Gene Summary

Gene:PITX1; paired like homeodomain 1
Summary:This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pituitary homeobox 1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: PITX1 (cancer-related)

Jenkinson G, Abante J, Koldobskiy MA, et al.
Ranking genomic features using an information-theoretic measure of epigenetic discordance.
BMC Bioinformatics. 2019; 20(1):175 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Establishment and maintenance of DNA methylation throughout the genome is an important epigenetic mechanism that regulates gene expression whose disruption has been implicated in human diseases like cancer. It is therefore crucial to know which genes, or other genomic features of interest, exhibit significant discordance in DNA methylation between two phenotypes. We have previously proposed an approach for ranking genes based on methylation discordance within their promoter regions, determined by centering a window of fixed size at their transcription start sites. However, we cannot use this method to identify statistically significant genomic features and handle features of variable length and with missing data.
RESULTS: We present a new approach for computing the statistical significance of methylation discordance within genomic features of interest in single and multiple test/reference studies. We base the proposed method on a well-articulated hypothesis testing problem that produces p- and q-values for each genomic feature, which we then use to identify and rank features based on the statistical significance of their epigenetic dysregulation. We employ the information-theoretic concept of mutual information to derive a novel test statistic, which we can evaluate by computing Jensen-Shannon distances between the probability distributions of methylation in a test and a reference sample. We design the proposed methodology to simultaneously handle biological, statistical, and technical variability in the data, as well as variable feature lengths and missing data, thus enabling its wide-spread use on any list of genomic features. This is accomplished by estimating, from reference data, the null distribution of the test statistic as a function of feature length using generalized additive regression models. Differential assessment, using normal/cancer data from healthy fetal tissue and pediatric high-grade glioma patients, illustrates the potential of our approach to greatly facilitate the exploratory phases of clinically and biologically relevant methylation studies.
CONCLUSIONS: The proposed approach provides the first computational tool for statistically testing and ranking genomic features of interest based on observed DNA methylation discordance in comparative studies that accounts, in a rigorous manner, for biological, statistical, and technical variability in methylation data, as well as for variability in feature length and for missing data.

Fisher RC, Bellamkonda K, Alex Molina L, et al.
Disrupting Inflammation-Associated CXCL8-CXCR1 Signaling Inhibits Tumorigenicity Initiated by Sporadic- and Colitis-Colon Cancer Stem Cells.
Neoplasia. 2019; 21(3):269-281 [PubMed] Free Access to Full Article Related Publications
Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC- and pCCSC-induced proliferation and angiogenesis.

Habeeb O, Rubin BP
The Molecular Diagnostics of Vascular Neoplasms.
Surg Pathol Clin. 2019; 12(1):35-49 [PubMed] Related Publications
In this review, we provide an update of the recently discovered, diagnostically significant genetic aberrations harbored by a subset of vascular neoplasms. From benign (epithelioid hemangioma, spindle cell hemangioma), to intermediate (pseudomyogenic hemangioendothelioma), to malignant (epithelioid hemangioendothelioma, angiosarcoma), each neoplasm features a mutation or gene fusion that facilitates its diagnosis by immunohistochemistry and/or molecular ancillary testing. The identification of these genetic anomalies not only assists with the objective classification and diagnosis of these neoplasms, but also serves to help recognize potential therapeutic targets.

Lin J, Hu Y, Zhao JJ
Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos.
J Vis Exp. 2018; (142) [PubMed] Free Access to Full Article Related Publications
The single-wall carbon nanotube (SWCNT) is a new type of nanoparticle, which has been used to deliver multiple kinds of drugs into cells, such as proteins, oligonucleotides, and synthetic small-molecule drugs. The SWCNT has customizable dimensions, a large superficial area, and can flexibly bind with drugs through different modifications on its surface; therefore, it is an ideal system to transport drugs into cells. Long noncoding RNAs (lncRNAs) are a cluster of noncoding RNA longer than 200 nt, which cannot be translated to protein but play an important role in biological and pathophysiological processes. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved lncRNA. It was demonstrated that higher MALAT1 levels are related to the poor prognosis of various cancers, including multiple myeloma (MM). We have revealed that MALAT1 regulates DNA repair and cell death in MM; thus, MALAT1 can be considered as a therapeutic target for MM. However, the efficient delivery of the antisense oligo to inhibit/knockdown MALAT1 in vivo is still a problem. In this study, we modify the SWCNT with PEG-2000 and conjugate an anti-MALAT1 oligo to it, test the delivery of this compound in vitro, inject it intravenously into a disseminated MM mouse model, and observe a significant inhibition of MM progression, which indicates that SWCNT is an ideal delivery shuttle for anti-MALAT1 gapmer DNA.

Jiang W, He Y, Shi Y, et al.
MicroRNA-1204 promotes cell proliferation by regulating PITX1 in non-small-cell lung cancer.
Cell Biol Int. 2019; 43(3):253-264 [PubMed] Related Publications
MicroRNA-1204 (miR-1204), a member of the PVT1 region, may improve B cell differentiation and metastasis in breast cancer. However, the role of miR-1204 in non-small-cell lung cancer (NSCLC) and its mechanism remain unclear. The GEO public database was first employed to find differentially expressed genes. The expression level of miR-1204 in patient tissues and NSCLC cell lines was determined using qRT-PCR. Cell proliferation assays were performed to investigate the impact of miR-1204 on cell growth. Bioinformatics analysis and dual-luciferase reporter assays were conducted to find potential target genes. Finally, we performed in vivo experiments to identify the effect of miR-1204 on tumor formation in nude mice. It was first found that miR-1204 was overexpressed in NSCLC tissues and cells. miR-1204 increased the proliferation of NSCLC cells and reduced cell cycle arrest in vitro. PITX1 (paired like homeodomain 1) was found as a potential target gene. In addition, PITX1 was also found to be low in expression in NSCLC tissues and cells. To show that PITX1 reversed the function of miR-1204 in promoting proliferation, confirmatory experiments were performed. Moreover, high miR-1204 and low PITX1 expression was highly correlated with tumor size, lymph node metastasis, and the TNM stage in patients diagnosed with NSCLC. Our results suggested that upregulated miR-1204 in NSCLC is associated with NSCLC progression and promotes NSCLC cell proliferation by downregulating PITX1. miR-1204 may act as a poor prognostic factor and a potential therapeutic target for NSCLC.

Tracey EH, Vij A
Updates in Melanoma.
Dermatol Clin. 2019; 37(1):73-82 [PubMed] Related Publications
Skin cancer is reaching epidemic levels in the United States. Recent advances in the understanding of the pathophysiology of melanoma have allowed improved risk stratification in the revised American Joint Committee on Cancer (AJCC) criteria, new tests to capture patients at higher risk than their stage may indicate, and new treatments to offer hope and cures to patients with advanced disease.

Song X, Zhao C, Jiang L, et al.
High PITX1 expression in lung adenocarcinoma patients is associated with DNA methylation and poor prognosis.
Pathol Res Pract. 2018; 214(12):2046-2053 [PubMed] Related Publications
BACKGROUND: Pituitary homeobox 1 (PITX1) is a member of the PITX gene family which is vital to proper development of early embryo. However, the relationship of PITX1 expression and overall survival (OS) in non-small cell lung cancer (NSCLC) is not clear.
METHODS: In our study, bioinformatic analysis was performed using UCSC Xena Browser. We used data based on the Cancer Genome Atlas-lung cancer (TCGA-LUNG). Kaplan Meier curves of overall survival were used to investigate the association between PITX1 gene expression and OS in NSCLC patients by the UCSC Xena browser.
RESULTS: Compared with normal lung tissue, PITX gene family was upregulated in NSCLC. Furthermore, higher PITX1 expression was significantly associated with worse OSin 2 yrs., 5 yrs. and 10 yrs. OS (p =  0.004754, 0.01469, 0.02935 respectively) in lung adenocarcinoma (LUAD) patients, but not in lung squamous cell carcinoma (LUSC) patients. PITX1 expression increased in male patients, advanced TNM stage, advanced T stage and advanced regional lymph node status of LUAD patients. PITX1 expressed lowest in bronchioid subtype, meanwhile PITX1 expression was highest in squamoid and magnoid subtype. The high DNA methylation of PITX1 indicated the poor OS in LUAD patients. GSEA revealed that inflammatory response, TNFα signaling via NFκB, TGFβ signaling, IL6 JAK STAT3 signaling and interferon Gamma response were significantly enriched in high PITX1 expression.
CONCLUSION: These findings suggested that PITX1 might serve as a potential biomarker for early detection and prognosis prediction of LUAD patients.

Lee H, Fu Z, Koo BH, et al.
The expression of TTF1, CDX2 and ISL1 in 74 poorly differentiated neuroendocrine carcinomas.
Ann Diagn Pathol. 2018; 37:30-34 [PubMed] Related Publications
BACKGROUND: The expression profile of immunohistochemical markers of origin in poorly differentiated neuroendocrine carcinoma (PDNEC) is not well studied.
MATERIALS AND METHODS: Seventy-four PDNECs from gastroenteropancreatic (GEP) organs and the lung, including 48 large cell NEC (LCNEC) and 26 small cell carcinomas (SmCC), were subject to immunohistochemical staining for CDX2, TTF1 and ISL1. The staining intensity (1 to 3) and percentage of positive tumor cells [0 (negative), 1 (<50%) and 2 (≥50%)] were assessed. The multiplicative index (maximum 6) was calculated and the average total score (aTS) was determined for each primary site and histologic subtype.
RESULTS: In the 38 GEP and 36 lung PDNECs, CDX2, TTF1 and ISL1 staining was observed in 71% (aTS 2.8), 16% (aTS 0.4), 63% (aTS 1.9), and 22% (aTS 0.6), 72% (aTS 2.9) and 92% (aTS 3.8), respectively. GEP PDNECs showed a higher aTS for CDX2 and lower aTS for TTF1 and ISL1, compared to that of lung PDNECs (Student's t-test, p < 0.001). SmCC had a higher aTS for TTF1 and ISL1 (p < 0.001) and lower aTS for CDX2 (p < 0.002) than that of LCNEC.
CONCLUSIONS: CDX2 and TTF1 demonstrate potential utility in suggesting the primary site of PDNEC. In addition, CDX2 may be useful in supporting the diagnosis of LCNEC in cases with overlapping or borderline morphology. Utility of ISL1 as an adjunctive diagnostic marker of SmCC remains to be studied.

Doxtader EE, Chute DJ
Evaluation of Carcinoma of Unknown Primary on Cytologic Specimens.
Surg Pathol Clin. 2018; 11(3):545-562 [PubMed] Related Publications
Carcinoma of unknown primary is defined as metastatic carcinoma without a clinically obvious primary tumor. Determining the tissue of origin in carcinoma of unknown primary is important for site-directed therapy. Immunohistochemistry is the most widely used tool for the work-up of metastases, but molecular profiling assays are also available. This review provides an overview of immunohistochemical stains in the work-up of metastatic carcinoma, with a focus on newer site-specific markers, and discusses the role of gene expression profiling assays for determining tissue of origin. The utility of cytopathology specimens in the evaluation of carcinoma of unknown primary also is highlighted.

Magi-Galluzzi C, Isharwal S, Falzarano SM, et al.
The 17-Gene Genomic Prostate Score Assay Predicts Outcome After Radical Prostatectomy Independent of PTEN Status.
Urology. 2018; 121:132-138 [PubMed] Related Publications
OBJECTIVE: To compare the ability of loss of phosphatase and tensin homolog (PTEN) and Genomic prostate score assay (GPS) in predicting the biochemical-recurrence (BCR) and clinical-recurrence (CR) after radical prostatectomy (RP) for clinically localized prostate cancer (PCa).
METHODS: Three hundred seventy seven patients with and without CR were retrospectively selected by stratified cohort sampling design from RP database. PTEN status (by immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH]) and GPS results were determined for RP specimens. BCR was defined as Prostate Specific Antigen (PSA) ≥ 0.2 ng/mL or initiation of salvage therapy for a rising PSA. CR was defined as local recurrence and/or distant metastases.
RESULTS: Baseline mean age, PSA, and GPS score for the cohort were 61.1 years, 8 ng/dL, and 32.8. PTEN loss was noted in 38% patients by FISH and 25% by IHC. The concordance between FISH and IHC for PTEN loss was 66% (Kappa coefficient 0.278; P < .001). On univariable analysis, loss of PTEN by FISH or IHC was associated with BCR and CR (P < .05). However, after adjusting for GPS results, PTEN loss was not a significant predictor for CR or BCR (P > .1). The GPS result remained strongly associated with CR and BCR after adjusting for PTEN status (P < .001). PTEN status and GPS results only weakly correlated. GPS was widely distributed regardless of PTEN status indicating the biological heterogeneity of PCa even in PTEN-deficient cases.
CONCLUSION: GPS is a significant predictor of aggressive PCa, independent of PTEN status. After adjustment for GPS results, PTEN was not independently associated with recurrence for PCa.

Krishna BA, Miller WE, O'Connor CM
US28: HCMV's Swiss Army Knife.
Viruses. 2018; 10(8) [PubMed] Free Access to Full Article Related Publications

Hashemi-Sadraei N, Müller-Greven GM, Abdul-Karim FW, et al.
Expression of LC3B and FIP200/Atg17 in brain metastases of breast cancer.
J Neurooncol. 2018; 140(2):237-248 [PubMed] Related Publications
BACKGROUND: Macroautophagy/autophagy is considered to play key roles in tumor cell evasion of therapy and establishment of metastases in breast cancer. High expression of LC3, a residual autophagy marker, in primary breast tumors has been associated with metastatic disease and poor outcome. FIP200/Atg17, a multi-functional pro-survival molecule required for autophagy, has been implicated in brain metastases in experimental models. However, expression of these proteins has not been examined in brain metastases from patients with breast cancer.
METHODS: In this retrospective study, specimens from 44 patients with brain metastases of infiltrating ductal carcinoma of the breast (IDC), unpaired samples from 52 patients with primary IDC (primary-BC) and 16 matched-paired samples were analyzed for LC3 puncta, expression of FIP200/Atg17, and p62 staining.
RESULTS: LC3-puncta
CONCLUSIONS: These results support assessments of precision medicine-guided targeting of autophagy in treatment of brain metastases in breast cancer patients.

Caraballo ER, Palacios DA, Suk-Ouichai C, et al.
Open partial nephrectomy when a non-flank approach is required: indications and outcomes.
World J Urol. 2019; 37(3):515-522 [PubMed] Related Publications
PURPOSE: To evaluate indications/outcomes for open partial nephrectomy (OPN) when non-flank approaches are required, with comparison to patients managed with the flank approach. Outcomes with a non-flank approach are presumed less favorable yet there have been no previous reports on this topic.
METHODS: 2747 OPNs were performed (1999-2015) and 76 (2.8%) required a non-flank approach. We also reviewed all traditional flank OPNs performed during odd years in this timeframe yielding 1467 patients for comparison.
RESULTS: Overall, median tumor size was 3.5 cm and 274 patients (18%) had a solitary kidney. Non-flank patients were younger, and tumor size and clinical/pathologic stage were significantly increased for this cohort, but the groups were otherwise comparable. Indications for non-flank OPN included large tumor size/locally advanced disease (n = 21), need for simultaneous surgery (n = 25), previous flank incision or failed thermoablation (n = 13), or congenital/vascular abnormalities (n = 9). The most common non-flank approach was anterior subcostal (n = 39, 51%). Operative times, estimated blood loss, positive margins, and functional decline were all modestly increased for non-flank patients. Intraoperative and genitourinary complications were more common in non-flank patients (p < 0.05), although all were manageable, typically with conservative measures. There were no mortalities among non-flank patients and none required long-term dialysis.
CONCLUSIONS: Our series, the first to address this topic, suggests that outcomes with non-flank OPN are generally less advantageous likely reflecting increased tumor/operative complexity. However, complications in this challenging patient population are manageable and final dispositions are generally favorable. Our findings should be useful for counseling regarding potential outcomes when a non-flank incision is required.

Zabell J, Isharwal S, Dong W, et al.
Acute Kidney Injury after Partial Nephrectomy of Solitary Kidneys: Impact on Long-Term Stability of Renal Function.
J Urol. 2018; 200(6):1295-1301 [PubMed] Related Publications
PURPOSE: Acute kidney injury often leads to chronic kidney disease in the general population. The long-term functional impact of acute kidney injury observed after partial nephrectomy has not been adequately studied.
MATERIALS AND METHODS: From 2004 to 2014 necessary studies for analysis were available for 90 solitary kidneys managed by partial nephrectomy. Functional data at 4 time points included preoperative serum creatinine, peak postoperative serum creatinine, new baseline serum creatinine 3 to 12 months postoperatively and long-term followup serum creatinine more than 12 months postoperatively. Adjusted acute kidney injury was defined by the ratio, observed peak postoperative serum creatinine/projected postoperative serum creatinine adjusted for parenchymal mass loss to reveal the true effect of ischemia. The long-term change in renal function (the long-term functional change ratio) was defined as the most recent glomerular filtration rate/the new baseline glomerular filtration rate. The relationship between the grade of the adjusted acute kidney injury and the long-term functional change was assessed by Spearman correlation analysis and multivariable regression.
RESULTS: Median patient age was 64 years and median followup was 45 months. Median parenchymal mass preservation was 80%. Adjusted acute kidney injury occurred in 42% of patients, including grade 1 injury in 20 (22%) and grade 2/3 in 18 (20%). On univariable analysis the degree of the adjusted acute kidney injury did not correlate with the long-term glomerular filtration rate change (p = 0.55). On multivariable analysis adjusted acute kidney injury was not associated with a long-term functional change (p >0.05) while diabetes and warm ischemia were modestly associated with a long-term functional decline (each p <0.05).
CONCLUSIONS: Acute kidney injury after partial nephrectomy was not a significant or independent predictor of long-term functional decline in our institutional cohort. A prospective study with larger sample sizes and longer followup is required to evaluate factors associated with long-term nephron stability.

Hirsch CM, Nazha A, Kneen K, et al.
Consequences of mutant TET2 on clonality and subclonal hierarchy.
Leukemia. 2018; 32(8):1751-1761 [PubMed] Related Publications
Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2

Yehia L, Eng C
65 YEARS OF THE DOUBLE HELIX: One gene, many endocrine and metabolic syndromes:
Endocr Relat Cancer. 2018; 25(8):T121-T140 [PubMed] Related Publications
An average of 10% of all cancers (range 1-40%) are caused by heritable mutations and over the years have become powerful models for precision medicine practice. Furthermore, such cancer predisposition genes for seemingly rare syndromes have turned out to help explain mechanisms of sporadic carcinogenesis and often inform normal development. The tumor suppressor

Schlanger S, Heemers HV
Functional Studies on Steroid Receptors.
Methods Mol Biol. 2018; 1786:117-130 [PubMed] Related Publications
Nuclear receptors play an important role in prostate cancer and the androgen receptor is a key transcription factor in regulation of cellular events. Androgen receptor-associated coregulators may be upregulated or downregulated in prostate cancer. Altered expression of regulators may potentiate androgen-induced proliferation, migration, and invasion. Therapies aimed to modulate the function of coregulators in prostate cancer may be based on the use of small molecule inhibitors. Expression and function of AR-associated proteins could be investigated after overexpression and gene silencing followed by hormonal treatment, real-time RT-PCR and ChIP.

Qiao F, Gong P, Song Y, et al.
Downregulated PITX1 Modulated by MiR-19a-3p Promotes Cell Malignancy and Predicts a Poor Prognosis of Gastric Cancer by Affecting Transcriptionally Activated PDCD5.
Cell Physiol Biochem. 2018; 46(6):2215-2231 [PubMed] Related Publications
BACKGROUND/AIMS: PITX1 has been identified as a potential tumor-suppressor gene in several malignant tumors. The molecular mechanism underlying PITX1, particularly its function as a transcription factor regulating gene expression during tumorigenesis, is still poorly understood.
METHODS: The expression level and location of PITX1 were determined by quantitative reverse transcription PCR (qRT-PCR) and immunohistochemical staining in gastric cancer (GC). The effect of PITX1 on the GC cell proliferation and tumorigenesis was analyzed in vitro and in vivo. To explore how PITX1 suppresses cell proliferation, we used PITX1-ChIP-sequencing to measure genome-wide binding sites of PITX1 and assessed global function associations based on its putative target genes. ChIP-PCR, electrophoretic mobility shift assay, and promoter reporter assays examined whether PITX1 bound to PDCD5 and regulated its expression. The function of PDCD5 in GC cell apoptosis was further examined in vitro and in vivo. The relationship between the PITX1 protein level and GC patient prognosis was evaluated by the Kaplan-Meier estimator. Meanwhile, the expression level of miR-19a-3p, which is related to PITX1, was also detected by luciferase reporter assay, qRT-PCR, and western blotting.
RESULTS: The expression level of PITX1 was decreased in GC tissues and cell lines. Elevated PITX1 expression significantly suppressed the cell proliferation of GC cells and tumorigenesis in vitro and in vivo. PITX1 knockdown blocked its inhibition of GC cell proliferation. PITX1 bound to whole genome-wide sites, with these targets enriched on genes with functions mainly related to cell growth and apoptosis. PITX1 bound to PDCD5, an apoptosis-related gene, during tumorigenesis, and cis-regulated PDCD5 expression. Increased PDCD5 expression in GC cells not only induced GC cell apoptosis, but also suppressed GC cell growth in vitro and in vivo. Moreover, PITX1 expression was regulated by miR-19a-3p. More importantly, a decreased level of PITX1 protein was correlated with poor GC patient prognosis.
CONCLUSION: Decreased expression of PITX1 predicts shorter overall survival in GC patients. As a transcriptional activator, PITX1 regulates apoptosis-related genes, including PDCD5, during gastric carcinogenesis. These data indicate PDCD5 to be a novel and feasible therapeutic target for GC.

Yu X, Li W, Deng Q, et al.
Cancer Res. 2018; 78(10):2457-2462 [PubMed] Related Publications
Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis.

Hu Y, Lin J, Fang H, et al.
Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma.
Leukemia. 2018; 32(10):2250-2262 [PubMed] Free Access to Full Article Related Publications
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma (MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP-ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single-wall carbon nanotube (SWCNT) conjugated with anti-MALAT1 oligos, we successfully knocked-down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment.

Suk-Ouichai C, Wu J, Dong W, et al.
Tumor Contact Surface Area As a Predictor of Functional Outcomes After Standard Partial Nephrectomy: Utility and Limitations.
Urology. 2018; 116:106-113 [PubMed] Related Publications
OBJECTIVE: To evaluate contact surface area (CSA) between the tumor and parenchyma as a predictor of ipsilateral parenchyma and function preserved after partial nephrectomy (PN). Previous studies suggested that CSA is a strong predictor of functional outcomes but the limitations of CSA have not been adequately explored.
PATIENTS AND METHODS: Four hundred nineteen patients managed with standard PN for solitary tumor with necessary studies to evaluate and analyze ipsilateral preoperative or postoperative parenchymal mass and function. Parenchymal mass and CSA were measured using contrast-enhanced computed tomography <2 months prior and 3-12months after PN. CSA was calculated: 2πrd, where r = radius and d = intraparenchymal depth. Pearson-correlation evaluated relationships between CSA and ipsilateral parenchymal mass or function preserved. Multivariable regression assessed predictors of function preserved. Conceptually, the CSA paradigm should function better for exophytic tumors than endophytic ones.
RESULTS: Median tumor size was 3.5 cm and R.E.N.A.L. was 8. Median global and ipsilateral glomerular filtration rate preserved were 89% and 79%, respectively. Median ipsilateral parenchymal mass preserved was 85% and significantly higher for exophytic masses (P = .001). Median CSA was 22.8 cm
CONCLUSION: CSA associates with functional outcomes after standard PN, although the strength of the correlations was modest, unlike previous studies, and CSA was not an independent predictor for endophytic tumors. Further study will be required to evaluate the utility of CSA in various clinical settings.

Jenkinson G, Abante J, Feinberg AP, Goutsias J
An information-theoretic approach to the modeling and analysis of whole-genome bisulfite sequencing data.
BMC Bioinformatics. 2018; 19(1):87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA methylation is a stable form of epigenetic memory used by cells to control gene expression. Whole genome bisulfite sequencing (WGBS) has emerged as a gold-standard experimental technique for studying DNA methylation by producing high resolution genome-wide methylation profiles. Statistical modeling and analysis is employed to computationally extract and quantify information from these profiles in an effort to identify regions of the genome that demonstrate crucial or aberrant epigenetic behavior. However, the performance of most currently available methods for methylation analysis is hampered by their inability to directly account for statistical dependencies between neighboring methylation sites, thus ignoring significant information available in WGBS reads.
RESULTS: We present a powerful information-theoretic approach for genome-wide modeling and analysis of WGBS data based on the 1D Ising model of statistical physics. This approach takes into account correlations in methylation by utilizing a joint probability model that encapsulates all information available in WGBS methylation reads and produces accurate results even when applied on single WGBS samples with low coverage. Using the Shannon entropy, our approach provides a rigorous quantification of methylation stochasticity in individual WGBS samples genome-wide. Furthermore, it utilizes the Jensen-Shannon distance to evaluate differences in methylation distributions between a test and a reference sample. Differential performance assessment using simulated and real human lung normal/cancer data demonstrate a clear superiority of our approach over DSS, a recently proposed method for WGBS data analysis. Critically, these results demonstrate that marginal methods become statistically invalid when correlations are present in the data.
CONCLUSIONS: This contribution demonstrates clear benefits and the necessity of modeling joint probability distributions of methylation using the 1D Ising model of statistical physics and of quantifying methylation stochasticity using concepts from information theory. By employing this methodology, substantial improvement of DNA methylation analysis can be achieved by effectively taking into account the massive amount of statistical information available in WGBS data, which is largely ignored by existing methods.

Sailer V, Charpentier A, Dietrich J, et al.
Intragenic DNA methylation of PITX1 and the adjacent long non-coding RNA C5orf66-AS1 are prognostic biomarkers in patients with head and neck squamous cell carcinomas.
PLoS One. 2018; 13(2):e0192742 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with squamous cell cancer of the head and neck region (HNSCC) are at risk for disease recurrence and metastases, even after initial successful therapy. A tissue-based biomarker could be beneficial to guide treatment as well as post-treatment surveillance. Gene methylation status has been recently identified as powerful prognostic biomarker in HNSCC. We therefore evaluated the methylation status of the homeobox gene PITX1 and the adjacent long intergenic non-coding RNA (lincRNA) C5orf66-AS1 in publicly available datasets.
METHODS: Gene methylation and expression data from 528 patients with HNSCC included in The Cancer Genome Atlas (TCGA, there obtained by using the Infinium HumanMethylation450 BeadChip Kit) were evaluated and methylation and expression levels of PITX1 and lincRNA C5orf66-AS1 was correlated with overall survival and other parameters. Thus, ten beads targeting PITX1 exon 3 and three beads targeting lincRNA C5orf66-AS1 were identified as significant candidates. The mean methylation of these beads was used for further correlation and the median was employed for dichotomization.
RESULTS: Both PITX1 exon 3 and lincRNA C5orf66-AS1 were significantly higher methylated in tumor tissue than in normal adjacent tissue (NAT) (PITX1 exon 3: tumor tissue 58.1%, NAT: 31.7%, p<0.001; lincRNA C5orf66-AS1: tumor tissue: 27.4%, NAT: 18.9%, p<0.001). In a univariate analysis, hypermethylation of both loci was significantly associated with the risk of death (univariate: exon 3: Hazard ratio (HR): 4.97 [1.78-16.71], p = 0.010, lincRNA C5orf66-AS1: Hazard ratio (HR): 12.23 [3.01-49.74], p<0.001). PITX1 exon 3 and lincRNA C5orf66-AS1 methylation was also significantly correlated with tumor localization, T category, human papilloma virus (HPV)-negative and p16-negative tumors and tumor grade. Kaplan-Meier analysis showed, that lincRNA C5orf66-AS1 hypomethylation was significantly associated with overall survival (p = 0.001) in the entire cohort as well in a subgroup of HPV-negative tumors (p = 0.003) and in patients with laryngeal tumors (p = 0.022).
CONCLUSION: Methylation status of PITX1 and even more so of lincRNA C5orf66-AS1 is a promising prognostic biomarker in HNSCC, in particular for HPV-negative patients. Further prospective evaluation is warranted.

Dejea CM, Fathi P, Craig JM, et al.
Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.
Science. 2018; 359(6375):592-597 [PubMed] Free Access to Full Article Related Publications
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of

Chung L, Thiele Orberg E, Geis AL, et al.
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Cell Host Microbe. 2018; 23(2):203-214.e5 [PubMed] Free Access to Full Article Related Publications
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc

Pederson HJ, Gopalakrishnan D, Noss R, et al.
Impact of Multigene Panel Testing on Surgical Decision Making in Breast Cancer Patients.
J Am Coll Surg. 2018; 226(4):560-565 [PubMed] Related Publications
BACKGROUND: With the advent of multigene panel testing for breast cancer patients, germline mutations with unknown association with cancer risk, known as variants of uncertain significance (VUS), are being increasingly identified. Some studies have shown higher rates of contralateral prophylactic mastectomies (CPM) in these patients, despite lack of evidence to support this intervention. We analyzed surgical choices in patients who were identified to have VUS.
STUDY DESIGN: A retrospective review was performed of patients with triple-negative breast cancer treated at a single institution after multigene panel tests became available (September 1, 2013 to February 28, 2017). Rates of genetic testing, results of testing, and surgical decision making were evaluated. Chi-square or Fisher's exact test was used to compare categorical variables. A p value <0.05 was considered statistically significant.
RESULTS: There were 477 triple-negative breast cancer patients identified; 331 met established criteria for genetic testing and 226 (68.3%) underwent genetic testing (multigene panel, n = 130 and BRCA1/2 testing, n = 96). All of them received risk-appropriate genetic counseling and follow-up. Of these, 29 (12.8%) patients had pathogenic mutations in BRCA1/2 or PALB2 (Mut+), 42 (18.6%) had VUS (VUS+), and 155 (68.6%) had no mutations identified (Mut-). Variants of uncertain significance in 6 of 42 patients (14.3%) were later reclassified as normal variants. Eighty-eight percent of Mut+ patients underwent CPM compared with 20.1% of Mut- and 21.4% of VUS+ patients (p < 0.001 for both). Rates of CPM were not significantly different between VUS+ and Mut- (p = 0.37). Multigene panel testing detected pathogenic mutations in non-breast cancer-associated genes in 6 patients, with significant management implications.
CONCLUSIONS: When combined with risk-appropriate genetic counseling, detection of VUS did not lead to excessive CPM in this cohort of triple-negative breast cancer patients. Furthermore, panel testing detected mutations in non-breast cancer-associated genes, which had significant implications on management and outcomes.

Byrd V, Getz T, Padmanabhan R, et al.
The microbiome in
Endocr Relat Cancer. 2018; 25(3):233-243 [PubMed] Free Access to Full Article Related Publications

Doherty MR, Cheon H, Junk DJ, et al.
Interferon-beta represses cancer stem cell properties in triple-negative breast cancer.
Proc Natl Acad Sci U S A. 2017; 114(52):13792-13797 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to-mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-β) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-β, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-β metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-β reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors.

Isharwal S, Ye W, Wang A, et al.
Impact of Comorbidities on Functional Recovery from Partial Nephrectomy.
J Urol. 2018; 199(6):1433-1439 [PubMed] Related Publications
PURPOSE: Parenchymal mass preservation, and ischemia type and/or duration can influence functional recovery after partial nephrectomy. Some groups have hypothesized that relevant comorbidities may also impact nephron stability and functional recovery but this has not been adequately investigated.
MATERIALS AND METHODS: At our center 405 patients treated with partial nephrectomy from 2007 to 2015 had the necessary data to determine the function and parenchymal mass preserved in the ipsilateral kidney. Comorbidities potentially associated with renal functional status were reviewed, including various degrees of hypertension, diabetes, cardiovascular disease, obesity, smoking status and related medications. Multivariable linear regression was done to assess factors associated with functional recovery, defined as the percent of preserved ipsilateral glomerular filtration rate.
RESULTS: Median tumor size was 3.5 cm and the median R.E.N.A.L. (radius, exophytic/endophytic properties, nearness of tumor to collecting system or sinus, anterior/posterior, location relative to polar lines and tumor touching main renal artery or vein) score was 8. Warm and cold ischemia were done in 264 (65%) and 141 patients for a median duration of 21 and 27 minutes, respectively. The median preserved ipsilateral glomerular filtration rate was 79%. Patient age, comorbidity index, hypertension and proteinuria were each associated with the preoperative glomerular filtration rate (all p <0.01). On univariable and multivariable analyses the preserved parenchymal mass, and ischemia type and duration were significantly associated with functional recovery (all p <0.001). On univariable analysis of comorbidities only hypertension was significantly associated with functional recovery. However, on multivariable analysis none of the analyzed comorbidities were associated with functional recovery.
CONCLUSIONS: Recovery of function after partial nephrectomy depends primarily on parenchymal mass preservation and ischemia characteristics. Comorbidities failed to be associated with functional outcomes. Comorbidities can impact function, leading to surgery, and may influence long-term functional stability. However, our data suggest that they do not influence short-term recovery after partial nephrectomy.

Mazumder S, Johnson JM, Swank V, et al.
Primary Immunoprevention of Epithelial Ovarian Carcinoma by Vaccination against the Extracellular Domain of Anti-Müllerian Hormone Receptor II.
Cancer Prev Res (Phila). 2017; 10(11):612-624 [PubMed] Related Publications
Epithelial ovarian carcinoma (EOC) is the most prevalent form of ovarian cancer in the United States, representing approximately 85% of all cases and causing more deaths than any other gynecologic malignancy. We propose that optimized control of EOC requires the incorporation of a vaccine capable of inducing safe and effective preemptive immunity in cancer-free women. In addition, we hypothesize that ovarian-specific self-proteins that are "retired" from autoimmune-inducing expression levels as ovaries age but are expressed at high levels in emerging EOC may serve as vaccine targets for mediating safe and effective primary immunoprevention. Here, we show that expression of the extracellular domain of anti-Müllerian hormone receptor II (AMHR2-ED) in normal tissues is confined exclusively to the human ovary, drops to nonautoimmune inducing levels in postmenopausal ovaries, and is at high levels in approximately 90% of human EOC. We found that AMHR2-ED vaccination significantly inhibits growth of murine EOC and enhances overall survival without inducing oophoritis in aged female mice. The observed inhibition of EOC growth was mediated substantially by induction of AMHR2-ED-specific IgG antibodies that agonize receptor signaling of a Bax/caspase-3-dependent proapoptotic cascade. Our results indicate that AMHR2-ED vaccination may be particularly useful in providing safe and effective preemptive immunity against EOC in women at high genetic or familial risk who have the greatest need for a preventive vaccine and ultimately in cancer-free postmenopausal women who account for 75% of all EOC cases.

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