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KLLN (killin, p53-regulated DNA replication inhibitor)

Written2013-03Emily Nizialek, Emma Lessieur, Charis Eng
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (EN, EL, CE); Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (EN, EL, CE); Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA (CE); Department of Genetics, Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA (EN, CE); CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA (CE); HHMI Program in Molecular Medicine, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, 44195, USA (EL, CE)

(Note : for Links provided by Atlas : click)


Alias (NCBI)CWS4
HGNC Alias symbkillin
HGNC Previous namekillin, p53-regulated DNA replication inhibitor
LocusID (NCBI) 100144748
Atlas_Id 52121
Location 10q23.31  [Link to chromosome band 10q23]
Location_base_pair Starts at 87859161 and ends at 87863437 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping KLLN.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description A single exon of 4277 bases.
Transcription KLLN shares a transcription start site with PTEN and is transcribed from the minus strand.
Pseudogene None.


Note Calculated molecular weight: 19827 Da.
  Amino acid sequence.
Description 178 amino acids, DNA binding domain amino acids 8-50.
Localisation Nucleus.
Function KLLN, a target gene of the tumor suppressor p53, is involved in cell cycle arrest and apoptosis (Cho and Liang, 2008). In breast cancer cell lines, KLLN overexpression inhibits cellular proliferation and leads to cell cycle arrest and apoptosis while KLLN knockdown increases cellular proliferation (Wang et al., 2013b). KLLN can bind to DNA and act as a transcription factor; regulating the expression of genes including TP53, TP73, AR and CHK1 (Nizialek et al., 2013 ; Wang et al., 2013b).
Homology None.


Germinal 37% of Cowden syndrome patients who were PTEN mutation negative had KLLN promoter hypermethylation which was not seen in controls. Patients with KLLN promoter hypermethylation have an increased risk of breast and renal cancer compared to PTEN mutation positive patients. Methylation leads to a 250-fold decrease in KLLN expression (Bennett et al., 2010).
Germline KLLN promoter methylation has been observed in 56% of patients with apparently sporadic renal cell carcinoma (Bennett et al., 2011).
Germline KLLN mutations have been associated with apparently sporadic breast cancer. 3% of patients with sporadic breast cancer were found to have KLLN mutations while no mutations were observed in controls. Patients with KLLN mutations had a significant family history of breast cancer. These variants were found to dysregulate G2 cell cycle arrest possibly through dysregulated CHK1 expression (Nizialek et al., 2013).
Somatic Somatic KLLN promoter hypermethylation is seen in renal cell carcinoma (Bennett et al., 2011).
Somatic KLLN deletions were observed in 20% of breast carcinomas (Nizialek et al., 2013).

Implicated in

Entity Cowden syndrome
Note Cowden syndome (CS) is an autosomal dominant syndrome and can be attributed to a PTEN mutation in 25% of cases and to KLLN promoter hypermethylation in 37% of PTEN mutation negative CS/CS-like cases. CS is characterized by benign harmatomas as well as malignancies including breast, thyroid, endometrial, and other cancers. Patients with KLLN epimutations are at increased risk for breast and renal cancer compared to patients with PTEN mutations (Bennett et al., 2010).
Entity Breast cancer
Note Germline KLLN mutations have been identified in 3% of patients with apparently sporadic breast cancer (Nizialek et al., 2013). KLLN is thought to be a low-penetrance breast cancer susceptibility gene. KLLN mutations were not associated with breast cancer in a cohort of high-risk Australian and New Zealand patients (Thompson et al., 2012).
Somatic deletions of the KLLN gene are observed in 20% of breast tumors. Patients with somatic KLLN deletions are more likely to have estrogen receptor and progesterone receptor negative tumors and tumors of a basal sub-type (Nizialek et al., 2013).
Loss of KLLN expression is seen in all subtypes of breast cancer and decreased KLLN in breast tumors is associated with increased tumor grade and with breast cancer metastasis (Wang et al., 2013a).
Entity Renal cell carcinoma
Note 56% of patients with renal cell carcinoma were found to have germline KLLN promoter methylation of at least one of four CpG-rich regions housed in the genomic region between KLLN and PTEN. Somatic KLLN promoter methylation was also seen in renal tumors, possibly increasing with more advanced stage of disease (Bennett et al., 2011).
Entity Prostate cancer
Note KLLN mRNA expression is significantly decreased in prostate tumors compared to normal prostate tissue. Immunohistochemistry staining of prostate tumors for KLLN expression shows decreased staining associated with high Gleason score (Wang et al., 2013b).


Germline and somatic DNA methylation and epigenetic regulation of KILLIN in renal cell carcinoma.
Bennett KL, Campbell R, Ganapathi S, Zhou M, Rini B, Ganapathi R, Neumann HP, Eng C.
Genes Chromosomes Cancer. 2011 Aug;50(8):654-61. doi: 10.1002/gcc.20887. Epub 2011 May 16.
PMID 21584899
Killin is a p53-regulated nuclear inhibitor of DNA synthesis.
Cho YJ, Liang P.
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5396-401. doi: 10.1073/pnas.0705410105. Epub 2008 Apr 2.
PMID 18385383
Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.
Nizialek EA, Peterson C, Mester JL, Downes-Kelly E, Eng C.
Hum Mol Genet. 2013 Jun 15;22(12):2451-61. doi: 10.1093/hmg/ddt097. Epub 2013 Feb 27.
PMID 23446638
Analysis of KLLN as a high-penetrance breast cancer predisposition gene.
Thompson ER, Gorringe KL, Choong DY, Eccles DM; kConFab, Mitchell G, Campbell IG.
Breast Cancer Res Treat. 2012 Jul;134(2):543-7. doi: 10.1007/s10549-012-2088-3. Epub 2012 May 13.
PMID 22580995
Androgen receptor-induced tumor suppressor, KLLN, inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas.
Wang Y, He X, Yu Q, Eng C.
Hum Mol Genet. 2013a Jun 1;22(11):2263-72. doi: 10.1093/hmg/ddt077. Epub 2013 Feb 14.
PMID 23418309
Transcription factor KLLN inhibits tumor growth by AR suppression, induces apoptosis by TP53/TP73 stimulation in prostate carcinomas, and correlates with cellular differentiation.
Wang Y, Radhakrishnan D, He X, Peehl DM, Eng C.
J Clin Endocrinol Metab. 2013b Mar;98(3):E586-94. doi: 10.1210/jc.2012-3490. Epub 2013 Feb 5.
PMID 23386643


This paper should be referenced as such :
Nizialek, E ; Lessieur, E ; Eng, C
KLLN (killin, p53-regulated DNA replication inhibitor)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):563-564.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)KLLN   37212
LRG (Locus Reference Genomic)LRG_1087
Entrez_Gene (NCBI)KLLN    killin, p53 regulated DNA replication inhibitor
GeneCards (Weizmann)KLLN
Ensembl hg19 (Hinxton)ENSG00000227268 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000227268 [Gene_View]  ENSG00000227268 [Sequence]  chr10:87859161-87863437 [Contig_View]  KLLN [Vega]
ICGC DataPortalENSG00000227268
Genatlas (Paris)KLLN
SOURCE (Princeton)KLLN
Genetics Home Reference (NIH)KLLN
Genomic and cartography
GoldenPath hg38 (UCSC)KLLN  -     chr10:87859161-87863437 -  10q23.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLLN  -     10q23.31   [Description]    (hg19-Feb_2009)
GoldenPathKLLN - 10q23.31 [CytoView hg19]  KLLN - 10q23.31 [CytoView hg38]
Genome Data Viewer NCBIKLLN [Mapview hg19]  
OMIM612105   615107   
Gene and transcription
Genbank (Entrez)EU552092
RefSeq transcript (Entrez)NM_001126049
Consensus coding sequences : CCDS (NCBI)KLLN
Gene ExpressionKLLN [ NCBI-GEO ]   KLLN [ EBI - ARRAY_EXPRESS ]   KLLN [ SEEK ]   KLLN [ MEM ]
Gene Expression Viewer (FireBrowse)KLLN [ Firebrowse - Broad ]
GenevisibleExpression of KLLN in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)100144748
GTEX Portal (Tissue expression)KLLN
Human Protein AtlasENSG00000227268-KLLN [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtB2CW77   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtB2CW77  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProB2CW77
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)KLLN
AlphaFold pdb e-kbB2CW77   
Human Protein Atlas [tissue]ENSG00000227268-KLLN [tissue]
Protein Interaction databases
IntAct (EBI)B2CW77
Ontologies - Pathways
Ontology : AmiGODNA binding  nucleoplasm  nucleolus  apoptotic process  cell cycle  
Ontology : EGO-EBIDNA binding  nucleoplasm  nucleolus  apoptotic process  cell cycle  
NDEx NetworkKLLN
Atlas of Cancer Signalling NetworkKLLN
Wikipedia pathwaysKLLN
Orthology - Evolution
GeneTree (enSembl)ENSG00000227268
Phylogenetic Trees/Animal Genes : TreeFamKLLN
Homologs : HomoloGeneKLLN
Homology/Alignments : Family Browser (UCSC)KLLN
Gene fusions - Rearrangements
Fusion : QuiverKLLN
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLLN [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLLN
Exome Variant ServerKLLN
GNOMAD BrowserENSG00000227268
Varsome BrowserKLLN
ACMGKLLN variants
Genomic Variants (DGV)KLLN [DGVbeta]
DECIPHERKLLN [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLLN 
ICGC Data PortalKLLN 
TCGA Data PortalKLLN 
Broad Tumor PortalKLLN
OASIS PortalKLLN [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLLN  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DKLLN
Mutations and Diseases : HGMDKLLN
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)KLLN
DoCM (Curated mutations)KLLN
CIViC (Clinical Interpretations of Variants in Cancer)KLLN
NCG (London)KLLN
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM612105    615107   
Orphanet243    19054   
Genetic Testing Registry KLLN
NextProtB2CW77 [Medical]
Target ValidationKLLN
Huge Navigator KLLN [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDKLLN
Pharm GKB GenePA166049027
Clinical trialKLLN
DataMed IndexKLLN
PubMed20 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:21:01 CEST 2021

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