumors. While there are numerous population-based analyses of TP53, yet none have examined the relationship between somatic mutations in TP53 and tumor invasive immune cells. METHODS: Clinical and genetic data from 601 women drawn from The Cancer Genome Atlas (TCGA) were used to test the association between somatic TP53 mutation and immune-rich or immune-poor tumor status; determined using the CIBERSORT-based gene expression signature of 22 immune cell types. Our validation dataset, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), used a pathologist-determined measure of lymphocyte infiltration. RESULTS: Within TP53-mutated samples, a mutation at codon p.R175H was shown to be present at higher frequency in immune-rich tumors. In validation analysis, any somatic mutation in TP53 was associated with immune-rich status, and the mutation at p.R175H had a significant association with tumor-invasive lymphocytes. TCGA-only analysis of invasive immune cell type identified an increase in M0 macrophages associated with p.R175H. CONCLUSIONS: These findings suggest that TP53 somatic mutations, particularly at codon p.R175H, are enriched in tumors with infiltrating immune cells. Our results confirm recent research showing inflammation-related gain of function in specific TP53 mutations.