KRIT1

Gene Summary

Gene:KRIT1; KRIT1, ankyrin repeat containing
Aliases: CAM, CCM1
Location:7q21.2
Summary:This gene encodes a protein containing four ankyrin repeats, a band 4.1/ezrin/radixin/moesin (FERM) domain, and multiple NPXY sequences. The encoded protein is localized in the nucleus and cytoplasm. It binds to integrin cytoplasmic domain-associated protein-1 alpha (ICAP1alpha), and plays a critical role in beta1-integrin-mediated cell proliferation. It associates with junction proteins and RAS-related protein 1A (Rap1A), which requires the encoded protein for maintaining the integrity of endothelial junctions. It is also a microtubule-associated protein and may play a role in microtubule targeting. Mutations in this gene result in cerebral cavernous malformations. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:krev interaction trapped protein 1
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Retina
  • Brain
  • Hemangioma, Cavernous
  • Risk Assessment
  • Sex Factors
  • Apoptosis Regulatory Proteins
  • Skin Diseases, Vascular
  • Signal Transduction
  • RNA Splicing
  • Spain
  • Hemangioma, Cavernous, Central Nervous System
  • Brain Tumours
  • Pyramidal Cells
  • Brain Tumours
  • Skin Abnormalities
  • Retinal Neoplasms
  • X-Ray Computed Tomography
  • Switzerland
  • Childhood Cancer
  • Carrier Proteins
  • Skin Cancer
  • Vestibulocochlear Nerve
  • Seizures
  • Chromosome 7
  • Pedigree
  • Siblings
  • Genetic Predisposition
  • Brain and CNS Tumours
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Two-Hybrid System Techniques
  • Sequence Deletion
  • Exons
  • Mutation
  • Severity of Illness Index
  • RTPCR
  • DNA Mutational Analysis
  • Magnetic Resonance Imaging
  • Veins
  • Risk Factors
  • Adolescents
Tag cloud generated 15 March, 2017 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: KRIT1 (cancer-related)

Peckova K, Martinek P, Pivovarcikova K, et al.
Cystic and necrotic papillary renal cell carcinoma: prognosis, morphology, immunohistochemical, and molecular-genetic profile of 10 cases.
Ann Diagn Pathol. 2017; 26:23-30 [PubMed] Related Publications
Conflicting data have been published on the prognostic significance of tumor necrosis in papillary renal cell carcinoma (PRCC). Although the presence of necrosis is generally considered an adverse prognostic feature in PRCC, we report a cohort of 10 morphologically distinct cystic and extensively necrotic PRCC with favorable biological behavior. Ten cases of type 1 PRCC with a uniform morphologic pattern were selected from the 19 500 renal tumors, of which 1311 were PRCCs in our registry. We focused on precise morphologic diagnosis supported by immunohistochemical and molecular-genetic analysis. Patients included 8 men and 2 women with an age range of 32-85 years (mean, 62.6 years). Tumor size ranged from 6 to 14 cm (mean, 9.4 cm). Follow-up data were available in 7 patients, ranging from 0.5 to 14 years (mean, 4 years). All tumors were spherical, cystic, and circumscribed by a thick fibrous capsule, filled with hemorrhagic/necrotic contents. Limited viable neoplastic tissue was present only as a thin rim in the inner surface of the cyst wall, consistent with type 1 PRCC. All cases were positive for AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin. Chromosome 7 and 17 polysomy was found in 5 of 9 analyzable cases, 2 cases demonstrated chromosome 7 and 17 disomy, and 1 case showed only chromosome 17 polysomy. Loss of chromosome Y was found in 5 cases, including 1 case with disomic chromosomes 7 and 17. No VHL gene abnormalities were found. Papillary renal cell carcinoma type 1 can present as a large hemorrhagic/necrotic unicystic lesion with a thick fibroleiomyomatous capsule. Most cases showed a chromosomal numerical aberration pattern characteristic of PRCC. All tumors followed a nonaggressive clinical course. Large liquefactive necrosis should not necessarily be considered an adverse prognostic feature, particularly in a subset of type 1 PRCC with unilocular cysts filled with necrotic/hemorrhagic material.

Xu X, Liu J, Shen C, et al.
The role of ubiquitin-specific protease 14 (USP14) in cell adhesion-mediated drug resistance (CAM-DR) of multiple myeloma cells.
Eur J Haematol. 2017; 98(1):4-12 [PubMed] Related Publications
OBJECTIVE: Cell adhesion-mediated drug resistance (CAM-DR) is one of the mechanisms underlying the drug resistance in multiple myeloma (MM). Ubiquitin-specific protease 14 (USP14) is downregulated in the apoptotic model and upregulated in the adhesive model of MM. This study was undertaken to determine the role of USP14 in CAM-DR of MM cells.
METHODS: We examined the expression of USP14 in the apoptotic model of MM. The mechanism of USP14 in the process of apoptosis was further explored by flow cytometry assay and co-immunoprecipitation. We then performed the cell co-culture and adhesion assay and cell viability assay to investigate the effect of USP14 on adhesive rate and drug resistance in MM.
RESULTS: We discovered that USP14 played a negative role in cell apoptosis, which is correlated with Bcl-xl. Moreover, overexpression of USP14 in MM cell adhesion model could enhance the ability of cell adhesion by regulating Wnt-signaling pathways, thereby promoting the CAM-DR in MM.
CONCLUSION: USP14 participates in CAM-DR of MM through acting as a bridge between Bcl-xl apoptotic pathway and Wnt-signaling pathways and may be represented as a good candidate for pursuing clinical trials in MM.

Bigagli E, De Filippo C, Castagnini C, et al.
DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up.
Cell Oncol (Dordr). 2016; 39(6):545-558 [PubMed] Related Publications
BACKGROUND: DNA copy number alterations (CNAs) and gene expression changes have amply been encountered in colorectal cancers (CRCs), but the extent at which CNAs affect gene expression, as well as their relevance for tumor development, are still poorly defined. Here we aimed at assessing the clinical relevance of these parameters in a 10 year follow-up study.
METHODS: Tumors and normal adjacent colon mucosa, obtained at primary surgery from 21 CRC patients, were subjected to (i) high-resolution array CGH (a-CGH) for the detection of CNAs and (ii) microarray-based transcriptome profiling for the detection of gene expression (GE) changes. Correlations between these genomic and transcriptomic changes and their associations with clinical and histopathological parameters were assessed with the aim to identify molecular signatures associated with disease-free survival of the CRC patients during a 10 year follow-up.
RESULTS: DNA copy number gains were frequently detected in chromosomes 7, 8q, 13, 19, 20q and X, whereas DNA copy number losses were frequently detected in chromosomes 1p, 4, 8p, 15, 17p, 18, 19 and 22q. None of these alterations were observed in all samples. In addition, we found that 2,498 genes were up- and that 1,094 genes were down-regulated in the tumor samples compared to their corresponding normal mucosa (p < 0.01). The expression of 65 genes was found to be significantly associated with prognosis (p < 0.01). Specifically, we found that up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, were strongly associated with a poor survival. Subsequent integrated analyses revealed that increased expression levels of the MMP9, BMP7, UBE2C, I-CAM, NOTCH3, NOTCH1, PTGES2, HMGB1 and ERBB3 genes were associated with copy number gains, whereas decreased expression levels of the MUC1, E2F2, HRAS and SIRT3 genes were associated with copy number losses. Pathways related to cell cycle progression, eicosanoid metabolism, and TGF-β and apoptosis signaling, were found to be most significantly affected.
CONCLUSIONS: Our results suggest that CNAs in CRC tumor tissues are associated with concomitant changes in the expression of cancer-related genes. In other genes epigenetic mechanism may be at work. Up-regulation of the IL17RA, IGF2BP2 and ABCC2 genes, and of genes acting in the mTOR and cytokine receptor pathways, appear to be associated with a poor survival. These alterations may, in addition to Dukes' staging, be employed as new prognostic biomarkers for the prediction of clinical outcome in CRC patients.

Zhang T, Liu W, Zeng XC, et al.
Down-regulation of microRNA-338-3p promoted angiogenesis in hepatocellular carcinoma.
Biomed Pharmacother. 2016; 84:583-591 [PubMed] Related Publications
miRNAs are involved in substantial biological passways, including tumorigenesis, cancer development and progression. Angiogenesis plays a vital role in the progression of hepatocellular carcinoma (HCC), and VEGF is closely associated with the angiogenesis. However, the molecular mechanism of miRNAs in regulation tumorigenesis of HCC remains to be investigated. In the present research, we confirmed that miR-338-3p was suppressed both in HCC tissues and HCC cell lines. Then the tube formation, transwell and Chorioallantoic membrane (CAM) assay were carried out, such indicated that down-regulation of miR-338-3p can sharply increased, while up-regulation drastically suppressed angiogenesis of HCC cells in vitro. Moreover, MACC1 is predicted to be a target of miR-338-3p and we checked the prediction through luciferase assay. And then, our research showed that negative correlation existed between miR-338-3p and MACC1, β-catenin and VEGF that has been reported participated in cancer behavior in HCC cell lines. Subsequently, our assays illustrated that suppression miR-338-3p can up-regulate MACC1, β-catenin and VEGF expression of HCC cells. In conclusion, our research discovered that miR-338-3p can contribute to HCC angiogenesis by targeting MACC1, β-catenin and VEGF.

Noda T, Iijima M, Noda S, et al.
Gene Expression Profile of Inflammatory Myopathy with Malignancy is Similar to that of Dermatomyositis rather than Polymyositis.
Intern Med. 2016; 55(18):2571-80 [PubMed] Related Publications
Objective An association has been reported between inflammatory myopathies (IMs), which include polymyositis (PM) and dermatomyositis (DM), and malignancy, and the concept of cancer-associated myositis (CAM) was recently proposed. We herein attempted to determine the features and etiologies of these myopathies. Methods We analyzed the gene expression levels via microarray and real-time quantitative reverse transcription polymerase chain reaction analyses to identify genes that were specifically upregulated or downregulated with suspected inflammatory involvement and verified the microarray data via an immunohistochemical (IHC) analysis in additional cases. Patients We selected 14 patients with the following conditions: PM without malignancy (n=3), DM without malignancy (n=3), CAM (n=3), and Controls (no pathological changes or malignancy; n=5). Results PM was distinct from DM and CAM in a clustering analysis and exhibited the highest numbers of overexpressed genes and specific pathologies in a gene ontology analysis. The IHC analysis confirmed the gene expression results. Conclusion PM is associated with severe inflammatory pathological findings, primarily in the cell-mediated immune system. DM and CAM exhibit similarities in the gene expression and IHC results, which suggest that humoral immunity is the main etiology for both myopathies, indicating the importance of cancer screening in patients with IMs, particularly DM.

Pusung M, Zeki S, Fitzgerald R
Genomics of Esophageal Cancer and Biomarkers for Early Detection.
Adv Exp Med Biol. 2016; 908:237-63 [PubMed] Related Publications
In-depth molecular characterization of esophageal oncogenesis has improved over the recent years. Advancement in molecular biology and bioinformatics has led to better understanding of its genomic landscape. More specifically, analysis of its pathogenesis at the genetic level has uncovered the involvement of a number of tumor suppressor genes, cell cycle regulators, and receptor tyrosine kinases. Due to its poor prognosis, the development of clinically applicable biomarkers for diagnosis, progression, and treatment has been the focus of many research studies concentrating on upper gastrointestinal malignancies. As in other cancers, early detection and subsequent intervention of the preneoplastic condition significantly improves patient outcomes. Currently, clinically approved surveillance practices heavily depend on expensive, invasive, and sampling-error-prone endoscopic procedures. There is, therefore, a great demand to establish clearly reliable biomarkers that could identify those patients at higher risk of neoplastic progression and hence would greatly benefit from further monitoring and/or intervention. This chapter will present the most recent advances in the analysis of the esophageal cancer genome serving as basis for biomarker development.

Chen Y, Teng F, Wang G, Nie Z
Overexpression of CXCR7 induces angiogenic capacity of human hepatocellular carcinoma cells via the AKT signaling pathway.
Oncol Rep. 2016; 36(4):2275-81 [PubMed] Related Publications
Angiogenesis is essential for tumor growth, especially in hepatocellular carcinoma (HCC). The hypervascularity is associated with poor prognosis and highly invasive HCC. The C‑X‑C chemokine receptor type 7 (CXCR7) has been implied overexpressed in many tumor types. Our study aimed to investigate the CXCR7 function in HCC. The tube formation, Transwell migration assay of human umbilical vein endothelial cells (HUVECs) and chicken chorioallantoic membrane (CAM) assay were used. We confirmed that CXCR7 induces angiogenic capacity. Moreover, overexpressing CXCR7 increased the phosphorylated (but not total) AKT expression in HCC cells. Furthermore, overexpressing CXCR7 increased the expression of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑8 in HCC cells. Additionally, inhibition of AKT by LY294002 abrogated CXCR7‑induced angiogenic capacity in HCC cells. Our study suggested that CXCR7 plays an important pro‑angiogenic role in HCC via activation of the AKT pathway. So CXCR7 may be a potential target for anti‑angiogenic therapy in HCC.

Zhu L, Finkelstein D, Gao C, et al.
Multi-organ Mapping of Cancer Risk.
Cell. 2016; 166(5):1132-1146.e7 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene, and tumor suppressor alleles to define populations of stem and non-stem cells in mouse organs and test their life-long susceptibility to tumorigenesis. We show that tumor incidence is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a "perfect storm" that ultimately determines organ cancer risk. VIDEO ABSTRACT.

Furukawa Y, Kikuchi J
Epigenetic regulation of cell adhesion-mediated drug resistance acquisition in multiple myeloma.
Rinsho Ketsueki. 2016; 57(5):546-55 [PubMed] Related Publications
Elucidation of the epigenetic mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified trimethylation of histone H3 at lysine-27 (H3K27me3) as a critical histone modification for cell adhesion-mediated drug resistance (CAM-DR), which is the most important form of drug resistance in multiple myeloma. Cell adhesion counteracted drug-induced hypermethylation of H3K27 via inactivating phosphorylation of EZH2, leading to sustained expression of anti-apoptotic genes including IGF1, BCL2 and HIF1A. Inhibition of the IGF-1R/PI3K/Akt pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. To our knowledge, this is the first demonstration of an epigenetic mechanism underlying CAM-DR and provides a rationale for the inclusion of kinase inhibitors counteracting EZH2 phosphorylation in combination chemotherapy aimed at increasing the therapeutic index.

Liu H, Ding L, Shen Y, et al.
RBQ3 participates in multiple myeloma cell proliferation, adhesion and chemoresistance.
Int J Biol Macromol. 2016; 91:115-22 [PubMed] Related Publications
Cell adhesion mediated drug resistance (CAM-DR) is a major factor that impedes the effect of chemotherapy in multiple myeloma (MM). RBQ3, which is a RB-binding protein, played a crucial role in cell cycle process. Here, we reported that RBQ3 expression was increased gradually during the proliferation process of myeloma cells. Knocking down of RBQ3 resulted in cell cycle arrest in G1 phase and increased myeloma cells adherent to fibronectin or bone marrow stromal cells (BMSCs). Furthermore, silencing of RBQ3 reduced sensitivity to chemotherapeutic drugs in myeloma cell lines adherent to BMSCs and reduced two apoptotic marker proteins cleaved caspase-3 and cleaved PARP expression. Besides, we also found that RBQ3 participated in MAPK/ERK signal transduction pathway. In summary, these results may shed new insights into the role of RBQ3 in the development of multiple myeloma.

Jing Z, Xu H, Chen X, et al.
The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer.
PLoS One. 2016; 11(4):e0152789 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor survival and is the sixth most common cancer worldwide. Gastroesophageal reflux is a common event in SCCHN patients. GPR4 is a proton-sensing G-protein coupled receptor, which can be activated by acidosis. The objective of this study was to explore the role of GPR4 in acid exposure and tumor angiogenesis in SCCHN. In this study, we confirmed that overexpressing GPR4 in SCCHN cells could increase the expression and secretion of IL6, IL8 and VEGFA at pH 5.9. This effect could be inhibited by SB203580 (a p38 inhibitor). Western blot analysis indicated that phosphorylation of p38 increased in GPR4 infected cells at pH 5.9, which could be inhibited by SB203580. In tube formation assay, HMEC-1 cells were incubated with conditioned medium (CM, pH 5.9, 6.5, 7.4) derived from control and GPR4 infected SCCHN cells. Tube length was significantly increased in HMEC-1 cells incubated with CM from GPR4 infected cells compared with control cells at pH5.9, which indicated the pro-angiogenic effect of GPR4 in acidic pH. The neutralizing antibodies of IL6, IL8 and VEGFA could inhibit tube formation of HMEC-1 cells. In vivo, the effect of GPR4 on angiogenesis was investigated with the chick chorioallantoic membrane (CAM) model. Control and GPR4 infected SCCHN cells were seeded onto the upper CAM surface (n = 5 in each group) and 5 μL DMEM/F12 (pH 5.9, 6.5, 7.4) was added to the surface of the cell every 24 h. Four days later, the upper CAM were harvested and the ratio of the vascular area to the CAM area was quantified using Image-Pro Plus 6.0 software. GPR4 infected cells could recruit more vascular than control cells at pH5.9. In conclusion, we suggested that GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in SCCHN.

Zhou Z, Tang AT, Wong WY, et al.
Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.
Nature. 2016; 532(7597):122-6 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

Huang JS, Yao CJ, Chuang SE, et al.
Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction.
BMC Cancer. 2016; 16:245 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BACKGROUND: Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo.
METHODS: By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining.
RESULTS: The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor.
CONCLUSIONS: Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs.

Sahakyan AB, Balasubramanian S
Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.
BMC Genomics. 2016; 17:225 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BACKGROUND: The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases.
RESULTS: We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations.
CONCLUSIONS: Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

Boutzen H, Saland E, Larrue C, et al.
Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia.
J Exp Med. 2016; 213(4):483-97 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired differentiation programs caused by recurrent mutations, such as the isocitrate dehydrogenase (IDH) mutations found in 15% of AML patients. These mutations result in the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG), leading to a hypermethylation phenotype that dysregulates hematopoietic differentiation. In this study, we identified mutant R132H IDH1-specific gene signatures regulated by key transcription factors, particularly CEBPα, involved in myeloid differentiation and retinoid responsiveness. We show that treatment with all-trans retinoic acid (ATRA) at clinically achievable doses markedly enhanced terminal granulocytic differentiation in AML cell lines, primary patient samples, and a xenograft mouse model carrying mutant IDH1. Moreover, treatment with a cell-permeable form of 2-HG sensitized wild-type IDH1 AML cells to ATRA-induced myeloid differentiation, whereas inhibition of 2-HG production significantly reduced ATRA effects in mutant IDH1 cells. ATRA treatment specifically decreased cell viability and induced apoptosis of mutant IDH1 blasts in vitro. ATRA also reduced tumor burden of mutant IDH1 AML cells xenografted in NOD-Scid-IL2rγ(null)mice and markedly increased overall survival, revealing a potent antileukemic effect of ATRA in the presence of IDH1 mutation. This therapeutic strategy holds promise for this AML patient subgroup in future clinical studies.

Carroll JS
Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer.
Eur J Endocrinol. 2016; 175(1):R41-9 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Most breast cancers are driven by a transcription factor called oestrogen receptor (ER). Understanding the mechanisms of ER activity in breast cancer has been a major research interest and recent genomic advances have revealed extraordinary insights into how ER mediates gene transcription and what occurs during endocrine resistance. This review discusses our current understanding on ER activity, with an emphasis on several evolving, but important areas of ER biology.

Semple RK
EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons.
Eur J Endocrinol. 2016; 174(5):R209-23 [PubMed] Related Publications
Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, 'insulin resistance (IR)', a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.

Bravi L, Malinverno M, Pisati F, et al.
Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition.
Stroke. 2016; 47(3):886-90 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Cerebral cavernous malformation (CCM) is characterized by multiple lumen vascular malformations in the central nervous system that can cause neurological symptoms and brain hemorrhages. About 20% of CCM patients have an inherited form of the disease with ubiquitous loss-of-function mutation in any one of 3 genes CCM1, CCM2, and CCM3. The rest of patients develop sporadic vascular lesions histologically similar to those of the inherited form and likely mediated by a biallelic acquired mutation of CCM genes in the brain vasculature. However, the molecular phenotypic features of endothelial cells in CCM lesions in sporadic patients are still poorly described. This information is crucial for a targeted therapy.
METHODS: We used immunofluorescence microscopy and immunohistochemistry to analyze the expression of endothelial-to-mesenchymal transition markers in the cavernoma of sporadic CCM patients in parallel with human familial cavernoma as a reference control.
RESULTS: We report here that endothelial cells, a cell type critically involved in CCM development, undergo endothelial-to-mesenchymal transition in the lesions of sporadic patients. This switch in endothelial phenotype has been described only in genetic CCM patients and in murine models of the disease. In addition, TGF-β/p-Smad- and β-catenin-dependent signaling pathways seem activated in sporadic cavernomas as in familial ones.
CONCLUSIONS: Our findings support the use of common therapeutic strategies for both sporadic and genetic CCM malformations.

Tulley S, Zhao Q, Dong H, et al.
Vita-Assay™ Method of Enrichment and Identification of Circulating Cancer Cells/Circulating Tumor Cells (CTCs).
Methods Mol Biol. 2016; 1406:107-19 [PubMed] Related Publications
The ability to capture, enrich, and propagate circulating cancer cells/circulating tumor cells (CTCs) for downstream analyses such as ex vivo drug-sensitivity testing of short-term cultures of CTCs, single cell sorting of CTCs by fluorescence activated cell sorting (FACS), animal injection tumor and/or metastasis formation studies, next generation sequencing (NGS), gene expression profiling, gene copy number determination, and epigenomic analyses is of high priority and of immense importance to both the basic research and translational/clinical research communities. Vitatex Inc.'s functional cell separation technology, constructed as Vita-Assay™ (AG6W, AN6W, AR6W) culture plates, is based on the preferential adhesion of invasive rare blood cells of tissue origin to a tissue or tumor microenvironment mimic-the so-called cell adhesion matrix (CAM), which has a demonstrated ability to enrich viable CTCs from blood up to one-million fold.The CAM-scaffold allows for the functional capture and identification of invasive CTCs (iCTCs) including invasive tumor progenitor (TP) cells from cancer-patients' blood. CAM-captured CTCs are capable of ingesting the CAM (CAM+) itself. Green and red fluorescent versions of Vita-Assay™ (AG6W and AR6W) allow for direct visualization of CAM-uptake by cancer cells. Vita-Assay™ CAM-enrichment has allowed for sensitive multiplex flow cytometric and microscopic detection of iCTCs from patients with cancers of the breast, ovary, prostate, pancreas, colorectum, and lung; it has also been successfully utilized for ex vivo drug-sensitivity testing of ovarian-cancer patient CTCs. The CAM enrichment method is equally suitable for the separation of iCTCs and TP cells in ascites and pleural fluid.

Choquet H, Trapani E, Goitre L, et al.
Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1.
Free Radic Biol Med. 2016; 92:100-9 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BACKGROUND: Familial Cerebral Cavernous Malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions. CCM lesions manifest across a range of different phenotypes, including wide differences in lesion number, size and susceptibility to intracerebral hemorrhage (ICH). Oxidative stress plays an important role in cerebrovascular disease pathogenesis, raising the possibility that inter-individual variability in genes related to oxidative stress may contribute to the phenotypic differences observed in CCM1 disease. Here, we investigated whether candidate oxidative stress-related cytochrome P450 (CYP) and matrix metalloproteinase (MMP) genetic markers grouped by superfamilies, families or genes, or analyzed individually influence the severity of CCM1 disease.
METHODS: Clinical assessment and cerebral susceptibility-weighted magnetic resonance imaging (SWI) were performed to determine total and large (≥5mm in diameter) lesion counts as well as ICH in 188 Hispanic CCM1 patients harboring the founder KRIT1/CCM1 'common Hispanic mutation' (CCM1-CHM). Samples were genotyped on the Affymetrix Axiom Genome-Wide LAT1 Human Array. We analyzed 1,122 genetic markers (both single nucleotide polymorphisms (SNPs) and insertion/deletions) grouped by CYP and MMP superfamily, family or gene for association with total or large lesion count and ICH adjusted for age at enrollment and gender. Genetic markers bearing the associations were then analyzed individually.
RESULTS: The CYP superfamily showed a trend toward association with total lesion count (P=0.057) and large lesion count (P=0.088) in contrast to the MMP superfamily. The CYP4 and CYP8 families were associated with either large lesion count or total lesion count (P=0.014), and two other families (CYP46 and the MMP Stromelysins) were associated with ICH (P=0.011 and 0.007, respectively). CYP4F12 rs11085971, CYP8A1 rs5628, CYP46A1 rs10151332, and MMP3 rs117153070 single SNPs, mainly bearing the above-mentioned associations, were also individually associated with CCM1 disease severity.
CONCLUSIONS: Overall, our candidate oxidative stress-related genetic markers set approach outlined CYP and MMP families and identified suggestive SNPs that may impact the severity of CCM1 disease, including the development of numerous and large CCM lesions and ICH. These novel genetic risk factors of prognostic value could serve as early objective predictors of disease outcome and might ultimately provide better options for disease prevention and treatment.

Wu Q, Paul A, Su D, et al.
Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites.
Mol Cell. 2016; 61(3):434-48 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BRCA1 accumulation at DNA damage sites is an important step for its function in the DNA damage response and in DNA repair. BRCA1-BRCT domains bind to proteins containing the phosphorylated serine-proline-x-phenylalanine (pSPxF) motif including Abraxas, Bach1/FancJ, and CtIP. In this study, we demonstrate that ionizing radiation (IR)-induces ATM-dependent phosphorylation of serine 404 (S404) next to the pSPxF motif. Crystal structures of BRCT/Abraxas show that phosphorylation of S404 is important for extensive interactions through the N-terminal sequence outside the pSPxF motif and leads to formation of a stable dimer. Mutation of S404 leads to deficiency in BRCA1 accumulation at DNA damage sites and cellular sensitivity to IR. In addition, two germline mutations of BRCA1 are found to disrupt the dimer interface and dimer formation. Thus, we demonstrate a mechanism involving IR-induced phosphorylation and dimerization of the BRCT/Abraxas complex for regulating Abraxas-mediated recruitment of BRCA1 in response to IR.

Xu J, Ji B, Wen G, et al.
Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6-mediated cellular behavior of human hepatocellular carcinoma.
Carcinogenesis. 2016; 37(3):290-300 [PubMed] Related Publications
Interleukin 6 (IL6) is a key cytokine involved in the development and progression of inflammation-associated hepatocellular carcinoma (HCC). However, the mechanisms of IL6 action on HCC remain largely unknown. Proton and Ca(2+) are two intracellular messenger ions, which are believed to play a central role in tumorigenesis and tumor progression. In this study, we found that IL6 stimulation markedly increased intracellualr pH recovery rates of human HCC cells, Huh7 and HepG2, after NH4Cl acidification, and the NH4Cl acidification induced transient intracellular Ca(2+) increases in the HCC cells. The inhibition of Na(+)/H(+) exchanger 1 (NHE1), Na(+)/Ca(2+) exchanger 1 (NCX1) and calmodulin (CaM) inhibited the IL6 stimulation-induced intracellular pH recovery increases and NH4Cl acidification-induced intracellular Ca(2+) increases. IL6 stimulation also induced the structural interaction of NHE1, NCX1 and CaM proteins. The protein expression levels of NHE1, NCX1 and CaM in native human HCC tissues were markedly higher than those in normal liver tissues. IL6 upregulated the expressions of NHE1, NCX1 and CaM in Huh7 and HepG2 cells. NHE1, NCX1 and CaM mediated the promotion of IL6 on the proliferation, migration and invasion of Huh7 and HepG2 cells and the growth of HCC in nude mice. In conclusion, IL6 activates the functional activity of NHE1 and induces the functional and structural interaction of NHE1, NCX1 and CaM. The interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human HCC.

Tsubaki M, Takeda T, Yoshizumi M, et al.
RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines.
Tumour Biol. 2016; 37(7):9099-110 [PubMed] Related Publications
Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.

Hong H, Brown CE, Ostberg JR, et al.
L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.
PLoS One. 2016; 11(1):e0146885 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

Zhou J, Wang W, Xie Y, et al.
Proteomics-Based Identification and Analysis of Proteins Associated with Helicobacter pylori in Gastric Cancer.
PLoS One. 2016; 11(1):e0146521 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacterium that causes the most common chronic infection in the human stomach. Approximately 1%-3% of infected individuals develop gastric cancer. However, the mechanisms by which H. pylori induces gastric cancer are not completely understood. The available evidence indicates a strong link between the virulence factor of H. pylori, cytotoxin-associated gene A (CagA), and gastric cancer. To further characterize H. pylori virulence, we established three cell lines by infecting the gastric cancer cell lines SGC-7901 and AGS with cagA+ H. pylori and transfecting SGC-7901 with a vector carrying the full-length cagA gene. We detected 135 differently expressed proteins from the three cell lines using proteome technology, and 10 differential proteins common to the three cell lines were selected and identified by LC-MS/MS as well as verified by western blot: β-actin, L-lactate dehydrogenase (LDH), dihydrolipoamide dehydrogenase (DLD), pre-mRNA-processing factor 19 homolog (PRPF19), ATP synthase, calmodulin (CaM), p64 CLCP, Ran-specific GTPase-activating protein (RanGAP), P43 and calreticulin. Detection of the expression of these proteins and genes encoding these proteins in human gastric cancer tissues by real-time PCR (RT-qPCR) and western blot revealed that the expression of β-ACTIN, LDH, DLD, PRPF19 and CaM genes were up-regulated and RanGAP was down-regulated in gastric cancer tissues and/or metastatic lymph nodes compared to peri-cancerous tissues. High gene expression was observed for H. pylori infection in gastric cancer tissues. Furthermore, the LDH, DLD and CaM genes were demethylated at the promoter -2325, -1885 and -276 sites, respectively, and the RanGAP gene was highly methylated at the promoter -570 and -170 sites in H. pylori-infected and cagA-overexpressing cells. These results provide new insights into the molecular pathogenesis and treatment targets for gastric cancer with H. pylori infection.

Tang J, Zhou H, Wang C, et al.
Cell adhesion downregulates the expression of Homer1b/c and contributes to drug resistance in multiple myeloma cells.
Oncol Rep. 2016; 35(3):1875-83 [PubMed] Related Publications
Previous studies have demonstrated that Homer1b/c plays an important pro-apoptotic role through classical mitochondrial apoptotic pathway. The present study was undertaken to determine the expression and functional significance of Homer1b/c in multiple myeloma (MM). We found that Homer1b/c was lowly expressed in MM cell apoptotic model induced by doxorubicin. The positive role of Homer1b/c in cell apoptosis was further confirmed by knocking down Homer1b/c. Further study confirmed that Homer1b/c was able to affect the CAM-DR via pro-apoptotic activity regulating the ability of cell adhesion. Collectively, these data indicate that Homer1b/c may represent a good candidate for pursuing clinical trial in MM.

Mukai S, Moriya S, Hiramoto M, et al.
Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines.
Int J Oncol. 2016; 48(1):45-54 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
Pancreatic cancer is one of the most difficult types of cancer to treat because of its high mortality rate due to chemotherapy resistance. We previously reported that combined treatment with gefitinib (GEF) and clarithromycin (CAM) results in enhanced cytotoxicity of GEF along with endoplasmic reticulum (ER) stress loading in non-small cell lung cancer cell lines. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) such as GEF induces autophagy in a pro-survival role, whereas CAM inhibits autophagy flux in various cell lines. Pronounced GEF-induced cytotoxicity therefore appears to depend on the efficacy of autophagy inhibition. In the present study, we compared the effect on autophagy inhibition among such macrolides as CAM, azithromycin (AZM), and EM900, a novel 12-membered non-antibiotic macrolide. We then assessed the enhanced GEF-induced cytotoxic effect on pancreatic cancer cell lines BxPC-3 and PANC-1. Autophagy flux analysis indicated that AZM is the most effective autophagy inhibitor of the three macrolides. CAM exhibits an inhibitory effect but less than AZM and EM900. Notably, the enhancing effect of GEF-induced cytotoxicity by combining macrolides correlated well with their efficient autophagy inhibition. However, this pronounced cytotoxicity was not due to upregulation of apoptosis induction, but was at least partially mediated through necroptosis. Our data suggest the possibility of using macrolides as 'chemosensitizers' for EGFR-TKI therapy in pancreatic cancer patients to enhance non-apoptotic tumor cell death induction.

Luzón-Toro B, Bleda M, Navarro E, et al.
Identification of epistatic interactions through genome-wide association studies in sporadic medullary and juvenile papillary thyroid carcinomas.
BMC Med Genomics. 2015; 8:83 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BACKGROUND: The molecular mechanisms leading to sporadic medullary thyroid carcinoma (sMTC) and juvenile papillary thyroid carcinoma (PTC), two rare tumours of the thyroid gland, remain poorly understood. Genetic studies on thyroid carcinomas have been conducted, although just a few loci have been systematically associated. Given the difficulties to obtain single-loci associations, this work expands its scope to the study of epistatic interactions that could help to understand the genetic architecture of complex diseases and explain new heritable components of genetic risk.
METHODS: We carried out the first screening for epistasis by Multifactor-Dimensionality Reduction (MDR) in genome-wide association study (GWAS) on sMTC and juvenile PTC, to identify the potential simultaneous involvement of pairs of variants in the disease.
RESULTS: We have identified two significant epistatic gene interactions in sMTC (CHFR-AC016582.2 and C8orf37-RNU1-55P) and three in juvenile PTC (RP11-648k4.2-DIO1, RP11-648k4.2-DMGDH and RP11-648k4.2-LOXL1). Interestingly, each interacting gene pair included a non-coding RNA, providing thus support to the relevance that these elements are increasingly gaining to explain carcinoma development and progression.
CONCLUSIONS: Overall, this study contributes to the understanding of the genetic basis of thyroid carcinoma susceptibility in two different case scenarios such as sMTC and juvenile PTC.

Whitworth WW, Hick RW, Nelson KC, Sidhu-Malik NK
Cerebral cavernous malformations associated with cutaneous angiokeratomas and hemangiomas.
Cutis. 2015; 96(5):329-32 [PubMed] Related Publications
We report the case of a 66-year-old man with adult-onset seizures and multiple cerebral cavernous malformations who developed numerous eruptive cutaneous angiokeratomas on the legs, scrotum, abdomen, and back as well as lobular and cavernous hemangiomas on the arms. Genetic analysis demonstrated a mutation in the KRIT1, ankyrin repeat containing gene (also known as CCM1).

Seibold P, Schmezer P, Behrens S, et al.
A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.
BMC Cancer. 2015; 15:978 [PubMed] Article available free on PMC after 25/08/2017 Related Publications
BACKGROUND: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment.
METHODS: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed.
RESULTS: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy.
CONCLUSIONS: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.

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