PPP1R13L

Gene Summary

Gene:PPP1R13L; protein phosphatase 1 regulatory subunit 13 like
Aliases: RAI, RAI4, IASPP, NKIP1
Location:19q13.32
Summary:IASPP is one of the most evolutionarily conserved inhibitors of p53 (TP53; MIM 191170), whereas ASPP1 (MIM 606455) and ASPP2 (MIM 602143) are activators of p53.[supplied by OMIM, Mar 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:relA-associated inhibitor
Source:NCBIAccessed: 30 August, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PPP1R13L (cancer-related)

Adhikary S, Chakravarti D, Terranova C, et al.
Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor.
Nat Commun. 2019; 10(1):1398 [PubMed] Free Access to Full Article Related Publications
The roles of Plant Homeodomain (PHD) fingers in catalysis of histone modifications are unknown. We demonstrated that the PHD finger of Ubiquitin Protein Ligase E3 Component N-Recognin7 (UBR7) harbors E3 ubiquitin ligase activity toward monoubiquitination of histone H2B at lysine120 (H2BK120Ub). Purified PHD finger or full-length UBR7 monoubiquitinated H2BK120 in vitro, and loss of UBR7 drastically reduced H2BK120Ub genome-wide binding sites in MCF10A cells. Low UBR7 expression was correlated with occurrence of triple-negative breast cancer and metastatic tumors. Consistently, UBR7 knockdown enhanced the invasiveness, induced epithelial-to-mesenchymal transition and promoted metastasis. Conversely, ectopic expression of UBR7 restored these cellular phenotypes and reduced tumor growth. Mechanistically, UBR7 loss reduced H2BK120Ub levels on cell adhesion genes, including CDH4, and upregulated the Wnt/β-Catenin signaling pathway. CDH4 overexpression could partially revert UBR7-dependent cellular phenotypes. Collectively, our results established UBR7 as a histone H2B monoubiquitin ligase that suppresses tumorigenesis and metastasis of triple-negative breast cancer.

Singh V, Singh AP, Sharma I, et al.
Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed] Related Publications
Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.

Mishra S, Verma SS, Rai V, et al.
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases.
Cell Mol Life Sci. 2019; 76(10):1947-1966 [PubMed] Related Publications
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.

van der Tuin K, Ventayol Garcia M, Corver WE, et al.
Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma.
Eur J Endocrinol. 2019; 180(4):235-241 [PubMed] Related Publications
Objective Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas. Design Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell- and 14 anaplastic thyroid carcinoma). Methods Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants. Results Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35). Conclusion Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Beksac AT, Cumarasamy S, Falagario U, et al.
Multiparametric Magnetic Resonance Imaging Features Identify Aggressive Prostate Cancer at the Phenotypic and Transcriptomic Level.
J Urol. 2018; 200(6):1241-1249 [PubMed] Related Publications
PURPOSE: Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features.
MATERIALS AND METHODS: We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model.
RESULTS: Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-β and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases.
CONCLUSIONS: The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.

Kapelko-Słowik K, Dybko J, Grzymajło K, et al.
Expression of the PIM2 gene is associated with more aggressive clinical course in patients with chronic lymphocytic leukemia.
Adv Clin Exp Med. 2019; 28(3):391-396 [PubMed] Related Publications
BACKGROUND: The PIM2 gene belongs to the PIM family, which encodes serine/threonine kinases involved in cell survival and apoptosis. The relation between the expression of the PIM2 gene and the course of chronic lymphocytic leukemia (CLL) has not been fully determined.
OBJECTIVES: The aim of the study was to evaluate the role of the PIM2 gene as a marker of CLL malignancy and its importance as a predictive and prognostic factor.
MATERIAL AND METHODS: Sixty-seven patients, 35 females and 32 males, aged 49-90 years, with de novo CLL, and 14 healthy individuals were enrolled in the study. Expression of the PIM2 gene was analyzed using TaqMan RQ-PCR assay and western blot test.
RESULTS: Median PIM2 gene expression in CLL patients was higher than in controls. Patients with high expression of the PIM2 gene had shorter progression-free survival and time to first treatment than patients with low PIM2 expression. It was found that patients with CR had lower expression of the PIM2 gene than patients without complete remission (CR). Notably, associations between high PIM2 expression and rapid lymphocyte doubling time, the percentage of malignant lymphocytes with ZAP70 expression and the Rai stage were revealed.
CONCLUSIONS: We found that the PIM2 gene is associated with a more aggressive clinical course of CLL.

Li Q, Xing W, Gong X, Wang Y
Long Non-Coding RNA Urothelial Carcinoma Associated 1 Promotes Proliferation, Migration and Invasion of Osteosarcoma Cells by Regulating microRNA-182.
Cell Physiol Biochem. 2018; 51(3):1149-1163 [PubMed] Related Publications
BACKGROUND/AIMS: Previous studies demonstrated the oncogenic roles of lncRNA UCA1 in osteosarcoma. This study aimed to explore the internal molecular mechanism of UCA1 on promoting osteosarcoma cell proliferation, migration and invasion.
METHODS: qRT-PCR was conducted to measure the expression levels of UCA1, miR-182 and TIMP2. Cell transfection was used to change the expression levels of UCA1, miR-182 and TIMP2. Cell viability, migration, invasion and apoptosis were measured using CCK-8 assay, two-chamber migration (invasion) assay and Guava Nexin assay, respectively. The associations between UCA1, miR-182 and iASPP were analyzed by dual luciferase activity assay. The protein expression levels of key factors involved in cell apoptosis, PI3K/AKT/GSK3β pathway and NF-κB pathway, as well as p53, Rb, RECQ family and iASPP were evaluated by western blotting.
RESULTS: UCA1 was highly expressed in osteosarcoma MG63 and OS-732 cells. Knockdown of UCA1 inhibited OS-732 cell viability, migration and invasion, but promoted cell apoptosis. miR-182 was up-regulated in OS-732 cells after UCA1 knockdown and participated in the effects of UCA1 on OS-732 cells. TIMP2 was downstream factor of miR-182 and involved in the regulatory roles of miR-182 on OS-732 cell viability, migration, invasion, apoptosis, as well as PI3K/AKT/GSK3β and NF-κB pathways. UCA1 knockdown up-regulated p53, Rb and RECQL5 levels in OS-732 cells, while down-regulated the expression of iASPP. TGF-β or TNF-α treatment could enhance the expression of UCA1 in OS-732 cells.
CONCLUSION: Our research verified that UCA1 exerted oncogenic roles in osteosarcoma cells by regulating miR-182 and TIMP2, as well as PI3K/AKT/GSK3β and NF-κB pathways.

Watanabe T, Tobinai K, Wakabayashi M, et al.
Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.
Lancet Haematol. 2018; 5(11):e520-e531 [PubMed] Related Publications
BACKGROUND: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial.
METHODS: In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m
FINDINGS: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5).
INTERPRETATION: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death.
FUNDING: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Khatoon J, Prasad KN, Rai RP, et al.
Expression levels of A disintegrin and metalloproteases (ADAMs), and Th17-related cytokines and their association with Helicobacter pylori infection in patients with gastroduodenal diseases.
Pathog Dis. 2018; 76(8) [PubMed] Related Publications
Expression levels of A disintegrin and metalloproteases (ADAMs) (10 and 17) and Th17-related cytokines [interleukin (IL) 17A, IL-17F, IL-33, IL-23, IL-23R] were investigated by quantitative real time polymerase chain reaction in gastric biopsies of patients with different gastroduodenal pathologies in the presence and absence of Helicobacter pylori infection. Patients with gastric cancer (GC) (n = 70, intestinal-type 38 and diffuse type 32), peptic ulcer disease [n = 50, duodenal ulcer (DU) 16 and gastric ulcer (GU) 34] and functional dyspepsia (n = 120) were included in the study. Further, the expression levels of ADAMs and Th17 cytokines were correlated with H. pylori cytotoxin-associated genes pathogenicity island (cagPAI) status. Expression levels of ADAMs (10 and 17) and Th17-related cytokines (IL-17A, IL-23, IL-23R) were significantly higher in H. pylori-positive than in H. pylori-negative gastric biopsies. Significant increase in ADAM17 and Th17 cytokines (IL-17A and IL-23) expressions was observed in patients with GU and intestinal-type GC in the presence of H. pylori infection and in strains harbouring intact cagPAI. Expression levels of IL-17A, IL-23 and ADAM17 were strongly correlated with GU and intestinal-type GC and weakly with DU and diffuse-type GC in the presence of H. pylori infection. Higher expression levels of ADAM17 and Th17 cytokines (IL-17A and IL-23), and their strong correlation with GU and intestinal-type GC patients in the presence of H. pylori and its intact cagPAI status, suggest a possible role of strain specificity in the pathogenesis of these diseases.

López-Trigo N, Aguín N, Castuera IP, et al.
Association of CASP3 genetic polymorphisms rs1049216, rs2705897 and rs4647603 with the risk of prostate cancer in Galicia (NW Spain).
Gene. 2018; 679:126-132 [PubMed] Related Publications
Malfunction of apoptosis plays a key role in carcinogenesis. Previous studies have reported that polymorphisms in caspase genes could lead to poor apoptotic signaling, thus facilitating the onset of several human cancers. The aim of this study was to evaluate the association between three polymorphisms (rs1049216, rs2705897 and rs4647603) of the CASP3 gene and the risk of prostate cancer (PCa) in Galicia (NW Spain).The relationship between these single nucleotide polymorphisms (SNPs) and PCa in European populations has yet to be studied. To test this hypothesis, we carried out a case-control study on a total of 243 patients with PCa and 191 healthy individuals, genotyping all polymorphisms using the matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) method. Overall, none of the polymorphisms were clearly associated with the risk of PCa. Nevertheless, the results drawn from this study suggest that genetic variability in the CASP3 gene, in combination with lifestyle and environmental factors may influence the predisposition to develop PCa in the Galician population. Specifically, the results of study seem to hint at a higher risk of PCa in smokers of up to 20 pack-years (PY) and carriers of both the CASP3-rs1049216 GG genotype and the G allele (OR = 3.61, p = 0.044; OR = 1.71; p = 0.018). In addition, the GG and AG genotypes showed increased predisposition to PCa in overweight individuals (OR = 4.43, p = 0.040; OR = 2.00; p = 0.022). Finally, the CASP3-rs4647603 CT genotype and T allele were associated with a higher susceptibility to PCa in obese individuals (OR

Yin JY, Ma YG, Vogel U, et al.
GLTSCR1, ATM, PPP1R13L and CD3EAP Genetic Variants and Lung Cancer Risk in a Chinese Population.
Curr Med Sci. 2018; 38(4):734-740 [PubMed] Related Publications
Genetic variants in glioma tumor suppressor candidate region gene 1 (GLTSCR1) and ATM serine/threonine kinase (ATM) have been associated with various cancer risks. Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors. However, little is known about the relationship between both gene polymorphisms and lung cancer risk. We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls. No significant differences in the single polymorphism (GLTSCR1 rs1035938 and ATM rs11212592) association were found in five genetic models (co-dominant, dominant, recessive, overdominant and log-additive models) (adjusted by smoking duration). Join effect of three SNPs (PPP1R13L rs1970764, CD3EAP rs967591, GLTSCR1 rs1035938) on chromosome 19q13.3 showed that the designated haplotype8 (rs 1970764

Al-Eryani L, Jenkins SF, States VA, et al.
miRNA expression profiles of premalignant and malignant arsenic-induced skin lesions.
PLoS One. 2018; 13(8):e0202579 [PubMed] Free Access to Full Article Related Publications
Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.

Bhat AA, Lu H, Soutto M, et al.
Exposure of Barrett's and esophageal adenocarcinoma cells to bile acids activates EGFR-STAT3 signaling axis via induction of APE1.
Oncogene. 2018; 37(46):6011-6024 [PubMed] Free Access to Full Article Related Publications
The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL-17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis.

Hillman RT, Celestino J, Terranova C, et al.
KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary.
Nat Commun. 2018; 9(1):2496 [PubMed] Free Access to Full Article Related Publications
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p = 0.02, two-sided Fisher's exact test). IHC detects additional non-KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.

Kumar A, Kumari N, Rai A, et al.
Expression and clinical significance of COMPASS family of histone methyltransferases in clear cell renal cell carcinoma.
Gene. 2018; 674:31-36 [PubMed] Related Publications
The regulation of histone 3 lysine 4 (H3K4) methylation code is indispensable for the cell as any disturbance in this has been associated with many pathologic conditions, like cancer. The SET domain-containing lysine methyltransferase 2 (KMT2) family of histone methyltransferases was the first to be identified as writers of H3K4 methylation. In mammals, seven members of the KMT2 family are responsible for carrying out the bulk of H3K4 methylation. Recent studies documented alterations in various histone methylases in human cancer, which were associated with therapeutic and prognostic potential. Notwithstanding, no report has documented the role of KMT2 family of histone methyltransferases in clear cell renal cell carcinoma (ccRCC). Therefore, we examined the expression profile of all the seven KMT2 family members of histone methyltransferases in ccRCC with the aim to establish their role as prognostic or therapeutic targets. Real-time PCR was employed to study the expression of KMT2 family genes using specific primers in 50 cases of ccRCC. The mRNA levels were correlated with stage, grade, and metastasis of the tumor. Among seven genes, KMT2G was significantly up-regulated in higher stages of the tumor as compared to low stage tumors (p = 0.017). Similarly, KMT2G levels were higher in the metastatic tumor (p = 0.027). Additionally, some of the KMT2G target genes were found to be up-regulated in metastatic tumors as compared to non-metastatic. ROC curve indicated KMT2G as a good marker for discriminating metastatic tumors from non-metastatic tumors (AUC = 0.738). Thus, we conclude that KMT2G histone methyltransferase could be a good prognostic marker for ccRCC. Additionally, KMT2G can also serve as a therapeutic target for ccRCC.

Lissanu Deribe Y, Sun Y, Terranova C, et al.
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.
Nat Med. 2018; 24(7):1047-1057 [PubMed] Free Access to Full Article Related Publications
Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.

Li C, Du X, Xia S, Chen L
MicroRNA-150 inhibits the proliferation and metastasis potential of colorectal cancer cells by targeting iASPP.
Oncol Rep. 2018; 40(1):252-260 [PubMed] Free Access to Full Article Related Publications
In the present study, the function of miR-150 and its downstream target iASPP in the growth and metastasis of colorectal cancer (CRC) cells was investigated. The expression of miR-150 and iASPP was first investigated in clinical CRC samples. Subsequently, the effects of miR-150 overexpression and iASPP inhibition on cell viability, cell cycle distribution, apoptosis, migration and invasion were detected with CCK-8, flow cytometry, scratch and Transwell assays. The interaction between miR-150 and iASPP was confirmed using a dual-luciferase assay. Subsequently, the key role of iASPP in the anti-CRC function of miR-150 was assessed by inducing the expression of the gene in miR-150 overexpressed SW480 cells. In clinical samples, the level of miR-150 was downregulated, while iASPP was induced. Enforced expression of miR-150 decreased the viability, induced G1 cell cycle arrest and apoptosis, and inhibited the migration and invasion of SW480 cells. Knockdown of iASPP exerted a similar effect on SW480 cells to that of the overexpression of miR-150. Dual-luciferase assay demonstrated that miR-150 directly bound to iASPP and inhibited its transcription. The function of miR-150 depended on the inhibition of iASPP; induced expression of iASPP in miR-150-knockdown SW480 and HCT116 cells restored cell viability, migration and invasion while inhibiting G1 cell cycle arrest and apoptosis. Increased expression of miR-150 suppressed viability, proliferation, migration and invasion of SW480 cells. Furthermore, iASPP was a direct target of miR-150 and played a key role in its anti-CRC function. miR-150 may be a promising predictor of prognosis in CRC patients.

Ojha J, Dyagil I, Finch SC, et al.
Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.
Environ Health. 2018; 17(1):43 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population.
METHODS: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively).
RESULTS: Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival.
CONCLUSIONS: No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

Kim TW, Elme A, Park JO, et al.
Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer.
Clin Colorectal Cancer. 2018; 17(3):206-214 [PubMed] Related Publications
INTRODUCTION: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS.
PATIENTS AND METHODS: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline.
RESULTS: Overall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS; hazard ratio [HR], 0.72; P = .015) and progression-free survival (PFS; HR, 0.45; P < .0001) were improved with panitumumab with BSC versus BSC. Similar improvements were seen for patients with wild type RAS, and wild type BRAF tumors (OS: HR, 0.75; P = .04; PFS: HR, 0.45; P < .0001). Median DpR was 16.9% for the evaluable panitumumab with BSC wild type RAS population. Overall, 69.5% experienced any type of tumor shrinkage at week 8; 38.2% experienced ≥ 20% shrinkage. Similar improvements in OS and PFS were seen with stratification according to ETS.
CONCLUSION: This analysis showed that panitumumab improved outcomes in wild type RAS mCRC and indicated that ETS and DpR could be used as additional efficacy markers.

Chan KK, Wong OG, Wong ES, et al.
Impact of iASPP on chemoresistance through PLK1 and autophagy in ovarian clear cell carcinoma.
Int J Cancer. 2018; 143(6):1456-1469 [PubMed] Related Publications
Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA-β-Gal staining and p21

Jones DZ, Schmidt ML, Suman S, et al.
Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells.
BMC Cancer. 2018; 18(1):421 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa).
METHODS: Serum-based miRNA profiling involved 15 men diagnosed with non-metastatic (stage I, III) and metastatic (stage IV) PCa and five age-matched disease-free men using miRNA arrays with select targets confirmed by quantitative real-time PCR (qRT-PCR). The effect of miR-186-5p inhibition or ectopic expression on cellular behavior of PCa cells (i.e., PC-3, MDA-PCa-2b, and LNCaP) involved the use bromodeoxyuridine (BrdU) incorporation, invasion, and colony formation assays. Assessment of the impact of miR-186-5p inhibition or overexpression on selected targets entailed microarray analysis, qRT-PCR, and/or western blots. Statistical evaluation used the modified t-test and ANOVA analysis.
RESULTS: MiR-186-5p was upregulated in serum from PCa patients and metastatic PCa cell lines (i.e., PC-3, MDA-PCa-2b, LNCaP) compared to serum from disease-free individuals or a normal prostate epithelial cell line (RWPE1), respectively. Inhibition of miR-186-5p reduced cell proliferation, invasion, and anchorage-independent growth of PC-3 and/or MDA-PCa-2b PCa cells. AKAP12, a tumor suppressor target of miR-186-5p, was upregulated in PC-3 and MDA-PCa-2b cells transfected with a miR-186-5p inhibitor. Conversely, ectopic miR-186-5p expression in HEK 293 T cells decreased AKAP12 expression by 30%. Both pAKT and β-catenin levels were down-regulated in miR-186-5p inhibited PCa cells.
CONCLUSIONS: Our findings suggest miR-186-5p plays an oncogenic role in PCa. Inhibition of miR-186-5p reduced PCa cell proliferation and invasion as well as increased AKAP12 expression. Future studies should explore whether miR-186-5p may serve as a candidate prognostic indicator and a therapeutic target for the treatment of aggressive prostate cancer.

Yadav U, Kumar P, Rai V
"NQO1 Gene C609T Polymorphism (dbSNP: rs1800566) and Digestive Tract Cancer Risk: A Meta-Analysis."
Nutr Cancer. 2018 May-Jun; 70(4):557-568 [PubMed] Related Publications
Several studies reported that polymorphism C609T (rs1800566) in (NAD(P)H): quinoneoxidoreductase 1 (NQO1) gene is associated with risk to digestive tract (DT) cancers, like esophageal cancer (EC), gastric cancer (GC), and colorectal cancer (CRC). Authors conducted a meta-analysis to investigate association between C609T polymorphism and DT cancer risk. Eligible studies were extracted from the databases of PubMed, Google Scholar, Science Direct, and Springer Link. All retrieved articles were evaluated. All statistical analyses were performed using Open Meta-Analyst and MIX1.7 programs. A total of 34 studies including 12,043 DT cancer cases and 15,209 healthy controls were included in the present meta- analysis. Results of meta-analysis revealed a significant association between NQO1 C609T polymorphism and DT cancer risk adopting all 5 genetic models (T vs. C: OR = 1.21, 95% CI = 1.11-1.31, p < 0.001; TT vs. CC: OR = 1.48, 95% CI = 1.22-1.79, p < 0.001; TT + CT vs. CC: OR = 1.23, 95% CI = 1.12-1.35, p < 0.001; TT vs. CT + CC: OR = 1.36, 95% CI = 1.15-1.60, p < 0.001; CT vs. CC: OR = 1.16, 95% CI = 1.07-1.27, p < 0.001). In the stratified analysis based on cancer types, significant associations were observed between NQO1 C609T polymorphism and GC (OR = 1.38, 95% CI = 1.11-1.72, p = 0.003) and CRC (OR = 1.18, 95% CI = 1.06-1.30, p = 0.001), but not with EC (OR = 1.16, 95% CI = 0.99-1.35, p = 0.06). Furthermore, stratified analysis based on ethnicity indicated that there was a significant association between NQO1 C609T polymorphism and DT cancer risk in the Asian (TT vs. CC: OR = 1.55, 95% CI = 1.21-2.00, p ≤ 0.001) as well as in Caucasian populations (TT vs. CC: OR = 1.34, 95% CI = 1.04-1.73, p = 0.02). In conclusion, the results of meta-analysis suggested that the NQO1 C609T polymorphism is a risk factor for DT cancers, including GC and CRC.

Jin Y, Van Nostrand D, Cheng L, et al.
Radioiodine refractory differentiated thyroid cancer.
Crit Rev Oncol Hematol. 2018; 125:111-120 [PubMed] Related Publications
Differentiated thyroid cancer (DTC) is usually curable with surgery, radioactive iodine (RAI), and thyroid-stimulating hormone (TSH) suppression. However, local recurrence and/or distant metastases occur in approximately 15% of cases during follow-up, and nearly two-thirds of these patients will become RAI-refractory (RR-DTC) with a poor prognosis. This review focuses on the most challenging and rapidly evolving aspects of RR-DTC, and we discuss the considerable improvement in more accurately defining RR-DTC, more effective therapeutic strategies, and describe the diagnosis, pathogenesis, and future prospects of RR-DTC. Along with the detection of serum thyroglobulin and anatomic imaging modalities, such as ultrasound and computer tomography, radionuclide molecular imaging plays a vital role in the evaluation of RR-DTC. In addition, continual progress has been made in the management of RR-DTC, including watchful waiting under appropriate TSH suppression, local treatment approaches, and systemic therapies (molecular targeted therapy, redifferentiation therapy, gene therapy, and cancer immunotherapy). These all hold promise to change the natural history of RR-DTC.

Thorsson V, Gibbs DL, Brown SD, et al.
The Immune Landscape of Cancer.
Immunity. 2018; 48(4):812-830.e14 [PubMed] Free Access to Full Article Related Publications
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

Chen H, Li C, Peng X, et al.
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples.
Cell. 2018; 173(2):386-399.e12 [PubMed] Free Access to Full Article Related Publications
The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.

Bailey MH, Tokheim C, Porta-Pardo E, et al.
Comprehensive Characterization of Cancer Driver Genes and Mutations.
Cell. 2018; 173(2):371-385.e18 [PubMed] Free Access to Full Article Related Publications
Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.

Huang KL, Mashl RJ, Wu Y, et al.
Pathogenic Germline Variants in 10,389 Adult Cancers.
Cell. 2018; 173(2):355-370.e14 [PubMed] Free Access to Full Article Related Publications
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Sanchez-Vega F, Mina M, Armenia J, et al.
Oncogenic Signaling Pathways in The Cancer Genome Atlas.
Cell. 2018; 173(2):321-337.e10 [PubMed] Free Access to Full Article Related Publications
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Ding L, Bailey MH, Porta-Pardo E, et al.
Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.
Cell. 2018; 173(2):305-320.e10 [PubMed] Free Access to Full Article Related Publications
The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

Liu Y, Sethi NS, Hinoue T, et al.
Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.
Cancer Cell. 2018; 33(4):721-735.e8 [PubMed] Free Access to Full Article Related Publications
We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

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