Atlas of Genetics and Cytogenetics in Oncology and Haematology


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MKI67 (marker of proliferation Ki-67)

Identity

Other namesKIA
MIB-1
HGNC (Hugo) MKI67
LocusID (NCBI) 4288
Location 10q26.2
Location_base_pair Starts at 129894925 and ends at 129924468 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order CLRN3, PTPRE, MKI67, LINC01163, MGMT.
 
  The local order of genes around MKI67. The MKI67 gene is surrounded by the genes CLRN3 (clarin 3), PTPRE (protein tyrosine phospatase receptor type E), MGMT (O-6-methylguanine-DNA methyltransferase).
Note MKI67 is the human homologue of the product recognized by the monoclonal antibody Ki67, which is used as a tumor proliferation marker.

DNA/RNA

Note MKI67 is located on chromosome 10 at locus 10q26.2, starting at 128096659 and ending at 128126204 bp from pter (according to GRCh38 Primary Assembly). The gene size is 29,545 bp consisting of 15 exons and 14 introns. The gene has a minus strand orientation.
 
  MKI67 gene structure. The UTRs are coloured green and the coding regions red. The introns are coloured yellow. MKI67 consists of 15 exons of which the first and a part of the second exon form the 5' UTR. The 3' UTR is formed from a major part of exon 15, which contains only a small coding region. The table at the bottom of the figure shows the length of exons, coding regions and introns according to the information provided by the NM_002417.4 NCBI reference sequence.
Description Promoter: The promoter of MKI67 is located upstream of the transcription start site. Several studies have shown that the 5' flanking region of the gene has promoter activity via reporter gene expression assays and deletion analysis (Zambon, 2010; Pei et al., 2012). The promoter region was shown to contain a TATA-less, GC rich region with several putative Sp1 binding sites and two evolutionary conserved E2F transcription factor binding sites (Zambon, 2010; Pei et al., 2012).
Gene: The gene consists of 15 exons and 14 introns. The first exon and a part of the second form the 5' Untranslated Region (5' UTR) of the mRNA transcript (Duchrow et al., 1996; Schlüter et al., 1993). The second exon contains the start codon (Schlüter et al., 1993), with the open reading frame extending to the 15th exon, which consists of a short coding sequences, the stop codon and the 3' UTR (Duchrow et al., 1996; Schlüter et al., 1993).
The 1080 bp 7th exon is not present in the alternatively spliced "short type" mRNA transcript. The 6845 bp 13th exon contains the characteristic sixteen homologous "Ki67 repeats", each of them having length of 366 bp. Within Ki67 repeats there is a highly conserved new motif of 66 bp named the "Ki67 motif" (Schlüter et al., 1993).
The introns, vary in size from 87 to 3561 bp. Three introns contain recognized homologue copies of "Alu-repeats". All the intron-exon transitions contain a potential branch site with the exception of the introns flanking exon 7 where there is not any donor-acceptor splicing signal (Durchow et al., 1996).
Transcription There are two mRNA splice variants of MKI67, that are shown to be processed through translation. These two mRNA variants are named as "long type" and "short type" since they differ only by the presence or absence of exon 7 (Schlüter et al., 1993).
The "long type" mRNA splice variant consists of 15 exons and its total annotated spliced exon length is 12497 bp (NCBI Reference Sequence: NM_002417.4). The "short type" mRNA splice variant consists of 14 exons lacking the 7th exon and its annotated spliced exon length is 11417 bp (NCBI Reference Sequence: NM_001145966.1).
Pseudogene There is one related pseudogene of MKI67 on chromosome X, named MKI67P1 (marker of proliferation Ki-67 pseudogene 1) with Gene ID 100271918. The MKI67P1 pseudogene is located on chromosomal locus Xp11. It has 1449 bp length and NCBI Reference Sequence: NG_011647.1.

Protein

Note The MKI67 protein can be found in two complete isoforms, the heavy isoform produced from the "long type" mRNA and the light isoform translated from the "short type" mRNA, lacking the 7th exon. The heavy isoform, referred as Antigen Ki67 isoform 1 with NCBI Reference Sequence: NP_002408.3, consists of 3256 aminoacids (aa) and weights approximately 395 kDa. The light isoform, referred as Antigen Ki67 isoform 2 with NCBI Reference Sequence: NP_001139438.1, consists of 2896 aa lacking the 360 aa encoded by exon 7 and has a molecular weight of about 345 kDa.
 
  The MKI67 mRNA and protein. The two types of mRNA transcripts, shown to be translated to protein, are depicted in the first part of the figure. The long type mRNA differs from the short type by the presence of the 7th exon which is alternatively spliced in the short type. The UTRs are coloured green and the coding regions red. At the second part of the figure, it is depicted the protein product of the long type mRNA which contains all the putative domains of this protein. The major protein domains are the FHA domain coloured red, the PPI binding site coloured purple, the Ki67 repeats coloured yellow and the ATP/ GTP binding site motif A-P loop coloured blue. There are other putative functional regions within these major domains, which are highlighted in different colours.
Description Starting from the N-terminus:

Major domains:

- Forkhead associated domain (FHA): 8-98 aa.
This domain is characterized as a modular phosphopeptide recognition domain with specificity to phosphothreonine containing sequences (Hammet et al., 2003; Durocher et al., 1999). The MKI67 FHA domain is shown to lie at the N-terminus of the protein. According to computer alignment, the core domain is found within 27-76 amino acids but the functional domain is believed to expand from 8 to 98 residue. So far, two proteins have been identified to interact with MKI67 FHA domain, the hNIFK (human nucleolar protein interacting with the FHA domain of pKi-67) and the Hklp2 (human kinesin-like protein 2).

- Protein phosphatase 1 binding site: 502-563 aa.
The Protein Phosphatase 1 (PPI) is a Ser/Thr phosphatase which belongs to the PPP family of phosphatases, and it is believed to dephosphorylate its substrates in large complexes consisting of regulatory as well as target proteins (Moorhead et al., 2008). In MKI67 protein there is a docking site of PPI at the N-terminal part of the protein within residues 502 to 563.

- Ki67 Repeats:
1) 1002-1113 aa, 2) 1124-1235 aa, 3) 1246-1357 aa, 4) 1368-1478 aa, 5) 1489-1599 aa, 6) 1610-1721 aa, 7) 1732-1843 aa, 8) 1854-1965 aa, 9) 1976-2087 aa, 10) 2098-2204 aa, 11) 2216-2327 aa, 12) 2337-2448 aa, 13) 2459-2570 aa, 14) 2582-2690 aa, 15) 2701-2806 aa, 16) 2820-2929 aa.
The Ki67 repeat is a cluster of 122 residues repeated 16 times within the 13th exon of the molecule with identity ranging from 43 to 62% to the consensus sequence. Within the Ki67 repeat there is a highly conserved motif of 22 amino acids named "the Ki67 motif" which has 72-100% identity to the consensus sequence and includes the F-K-E-L epitope recognized by the prototype Ki67 antibody (Schlüter et al., 1993). So far, their function remains an enigma.

- ATP/ GTP binding site motif A-P loop: 3034-3041 aa.
A-P-R-A-R-G-K-S
At the C-terminus of the protein there is a sequence resembling the predictive nucleotide binding site of Walker A motif. This well-known motif is a nucleotide binding fold recognized by Walker et al. (1982) and it is found in many nucleotide binding proteins.

Minor domains:

- PEST sequences:
The cDNA sequences show 40 weak and 10 strong PEST sites. These sites are named as PEST due to the fact that they are rich in proline, glutamic acid (E), serine and threonine and to a lesser extent aspartic acid. They are found in several proteins with diverse functions such as key metabolic enzymes, transcription factors, protein kinases, phosphatases and cyclins. The regulation of proteins based on PEST sequences is characterized by strict expression, high susceptibility to proteolysis and short half-life, especially in those proteins participating in cell cycle and mitosis regulation. In MKI67 protein, the 10 strongest PEST sequences are located within exon 13, surrounding the conserved cysteine residues at position 8 of the Ki67 repeats (Ross and Hall, 1995). PEST sequences seem to be functional in the MKI67 protein, based on its biological behavior with susceptibility to proteases, short half-life and rapid loss of the protein after mitosis (Ross and Hall, 1995; Schlüter et al., 1993).

- Putative Monopartite Nuclear Targeting Sequences: 502-505 and 687-690 aa.
The MKI67 protein has two putative monopartite nuclear targeting sequences at the N-terminal part of the protein, which could function as nuclear localization signals (NLS) through the classical importin a/b nuclear import mechanism.

- Putative Bipartite Nuclear Targeting Sequences: 1) 536-550 aa, 2) 1516-1530 aa, 3) 2244-2258 aa, 4) 2365-2379 aa, 5) 2651-2665 aa, 6) 2890-2904 aa, 7) 2997-3011 aa, 8) 3141-3155 aa.

There are other classical nuclear targeting sequences within this molecule, which could mediate nuclear localization with importin a/b pathway as well. These bipartite sequences are characterized by two clusters of basic residues separated by a 10 to 12 aa linker that is tolerant to residue substitution (Kosugi et al., 2009).

- Post-translational modifications:
The predicted post-translational modifications of MKI67 protein comprise 19 N-myristoylation, 3 amidation and over 200 phosphorylation sites (143 PKC, 89 casein kinase II, 2 tyrosine kinase sites and 8 consensus sites for Cdc2 kinase) (Schlüter et al., 1993).

- MKI67 protein interactions:
The MKI67 protein has been found to interact directly with four proteins. The HP1 proteins, which are small non-histone chromosomal proteins found in several chromatin complexes, interact with its C-terminal region (Kametaka et al., 2002). The Hklp2, a kinesin-like motor, interacts with the N-terminal FHA domain of MKI67 protein (Sueishi et al., 2000). Another protein shown to interact with the N-terminal FHA domain of MKI67 protein is a putative RNA-binding protein with length of 293 residues, named hNIFK (Takagi et al., 2001). MKI67 protein was found to be a candidate protein for interacting with the HiNF-P transcription factor in a yeast two-hybrid screen (Miele et al., 2007).
Finally, several studies have shown that MKI67 protein interacts with DNA and more specifically with the heterochromatin (Kreitz et al., 2000; Bridger et al., 1998).

Expression The expression profile of MKI67 is much more related to the proliferating state of a cell rather than to the histological background of that cell. Through immunostaining experiments Gerdes et al. (1983) showed that this gene is present in proliferating normal cells such as germinal centers of cortical follicles, cortical thymocytes, neck cells of gastrointestinal mucosa and other cell lines but absent in resting differentiated cells such as lymphocytes, monocytes, hepatocytes, renal, brain, or parietal cells and many others. A very important finding was that the expression of MKI67 was triggered in differentiated cells after proliferative stimulation and disappeared after differentiation of proliferating cells (Gerdes et al., 1983). During cell cycle this gene is always detectable through G1, S, G2 and M phase at continuously proliferating cells but totally absent in resting cells at G0 phase (Gerdes et al., 1984).
Localisation Distribution of MKI67 protein during cell cycle:

1. Interphase:
a. Early G1 phase: Accumulates in several foci within the nucleoplasm (Gerdes et al., 1983; Kill, 1996).
b. Late G1, S, G2 phase: Localizes predominantly within nucleoli at the dense fibrillar component but also there is diffuse nucleoplasmic staining (Gerdes et al., 1983; Kill, 1996).

2. Mitosis: Coats chromosome surface (Gerdes et al., 1983).
a. Metaphase: a reticulate but uniform network of fibrils around chromosomes, at the perichromosomal layer (Ross and Hall, 1995).
b. Anaphase: a reticulate more granular network of fibrils around chromosomes with the highest density of staining (Ross and Hall, 1995).
c. Telophase: the staining moves from the perichromosomal layer and becomes speckled at the nucleoplasm and subsequently concentrates at the newly reformed nucleoli (Ross and Hall, 1995).

Function The function of MKI67 protein during cell cycle is still unknown. However, experiments with anti-sense oligonucleotides and antibodies against MKI67 revealed a decreased rate of cell division, indicating the important role of this protein in cell cycle (Schlüter et al., 1993; Starborg et al., 1996). More details for MKI67 function are unavailable, although there are some assumptions based on localization and protein-protein interactions experimental data.

Models:

1. Nucleolar localization of MKI67 protein is believed to be related to:
a. Structural modulation of the nucleolus in order to enhance the high rates of ribosomal synthesis during cell proliferation, since its expression is related to high rates of protein synthesis (Plaat et al., 1999; Scholzen et al., 2002).
b. Sequestration of MKI67 protein within nucleoli until the mitosis starts again. During mitosis the nucleolar structures are dispersed and the MKI67 protein is free to interact with nuclear components (Scholzen et al., 2002).

2. Localization of MKI67 to the surfaces of chromosomes during mitosis (prometaphase to anaphase) is believed to be related to:
a. Protection of chromosomal surface during mitosis (Verheijen et al., 1989; Yasuda and Maul, 1990).

3. DNA interaction:
a. It was believed that the central part of the MKI67 protein and especially the "Ki67 repeat" region has the ability to bind DNA through its Thr-Pro-X-X motif (Schlüter et al., 1993).
b. The LR domain has the ability to bind DNA in order to compact chromatin (Kametaka et al., 2002).

Homology The MKI67 gene has homologous genes in several organisms such as chimpanzee, rhesus monkey, dog, cattle, mouse and rat. Additionally, through genome annotation studies, 53 other organisms have been found to carry an MKI67 orthologue. However, the most interesting case is a similar but not homologous gene, found in the long-nosed rat Kangaroo, named chmadrin (Takagi et al., 1999). The chmadrin protein has primary structural similarities with the MKI67 protein. The N-terminal region of the chmadrin protein has a nucleotide binding motif which is similar to a putative one found in MKI67 at the C-terminal region (Takagi et al., 1999). The central region of chmadrin contains a repetitive sequence domain, named the "chmadrin repeat domain" which resembles the "Ki67 repeat domain" (Takagi et al., 1999). Finally, both of these proteins have LR domains with conserved functionality but different amino acid sequence (Takagi et al., 1999).

Mutations

Note MKI67 is used as a tumor proliferation marker with an unknown function. The contribution of this gene in tumor development is unknown. In 2003, Buban et al. found eight different point mutations in four tumor cell lines (HeLa, CXF94, SW480, A549) indicating that MKI67 might provide a genetic background in tumor development. These mutations include a deletion in position 1496 resulting in a truncated product, a base exchange silent mutation in position 433 (A433T) and six other exchange mutations resulting in residue changes (Buban et al., 2004).

Implicated in

Entity Several cancers
Note Although the MKI67 gene is not associated with any type of human cancer as a causative factor, it is implicated in many of them as a prognostic factor based on the expression profile of this gene at tumor cells. Additionally, a new application of MKI67 expression is the implication in diagnosis of certain diseases such as lymphoma. The prognostic value of MKI67 expression in malignancy was categorized by Brown and Gatter (2002) into three classes:
1. Group of malignancies where >75% of the studies shown significant prognostic value: breast cancer, soft tissue tumors, lung cancer, astrocytoma and meningioma.
2. Group of malignancies where 25-75% of the studies shown significant prognostic value: cervical cancer, prostate cancer.
3. Group of malignancies where <25% of the studies shown significant prognostic value: colorectal cancer.
  
Entity Breast cancer
Note In breast cancer, most of the studies show significant correlation between MKI67 expression in tumor cells and clinical outcomes both in univariate and multivariate analysis (Brown and Gatter, 2002; Kontzoglou et al., 2013). The prognostic value of MKI67 expression in breast cancer is comprised in the following conclusions:
1. MKI67 expression is associated with common histopathological parameters and the strongest correlation is established with tumor grading (Inwald et al., 2013).
2. MKI67 expression is an independent prognostic parameter of overall and disease-free survival (Inwald et al., 2013).
3. MKI67 expression is associated with earlier central nervous system metastases (Ishihara et al., 2013).
4. In triple negative breast cancer (TNBC) MKI67 expression could be used to classify TNBC into two subtypes with different prognosis (Keam et al., 2011).
5. In node-negative breast cancer, which is treated with surgery and subsequent radiation but not with adjuvant systemic therapy, MKI67 expression and hormone receptor status is a significant prognostic parameter of survival (Pathmanathan et al., 2014).
6. The expression of MKI67 gene after neoadjuvant chemotherapy is prognostic of disease relapse and death (von Minckwitz et al., 2013; Tanei et al., 2011).
7. The prognostic value of MKI67 expression is available in samples of breast tumors acquired via fine needle aspirate with accuracy comparable to histological evaluation (Konofaos et al., 2013).
8. Breast cancer patients with Grade 3 tumors positive for MS110, Lys27H3, VIM (vimentin) and MKI67 expression are at high risk of carrying BRCA1 mutations and therefore could be screened for such mutations (Hassanein et al., 2013).

Additionally, another diagnostic use of MKI67 expression in breast cancer addresses two specific subtypes of this malignancy:
1. In Phyllodes tymor the expression of MKI67 and TP53 mRNA is associated with the grade of this tumor and could help in distinguishing the benign from the malignant form (Kucuk et al., 2013).
2. The expression profile of the estrogen receptor, ERBB2 (c-erbB2) and MKI67 mRNA could help in distinguishing between Toker cells, which are normal components of nipple epidermis, and cells of Paget's disease (Park and Suh, 2009).

  
Entity Endometrial cancer
Note Although in endometrial cancer MKI67 expression is used as a proliferation marker associated with specific characteristics of this tumor, there is not yet any validated prognostic or diagnostic connection as there is for breast cancer. More specifically:
1. High MKI67 expression is associated with endometrial cancer and the overexpression of MKI67 and TP53 genes indicates a more malignant phenotype with poor differentiation of the tumor cells (Markova et al., 2010).
2. High MKI67 expression is correlated with poorly differentiated carcinomas, invasion of the myometrium and stage III tumor (Stoian et al., 2011). There is also a significant correlation with the degree of differentiation, the stage of tumor and vascular invasion (Stoian et al., 2011).
3. MKI67 expression is higher in high-grade endometrial carcinomas and complete negative in atrophic endometrium (Mourtzikou et al., 2012).
4. High MKI67 expression correlates with morphologic features of aggressiveness and high grade of endometrial cancer (Konstantinos et al., 2013).
5. Although previous studies associated MKI67 expression with survival, recent ones correlate survival with estrogen and progesterone receptors expression rather than MKI67 gene (Li et al., 2014; Salvesen et al., 1999; Gassel et al., 1998).
  
Entity Cervical cancer
Note In cervical cancer MKI67 expression is used as a proliferation index marker of malignant cells, associated with specific characteristics of the tumor but not as a prognostic factor of survival or disease relapse. Additionally, it is suggested that under certain circumstances MKI67 expression could be used in low-grade lesion triage for referral colposcopy. More specifically:
1. There is no significant correlation between MKI67 expression and classical prognostic factors (Ancuta et al., 2009).
2. MKI67 and CDKN2A (P16) gene is expressed in cervical intraepithelial neoplasia (CIN) and the intensity of positive expression is significantly correlated with CIN grade (Shi et al., 2007). In another study these two markers were shown to increase linearly from control cases to more dysplastic lesion to squamous cell carcinoma (Gatta et al., 2011). This indicates that CDKN2A and MKI67 gene could be useful markers in diagnosis and staging of CIN lesions (Shi et al., 2007).
3. Expression of CDKN2A, MKI67 gene and ProxEX C (a cocktail of monoclonal antibodies against proteins associated with aberrant S phase cell cycle induction) are most associated with the severity of cervical dysplasia and related to HPV-16 infection (Conesa-Zamora et al., 2009).
4. MKI67 expression is enhanced in high grade CIN lesions and cervical squamous cell carcinoma (Looi et al., 2008). TP63 and MKI67 expression is correlated better with cancer progress than TP53 expression (Vasilescu et al., 2009).
5. CDKN2A/MKI67 expression increases according to histologic severity and could be used to predict high-grade lesion better than HPV DNA testing since it is more accurate in patients with atypical squamous cells (Koo et al., 2013). Additionally, they could be used for low-grade squamous intraepithelial lesions triage better than HPV DNA testing and reduce referral colposcopy to almost the half by detecting the more severe cases of CIN3 (Wentzensen et al., 2012).
  
Entity Ovarian cancer
Note In ovarian cancer MKI67 expression is associated with several histopathological characteristics of the malignancy and in some subtypes with the overall survival. However, more studies are needed in order to validate such correlations. More specifically:
1. PIK3CA amplifications and MKI67 expression are strong predictors of an early tumor-associated death (Woenckhaus et al., 2007).
2. The combined evaluation of CDKN1B (P27KIP1) and MKI67 expression in ovarian carcinomas is an independent and more accurate prognostic marker of overall survival than each marker alone (Korkolopoulou et al., 2002).
3. In stage III ovarian carcinomas, MKI67 expression is an independent prognostic marker where high expression of this gene is significantly associated with shorter survival (Khouja et al., 2007).
4. The expression of MKI67 gene is higher in malignant ovarian tissues than control ones and within the malignant tissues it is enhanced in low differential carcinoma and stage III-IV (Wang et al., 2010b).
5. The expression of MKI67 gene is higher in primary ovarian tumors than in metastatic cells (Wang et al., 2010b).
6. The high-grade ovarian carcinomas have significantly higher expression of MKI67 gene than the low-grade, but there is little correlation between this expression and overall or disease-free survival (Shen et al., 2011).
7. The MKI67 expression is associated with higher cancer stage and histological grade and a worse outcome for patients (Heeran et al., 2013).
8. The MKI67 expression was found to be associated with poorer overall survival in ovarian cancer patients (Kucukgoz Gulec et al., 2014).
  
Entity Vulvar cancer
Note The vulvar carcinomas, mainly represented by squamous cell carcinoma (SCC) and non-invasive lesion of vulvar intraepithelial neoplasias (VINs), are associated with MKI67 expression in several studies. The general idea is that the expression of this gene is associated with dysplastic lesions and it is more intense in more malignant lesions. More specifically:
1. The expression of MKI67 and CDKN2A are statistically positively related with HPV-associated dysplastic lesions (Gincheva et al., 2009).
2. There is an increase in MKI67 and TOP2A (topoisomerase IIa) expression in VIN lesions and SCC comparing to normal vulvar epithelia, indicating these two genes as markers of proliferation in vulvar epithelial tissues (Brustmann and Naude, 2002).
3. In differentiated VIN lesions the MKI67 expression is confined in the basal and parabasal layers. However, in usual VIN lesions associated with high-risk HPV virus infection, MKI67 is highly expressed (Hoevenaars et al., 2008; Ding et al., 2012).
  
Entity Bladder cancer
Note In bladder cancer MKI67 expression is examined in several studies classifying this gene as a common marker used in diagnosis and staging of this malignancy. The expression of this gene is correlated with the grade and the stage of the malignancy and it is higher in females (Wang et al., 2013).
  
Entity Gliomas: astrocytomas, oligodendrogliomas
Note In these brain tumors the MKI67 gene has great potential as a marker of cell proliferation, survival, therapy response and even discrimination between subtypes of gliomas. High expression of this gene is related with shorter overall survival of patients (Liu et al., 2013b). Additionally, MKI67 expression was shown to be correlated with survival of patients with a specific subtype of gliomas in univariable analysis, indicating the prognostic potential of this gene in glioma tumors (Preusser et al., 2012). The MKI67 expression could also be associated with post-treatment results, such as in adjuvant radiotherapy of gliomas where high expression is correlated with worse response to the therapy (Horbinski et al., 2012). Another interesting study showed that MKI67 might have differential expression between subtypes of gliomas indicating a role in diagnosis of these subtypes in accordance to other promising molecular markers (Huang et al., 2011).
  
Entity Meningiomas
Note MKI67 is believed to have some influence in meningioma development and progression since there is significant correlation between its expression and tumor grade, certain subtypes, tumor recurrence and size (Pavelin et al., 2013; Wang et al., 2010a). Another interesting correlation was proposed by Uzum and Ataoglu (2008) in which the tumor grade is the most important prognostic factor of meningiomas, which in turn is significantly correlated with MKI67 expression. Terzi et al. (2008) proposed that MKI67 and TP53 expression could be useful additional markers for grade classification in borderline cases.
  
Entity Pituitary adenomas
Note The MKI67 expression is correlated with neoplasm recurrence and visual field defect (Paek et al., 2005). Additionally, it is believed to be an independent predictor of pituitary adenomas' progression after surgery (Gejman et al., 2008). In general MKI67 is a useful marker in predicting tumor recurrence or invasiveness in accordance to other factors (de Aguiar et al., 2010).
  
Entity Gastric cancer
Note In gastric cancer the relation of MKI67 with the characteristics of this malignancy are not well established. Expression of MKI67 and PCNA are correlated with high grade of gastric cancer (Czyzewska et al., 2004). The overexpression of TSPAN1 and MKI67 genes are negatively correlated with carcinoma differentiation (Chen et al., 2008). Additionally, MKI67 expression is shown to be related to tumor size (Giaginis et al., 2011).
  
Entity Gastrointestinal stromal tumor
Note MKI67 expression is higher in the malignant gastrointestinal stromal tumors than in benign ones, indicating a role in predicting malignant potential of GIST in accordance with other tumor markers such as TP53 and KIT (c-kit) (Aoyagi et al., 2009). Addditionally, MKI67 expression was correlated with GIST recurrence and patient survival (Belev et al., 2013; Liu et al., 2013a).
  
Entity Colorectal cancer
Note In colorectal cancer, the MKI67 gene is associated with several characteristics of this malignancy. Additionally, there is a strong correlation of gene expression with the response of this cancer to potential therapeutic approaches. More specifically:
1. MKI67 in addition to other tumor markers such as CD34, KRT19 (CK19), KRT20 (CK20) are highly expressed in colorectal cancer compared to normal tissues. Additionally, expression of CD34 and MKI67 are significantly correlated with tumor stage, differentiation and low survival (Ma et al., 2010).
2. MKI67 and BMI1 overexpression in colorectal cancer is significantly related to tumorigenesis, metastasis and prognosis (Lin et al., 2008).
3. MKI67 expression is a reliable marker for predicting metastatic potential of rectal carcinoid (Hotta et al., 2006).
4. The expression of MKI67, PDPN (podoplanin) and cytokeratin are correlated with increased lympangiogenesis but not with poorer prognosis (Omachi et al., 2007).
5. Decreased expression of MKI67, HIF1A and BCL2 markers were found after chemoradiotherapy of rectal cancer (Havelund et al., 2013).
6. Rectal tumors with lower MKI67 expression were more sensitive to neoadjuvant therapy and the gene expression was decreased after the therapy (Jiang et al., 2008).
7. High MKI67 expression in colon cancer is associated with better relapse-free survival in patients who underwent surgery and adjuvant chemotherapy (Fluge et al., 2009).
8. MKI67 expression and the inflammation marker, C-reactive protein are correlated with poorer survival in patients undergoing surgery for colorectal cancer (Canna et al., 2008).
  
Entity Lung cancer
Note The MKI67 gene is not a validated prognostic marker in non-small cell lung cancer and more studies with standardized methodology are required to elucidate the role of this marker in this lung cancer subtype (Jakobsen and Sorensen, 2013).
  
Entity Lymphoma
Note In lymphoma malignancies, MKI67 is considered as a powerful tool in distinguishing benign from malignant cases (Bryant et al., 2006). Additionally, MKI67 can be used as a prognostic factor of survival, with highly expressing tumors being correlated with worse overall survival (Kim et al., 2007). However, in specific subtypes such as diffuse large B-cell lymphoma low expression of MKI67 is an adverse prognostic factor (Hasselblom et al., 2008). Another use of MKI67 expression is the evaluation of prognosis after therapy in specific lymphoma subtypes (Determann et al., 2008).
  
Entity Neuroendocrine tumors
Note In neuroendocrine tumors, MKI67 expression is the sole strong independent risk factor for poor outcome and it is considered as predictor marker of disease progression and it is significantly associated with patients' overall survival (Panzuto et al., 2012). The use of MKI67 expression is believed to be a better prognostic marker than mitotic count in these malignancies (Khan et al., 2013). This gene is incorporated in the grading of neuroendocrine neoplasms into two major categories: a) well differentiated neuroendocrine tumors (grade 1 and 2) and b) poorly differentiated endocrine carcinomas (grade 3) (Fung et al., 2013). In ileal well-differentiated neuroendocrine tumors, MKI67 predicts the progression-free survival (Dhall et al., 2012). However, a differentiation about the prognostic value of this gene is reported for the small cell lung patients where it has no prognostic value (Erler et al., 2011).
  
Entity Thyroid cancer
Note In thyroid carcinomas, MKI67 and TP53 are expressed with increasing frequency in progressed stages of this cancer (Saltman et al., 2006). MKI67 expression and mutational analysis of RET gene could be used as prognostic factors of more aggressive medullary thyroid carcinoma (Mian et al., 2011). MKI67 expression, LGALS3 (Galectin-3) and PTTG1 (pituitary tumor transforming 1) genes could be used not only to distinguish benign from malignant tumors but also to differentiate follicular carcinoma from papillary one (Cui et al., 2012).
  
Entity Other cancers
Note Basal cell carcinoma, cutaneous pilar leiomyoma, leiomyosarcoma, embryonal tumors, gallbladder carcinoma, hypopharyngeal-squamous cell carcinoma, squamous cell carcinoma of larynx, malignant fibrous histiocytoma, parathyroid cancer, hepatocellular carcinoma, prostate cancer, penile carcinoma, retinoblastoma and salivary gland tumors are some of the malignancies in which MKI67 expression is considered as proliferation, stage, grade or survival marker. However, more sophisticated studies are needed in order to elucidate the exact correlation of this gene with these tumors.
  
Entity Other non-malignant diseases
Note MKI67 is evaluated in several other not malignant diseases, mostly as a proliferation marker, such as hemimegalencephaly, eosinophilic esophagitis, hepatitis, Reinke's edema, problems in placental development, psoriasis, Barret's esophagus, endometriosis, multiple sclerosis, hemangioma, myocardial infarction, Alzheimer disease, Langerhans cell histiocytosis and endometrial polyps.
  

External links

Nomenclature
HGNC (Hugo)MKI67   7107
Cards
AtlasMKI67ID41369ch10q26
Entrez_Gene (NCBI)MKI67  4288  marker of proliferation Ki-67
GeneCards (Weizmann)MKI67
Ensembl (Hinxton)ENSG00000148773 [Gene_View]  chr10:129894925-129924468 [Contig_View]  MKI67 [Vega]
ICGC DataPortalENSG00000148773
cBioPortalMKI67
AceView (NCBI)MKI67
Genatlas (Paris)MKI67
WikiGenes4288
SOURCE (Princeton)NM_001145966 NM_002417
Genomic and cartography
GoldenPath (UCSC)MKI67  -  10q26.2   chr10:129894925-129924468 -  10q26.2   [Description]    (hg19-Feb_2009)
EnsemblMKI67 - 10q26.2 [CytoView]
Mapping of homologs : NCBIMKI67 [Mapview]
OMIM176741   
Gene and transcription
Genbank (Entrez)AJ567755 AJ567756 AJ567757 AK299254 BM699306
RefSeq transcript (Entrez)NM_001145966 NM_002417
RefSeq genomic (Entrez)AC_000142 NC_000010 NC_018921 NT_030059 NW_001838011 NW_004929377
Consensus coding sequences : CCDS (NCBI)MKI67
Cluster EST : UnigeneHs.689823 [ NCBI ]
CGAP (NCI)Hs.689823
Alternative Splicing : Fast-db (Paris)GSHG0004450
Alternative Splicing GalleryENSG00000148773
Gene ExpressionMKI67 [ NCBI-GEO ]     MKI67 [ SEEK ]   MKI67 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP46013 (Uniprot)
NextProtP46013  [Medical]
With graphics : InterProP46013
Splice isoforms : SwissVarP46013 (Swissvar)
Domaine pattern : Prosite (Expaxy)FHA_DOMAIN (PS50006)   
Domains : Interpro (EBI)FHA_dom [organisation]   K167R [organisation]   PP1-bd [organisation]   SMAD_FHA_domain [organisation]  
Related proteins : CluSTrP46013
Domain families : Pfam (Sanger)FHA (PF00498)    K167R (PF08065)    PP1_bind (PF15276)   
Domain families : Pfam (NCBI)pfam00498    pfam08065    pfam15276   
Domain families : Smart (EMBL)FHA (SM00240)  
DMDM Disease mutations4288
Blocks (Seattle)P46013
PDB (SRS)1R21    2AFF   
PDB (PDBSum)1R21    2AFF   
PDB (IMB)1R21    2AFF   
PDB (RSDB)1R21    2AFF   
Human Protein AtlasENSG00000148773 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP46013
HPRD08902
IPIIPI00004233   IPI00413173   IPI00844453   IPI01011955   IPI01012421   IPI00426109   
Protein Interaction databases
DIP (DOE-UCLA)P46013
IntAct (EBI)P46013
FunCoupENSG00000148773
BioGRIDMKI67
InParanoidP46013
Interologous Interaction database P46013
IntegromeDBMKI67
STRING (EMBL)MKI67
Ontologies - Pathways
Ontology : AmiGOchromosome, centromeric region  condensed chromosome  protein binding  ATP binding  nucleus  nucleolus  cytoplasm  DNA metabolic process  meiotic nuclear division  protein C-terminus binding  cell proliferation  response to organic cyclic compound  membrane  hyaluronan metabolic process  organ regeneration  cellular response to heat  poly(A) RNA binding  
Ontology : EGO-EBIchromosome, centromeric region  condensed chromosome  protein binding  ATP binding  nucleus  nucleolus  cytoplasm  DNA metabolic process  meiotic nuclear division  protein C-terminus binding  cell proliferation  response to organic cyclic compound  membrane  hyaluronan metabolic process  organ regeneration  cellular response to heat  poly(A) RNA binding  
Protein Interaction DatabaseMKI67
Wikipedia pathwaysMKI67
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MKI67
snp3D : Map Gene to Disease4288
SNP (GeneSNP Utah)MKI67
SNP : HGBaseMKI67
Genetic variants : HAPMAPMKI67
Exome VariantMKI67
1000_GenomesMKI67 
ICGC programENSG00000148773 
Somatic Mutations in Cancer : COSMICMKI67 
CONAN: Copy Number AnalysisMKI67 
Mutations and Diseases : HGMDMKI67
Mutations and Diseases : intOGenMKI67
Genomic VariantsMKI67  MKI67 [DGVbeta]
dbVarMKI67
ClinVarMKI67
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM176741   
MedgenMKI67
GENETestsMKI67
Disease Genetic AssociationMKI67
Huge Navigator MKI67 [HugePedia]  MKI67 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMKI67
Homology/Alignments : Family Browser (UCSC)MKI67
Phylogenetic Trees/Animal Genes : TreeFamMKI67
Chemical/Protein Interactions : CTD4288
Chemical/Pharm GKB GenePA30825
Clinical trialMKI67
Cancer Resource (Charite)ENSG00000148773
Other databases
Probes
Litterature
PubMed434 Pubmed reference(s) in Entrez
CoreMineMKI67
iHOPMKI67
OncoSearchMKI67

Bibliography

Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold.
Walker JE, Saraste M, Runswick MJ, Gay NJ.
EMBO J. 1982;1(8):945-51.
PMID 6329717
 
Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation.
Gerdes J, Schwab U, Lemke H, Stein H.
Int J Cancer. 1983 Jan 15;31(1):13-20.
PMID 6339421
 
Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H.
J Immunol. 1984 Oct;133(4):1710-5.
PMID 6206131
 
Ki-67 detects a nuclear matrix-associated proliferation-related antigen. II. Localization in mitotic cells and association with chromosomes.
Verheijen R, Kuijpers HJ, van Driel R, Beck JL, van Dierendonck JH, Brakenhoff GJ, Ramaekers FC.
J Cell Sci. 1989 Apr;92 ( Pt 4):531-40.
PMID 2689459
 
A nucleolar auto-antigen is part of a major chromosomal surface component.
Yasuda Y, Maul GG.
Chromosoma. 1990 Apr;99(2):152-60.
PMID 2192841
 
The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins.
Schluter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD, Gerdes J.
J Cell Biol. 1993 Nov;123(3):513-22.
PMID 8227122
 
Ki67: from antibody to molecule to understanding?
Ross W, Hall PA.
Clin Mol Pathol. 1995 Jun;48(3):M113-7.
PMID 16695990
 
Molecular characterization of the gene locus of the human cell proliferation-associated nuclear protein defined by monoclonal antibody Ki-67.
Duchrow M, Schluter C, Wohlenberg C, Flad HD, Gerdes J.
Cell Prolif. 1996 Jan;29(1):1-12.
PMID 8603106
 
Localisation of the Ki-67 antigen within the nucleolus. Evidence for a fibrillarin-deficient region of the dense fibrillar component.
Kill IR.
J Cell Sci. 1996 Jun;109 ( Pt 6):1253-63.
PMID 8799815
 
The murine Ki-67 cell proliferation antigen accumulates in the nucleolar and heterochromatic regions of interphase cells and at the periphery of the mitotic chromosomes in a process essential for cell cycle progression.
Starborg M, Gell K, Brundell E, Hoog C.
J Cell Sci. 1996 Jan;109 ( Pt 1):143-53.
PMID 8834799
 
Association of pKi-67 with satellite DNA of the human genome in early G1 cells.
Bridger JM, Kill IR, Lichter P.
Chromosome Res. 1998 Jan;6(1):13-24.
PMID 9510506
 
Endometrial carcinoma: immunohistochemically detected proliferation index is a prognosticator of long-term outcome.
Gassel AM, Backe J, Krebs S, Schon S, Caffier H, Muller-Hermelink HK.
J Clin Pathol. 1998 Jan;51(1):25-9.
PMID 9577367
 
The FHA domain is a modular phosphopeptide recognition motif.
Durocher D, Henckel J, Fersht AR, Jackson SP.
Mol Cell. 1999 Sep;4(3):387-94.
PMID 10518219
 
Protein synthesis rate measured with L-[1-11C]tyrosine positron emission tomography correlates with mitotic activity and MIB-1 antibody-detected proliferation in human soft tissue sarcomas.
Plaat B, Kole A, Mastik M, Hoekstra H, Molenaar W, Vaalburg W.
Eur J Nucl Med. 1999 Apr;26(4):328-32.
PMID 10199937
 
Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study.
Salvesen HB, Iversen OE, Akslen LA.
J Clin Oncol. 1999 May;17(5):1382-90.
PMID 10334522
 
Chmadrin: a novel Ki-67 antigen-related perichromosomal protein possibly implicated in higher order chromatin structure.
Takagi M, Matsuoka Y, Kurihara T, Yoneda Y.
J Cell Sci. 1999 Aug;112 ( Pt 15):2463-72.
PMID 10393802
 
The proliferation-specific human Ki-67 protein is a constituent of compact chromatin.
Kreitz S, Fackelmayer FO, Gerdes J, Knippers R.
Exp Cell Res. 2000 Nov 25;261(1):284-92.
PMID 11082298
 
The forkhead-associated domain of Ki-67 antigen interacts with the novel kinesin-like protein Hklp2.
Sueishi M, Takagi M, Yoneda Y.
J Biol Chem. 2000 Sep 15;275(37):28888-92.
PMID 10878014
 
A novel nucleolar protein, NIFK, interacts with the forkhead associated domain of Ki-67 antigen in mitosis.
Takagi M, Sueishi M, Saiwaki T, Kametaka A, Yoneda Y.
J Biol Chem. 2001 Jul 6;276(27):25386-91. Epub 2001 May 7.
PMID 11342549
 
Ki67 protein: the immaculate deception?
Brown DC, Gatter KC.
Histopathology. 2002 Jan;40(1):2-11. (REVIEW)
PMID 11903593
 
Expression of topoisomerase IIalpha, Ki-67, proliferating cell nuclear antigen, p53, and argyrophilic nucleolar organizer regions in vulvar squamous lesions.
Brustmann H, Naude S.
Gynecol Oncol. 2002 Aug;86(2):192-9.
PMID 12144828
 
Interaction of the chromatin compaction-inducing domain (LR domain) of Ki-67 antigen with HP1 proteins.
Kametaka A, Takagi M, Hayakawa T, Haraguchi T, Hiraoka Y, Yoneda Y.
Genes Cells. 2002 Dec;7(12):1231-42.
PMID 12485163
 
The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients.
Korkolopoulou P, Vassilopoulos I, Konstantinidou AE, Zorzos H, Patsouris E, Agapitos E, Davaris P.
Gynecol Oncol. 2002 Jun;85(3):404-14.
PMID 12051866
 
The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure.
Scholzen T, Endl E, Wohlenberg C, van der Sar S, Cowell IG, Gerdes J, Singh PB.
J Pathol. 2002 Feb;196(2):135-44.
PMID 11793364
 
FHA domains as phospho-threonine binding modules in cell signaling.
Hammet A, Pike BL, McNees CJ, Conlan LA, Tenis N, Heierhorst J.
IUBMB Life. 2003 Jan;55(1):23-7. (REVIEW)
PMID 12716058
 
Detection of mutations in the cDNA of the proliferation marker Ki-67 protein in four tumor cell lines.
Buban T, Schmidt M, Broll R, Antal-Szalmas P, Duchrow M.
Cancer Genet Cytogenet. 2004 Feb;149(1):81-4.
PMID 15104289
 
Evaluation of proliferating markers Ki-67, PCNA in gastric cancers.
Czyzewska J, Guzinska-Ustymowicz K, Lebelt A, Zalewski B, Kemona A.
Rocz Akad Med Bialymst. 2004;49 Suppl 1:64-6.
PMID 15638377
 
Clinical significance of Ki-67 labeling index in pituitary macroadenoma.
Paek KI, Kim SH, Song SH, Choi SW, Koh HS, Youm JY, Kim Y.
J Korean Med Sci. 2005 Jun;20(3):489-94.
PMID 15953875
 
Ki67 staining pattern as a diagnostic tool in the evaluation of lymphoproliferative disorders.
Bryant RJ, Banks PM, O'Malley DP.
Histopathology. 2006 Apr;48(5):505-15.
PMID 16623776
 
Usefulness of Ki-67 for predicting the metastatic potential of rectal carcinoids.
Hotta K, Shimoda T, Nakanishi Y, Saito D.
Pathol Int. 2006 Oct;56(10):591-6.
PMID 16984615
 
Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression.
Saltman B, Singh B, Hedvat CV, Wreesmann VB, Ghossein R.
Surgery. 2006 Dec;140(6):899-905; discussion 905-6.
PMID 17188136
 
The clinical importance of Ki-67, p16, p14, and p57 expression in patients with advanced ovarian carcinoma.
Khouja MH, Baekelandt M, Nesland JM, Holm R.
Int J Gynecol Pathol. 2007 Oct;26(4):418-25.
PMID 17885492
 
Ki-67 expression is predictive of prognosis in patients with stage I/II extranodal NK/T-cell lymphoma, nasal type.
Kim SJ, Kim BS, Choi CW, Choi J, Kim I, Lee YH, Kim JS.
Ann Oncol. 2007 Aug;18(8):1382-7.
PMID 17693651
 
The interactome of the histone gene regulatory factor HiNF-P suggests novel cell cycle related roles in transcriptional control and RNA processing.
Miele A, Medina R, van Wijnen AJ, Stein GS, Stein JL.
J Cell Biochem. 2007 Sep 1;102(1):136-48.
PMID 17577209
 
Immunohistochemical demonstration of proliferating lymphatic vessels in colorectal carcinoma and its clinicopathological significance.
Omachi T, Kawai Y, Mizuno R, Nomiyama T, Miyagawa S, Ohhashi T, Nakayama J.
Cancer Lett. 2007 Feb 8;246(1-2):167-72. Epub 2006 Mar 30.
PMID 16574316
 
Association of p16, p53, Ki-67 expressions with high-risk human papilloma virus infection in cervical intraepithelial neoplasia.
Shi J, Zheng JS, Yin F, Hu WW, Huang XJ, Zhou XL.
Nan Fang Yi Ke Da Xue Xue Bao. 2007 Apr;27(4):515-7.
PMID 17545048
 
Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer.
Woenckhaus J, Steger K, Sturm K, Munstedt K, Franke FE, Fenic I.
Virchows Arch. 2007 Apr;450(4):387-95. Epub 2007 Feb 15.
PMID 17377809
 
The relationship between tumour proliferative activity, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer.
Canna K, Hilmy M, McMillan DC, Smith GW, McKee RF, McArdle CS, McNicol AM.
Colorectal Dis. 2008 Sep;10(7):663-7. Epub 2007 Nov 12.
PMID 18005189
 
Clinicopathological significance of overexpression of TSPAN1, Ki67 and CD34 in gastric carcinoma.
Chen L, Li X, Wang GL, Wang Y, Zhu YY, Zhu J.
Tumori. 2008 Jul-Aug;94(4):531-8.
PMID 18822690
 
Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group.
Determann O, Hoster E, Ott G, Wolfram Bernd H, Loddenkemper C, Leo Hansmann M, Barth TE, Unterhalt M, Hiddemann W, Dreyling M, Klapper W; European Mantle Cell Lymphoma Network and the German Low Grade Lymphoma Study Group.
Blood. 2008 Feb 15;111(4):2385-7. Epub 2007 Dec 12.
PMID 18077791
 
Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas.
Gejman R, Swearingen B, Hedley-Whyte ET.
Hum Pathol. 2008 May;39(5):758-66. doi: 10.1016/j.humpath.2007.10.004.
PMID 18439942
 
Low rather than high Ki-67 protein expression is an adverse prognostic factor in diffuse large B-cell lymphoma.
Hasselblom S, Ridell B, Sigurdardottir M, Hansson U, Nilsson-Ehle H, Andersson PO.
Leuk Lymphoma. 2008 Aug;49(8):1501-9. doi: 10.1080/10428190802140055.
PMID 18766962
 
A panel of p16(INK4A), MIB1 and p53 proteins can distinguish between the 2 pathways leading to vulvar squamous cell carcinoma.
Hoevenaars BM, van der Avoort IA, de Wilde PC, Massuger LF, Melchers WJ, de Hullu JA, Bulten J.
Int J Cancer. 2008 Dec 15;123(12):2767-73. doi: 10.1002/ijc.23857.
PMID 18798277
 
Correlation of VEGF and Ki67 expression with sensitivity to neoadjuvant chemoradiation in rectal adenocarcinoma.
Jiang SM, Wang RB, Yu JM, Zhu KL, Mu DB, Xu ZF.
Zhonghua Zhong Liu Za Zhi. 2008 Aug;30(8):602-5.
PMID 19102938
 
Expression and significance of Bmi-1 and Ki67 in colorectal carcinoma tissues.
Lin MX, Wen ZF, Feng ZY, He D.
Ai Zheng. 2008 Dec;27(12):1321-6.
PMID 19080002
 
Expression of p53, bcl-2 and Ki-67 in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix.
Looi ML, Dali AZ, Ali SA, Ngah WZ, Yusof YA.
Anal Quant Cytol Histol. 2008 Apr;30(2):63-70.
PMID 18561741
 
Displacement affinity chromatography of protein phosphatase one (PP1) complexes.
Moorhead GB, Trinkle-Mulcahy L, Nimick M, De Wever V, Campbell DG, Gourlay R, Lam YW, Lamond AI.
BMC Biochem. 2008 Nov 10;9:28. doi: 10.1186/1471-2091-9-28.
PMID 19000314
 
The significance of immunohistochemical expression of Ki-67, p53, p21, and p16 in meningiomas tissue arrays.
Terzi A, Saglam EA, Barak A, Soylemezoglu F.
Pathol Res Pract. 2008;204(5):305-14. doi: 10.1016/j.prp.2008.01.013.
PMID 18374497
 
Histopathological parameters with Ki-67 and bcl-2 in the prognosis of meningiomas according to WHO 2000 classification.
Uzum N, Ataoglu GA.
Tumori. 2008 May-Jun;94(3):389-97.
PMID 18705408
 
Tumor biomarkers in cervical cancer: focus on Ki-67 proliferation factor and E-cadherin expression.
Ancuta E, Ancuta C, Cozma LG, Iordache C, Anghelache-Lupascu I, Anton E, Carasevici E, Chirieac R.
Rom J Morphol Embryol. 2009;50(3):413-8.
PMID 19690767
 
Malignant potential of gastrointestinal stromal tumor of the stomach.
Aoyagi K, Kouhuji K, Yano S, Miyagi M, Imaizumi T, Takeda J, Shirouzu K.
Int Surg. 2009 Jan-Feb;94(1):1-9.
PMID 20099418
 
Effect of human papillomavirus on cell cycle-related proteins p16, Ki-67, Cyclin D1, p53, and ProEx C in precursor lesions of cervical carcinoma: a tissue microarray study.
Conesa-Zamora P, Domenech-Peris A, Orantes-Casado FJ, Ortiz-Reina S, Sahuquillo-Frias L, Acosta-Ortega J, Garcia-Solano J, Perez-Guillermo M.
Am J Clin Pathol. 2009 Sep;132(3):378-90. doi: 10.1309/AJCPO0WY1VIFCYDC.
PMID 19687314
 
Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis.
Fluge O, Gravdal K, Carlsen E, Vonen B, Kjellevold K, Refsum S, Lilleng R, Eide TJ, Halvorsen TB, Tveit KM, Otte AP, Akslen LA, Dahl O; Norwegian Gastrointestinal Cancer Group.
Br J Cancer. 2009 Oct 20;101(8):1282-9. doi: 10.1038/sj.bjc.6605333. Epub 2009 Sep 22.
PMID 19773751
 
The expression of p16(INK4a) and Ki-67 in atrophic-hyperplastic and dysdysplastic lesions of the vulva.
Gincheva D, Tomov C, Gorchev G, Nikolova M.
Akush Ginekol (Sofiia). 2009;48(2):16-20.
PMID 20198771
 
Six classes of nuclear localization signals specific to different binding grooves of importin alpha.
Kosugi S, Hasebe M, Matsumura N, Takashima H, Miyamoto-Sato E, Tomita M, Yanagawa H.
J Biol Chem. 2009 Jan 2;284(1):478-85. doi: 10.1074/jbc.M807017200. Epub 2008 Nov 10.
PMID 19001369
 
Useful immunohistochemical markers for distinguishing Paget cells from Toker cells.
Park S, Suh YL.
Pathology. 2009;41(7):640-4. doi: 10.3109/00313020903273092.
PMID 20001343
 
P53, p63 and Ki-67 assessment in HPV-induced cervical neoplasia.
Vasilescu F, Ceausu M, Tanase C, Stanculescu R, Vladescu T, Ceausu Z.
Rom J Morphol Embryol. 2009;50(3):357-61.
PMID 19690760
 
Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review.
de Aguiar PH, Aires R, Laws ER, Isolan GR, Logullo A, Patil C, Katznelson L.
Neurol Res. 2010 Dec;32(10):1060-71. doi: 10.1179/016164110X12670144737855. Epub 2010 May 18. (REVIEW)
PMID 20483025
 
Immunohistochemical analysis revealed CD34 and Ki67 protein expression as significant prognostic factors in colorectal cancer.
Ma YL, Peng JY, Zhang P, Liu WJ, Huang L, Qin HL.
Med Oncol. 2010 Jun;27(2):304-9. doi: 10.1007/s12032-009-9210-3. Epub 2009 Apr 2.
PMID 19340613
 
Selected immunohistochemical prognostic factors in endometrial cancer.
Markova I, Duskova M, Lubusky M, Kudela M, Zapletalova J, Prochazka M, Pilka R.
Int J Gynecol Cancer. 2010 May;20(4):576-82. doi: 10.1111/IGC.0b013e3181d80ac4.
PMID 20686376
 
Expression of HER2/neu in meningiomas: an immunohistochemistry and fluorescence in situ hybridization study.
Wang CL, Mei JH, Wang SS, Xu S, Xu LL, Xiong YF.
Zhonghua Bing Li Xue Za Zhi. 2010a Mar;39(3):156-60.
PMID 20450760
 
Expressions of Ki67, PCNA and mitotic index in ovarian epithelial tumors.
Wang S, Ma XY, Xia Y, Zhang LH.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2010b Jul;41(4):575-80.
PMID 20848772
 
Use of the Ki67 promoter to label cell cycle entry in living cells.
Zambon AC.
Cytometry A. 2010 Jun;77(6):564-70. doi: 10.1002/cyto.a.20890.
PMID 20235278
 
CD117, Ki-67, and p53 predict survival in neuroendocrine carcinomas, but not within the subgroup of small cell lung carcinoma.
Erler BS, Presby MM, Finch M, Hodges A, Horowitz K, Topilow AA, Matulewicz T.
Tumour Biol. 2011 Feb;32(1):107-11. doi: 10.1007/s13277-010-0104-y. Epub 2010 Nov 8.
PMID 21058037
 
Diagnostic implications of L1, p16, and Ki-67 proteins and HPV DNA in low-grade cervical intraepithelial neoplasia.
Gatta LB, Berenzi A, Balzarini P, Dessy E, Angiero F, Alessandri G, Gambino A, Grigolato P, Benetti A.
Int J Gynecol Pathol. 2011 Nov;30(6):597-604. doi: 10.1097/PGP.0b013e31821ac4fd.
PMID 21979598
 
MCM-2 and MCM-5 expression in gastric adenocarcinoma: clinical significance and comparison with Ki-67 proliferative marker.
Giaginis C, Giagini A, Tsourouflis G, Gatzidou E, Agapitos E, Kouraklis G, Theocharis S.
Dig Dis Sci. 2011 Mar;56(3):777-85. doi: 10.1007/s10620-010-1348-5. Epub 2010 Aug 6.
PMID 20694513
 
Correlation between loss of heterozygosity on chromosome 1p and 19q and expression of MGMT, p53 and Ki-67 proteins in gliomas.
Huang L, Jiang T, Yuan F, Li GL, Xu LX, Cui Y.
Zhonghua Zhong Liu Za Zhi. 2011 Oct;33(10):752-8.
PMID 22335907
 
Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis.
Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, Lee SH, Han W, Kim DW, Kim TY, Park IA, Noh DY, Heo DS, Bang YJ.
Breast Cancer Res. 2011 Mar 2;13(2):R22. doi: 10.1186/bcr2834.
PMID 21366896
 
Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification.
Mian C, Pennelli G, Barollo S, Cavedon E, Nacamulli D, Vianello F, Negro I, Pozza G, Boschin IM, Pelizzo MR, Rugge M, Mantero F, Girelli ME, Opocher G.
Eur J Endocrinol. 2011 Jun;164(6):971-6. doi: 10.1530/EJE-11-0079. Epub 2011 Mar 21.
PMID 21422198
 
Clinicopathologic study and immunohistochemistry comparison of Pax2, p53 and Ki-67 in low- and high-grade ovarian serous carcinomas.
Shen XX, Yu L, Bi R, Yang WT.
Zhonghua Bing Li Xue Za Zhi. 2011 Aug;40(8):511-6.
PMID 22169637
 
Endometrial carcinomas: correlation between ER, PR, Ki67 status and histopathological prognostic parameters.
Stoian SC, Simionescu C, Margaritescu C, Stepan A, Nurciu M.
Rom J Morphol Embryol. 2011;52(2):631-6.
PMID 21655654
 
Prognostic significance of Ki67 index after neoadjuvant chemotherapy in breast cancer.
Tanei T, Shimomura A, Shimazu K, Nakayama T, Kim SJ, Iwamoto T, Tamaki Y, Noguchi S.
Eur J Surg Oncol. 2011 Feb;37(2):155-61. doi: 10.1016/j.ejso.2010.10.009. Epub 2010 Dec 15.
PMID 21111561
 
The use of a combination of Ki-67, Galectin-3, and PTTG can distinguish the benign and malignant thyroid tumor.
Cui W, Lu X, Zheng S, Ma Y, Liu X, Zhang W.
Clin Lab. 2012;58(5-6):419-26.
PMID 22783570
 
Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors.
Dhall D, Mertens R, Bresee C, Parakh R, Wang HL, Li M, Dhall G, Colquhoun SD, Ines D, Chung F, Yu R, Nissen NN, Wolin E.
Hum Pathol. 2012 Apr;43(4):489-95. doi: 10.1016/j.humpath.2011.06.011. Epub 2011 Sep 19.
PMID 21937080
 
Vulvar intraepithelial neoplasia: a clinicopathologic study of twenty cases.
Ding XH, Hui YZ, Lu LJ, Yang ZC, Yao CJ, Sun LJ, Chen ZH, Shi Z.
Zhonghua Bing Li Xue Za Zhi. 2012 Jun;41(6):382-5. doi: 10.3760/cma.j.issn.0529-5807.2012.06.005.
PMID 22932405
 
Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas.
Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF.
Neuro Oncol. 2012 Jun;14(6):777-89. doi: 10.1093/neuonc/nos077. Epub 2012 Apr 5.
PMID 22492957
 
The use of an immunocytochemical double-labeling staining can display the distribution of Bcl-2/Ki-67 cells in endometrial adenocarcinomas as well as in normal endometrium.
Mourtzikou A, Kosmas K, Marouga A, Stamouli M, Pouliakis A, Karakitsos P.
Clin Lab. 2012;58(1-2):133-44.
PMID 22372356
 
Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors.
Panzuto F, Campana D, Fazio N, Brizzi MP, Boninsegna L, Nori F, Di Meglio G, Capurso G, Scarpa A, Dogliotti L, De Braud F, Tomassetti P, Delle Fave G, Falconi M.
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PMID 22205326
 
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Written05-2014Konstantinos Ntzeros, Philip Stanier, Dimitrios Mazis, Neoklis Kritikos, Meletios Rozis, Eustathios Anesidis, Chrisoula Antoniou, Michael Stamatakos
Astros Medical Center, Panarcadian General Hospital of Tripoli, Tripoli, Greece (KN); UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK (PS); REA Maternity Hospital, Athens, Greece (DM); Nursing Unit of Molaoi, General Hospital of Lakonia, Molaoi, Greece (NK, EA, MS); Surgery Department, General Hospital of Korinthos, Korinthos, Greece (MR); Obstetrics and Gynecology Department, General Hospital of Nikaia "St. Panteleimon", Piraeus, Greece (CA)

Citation

This paper should be referenced as such :
Ntzeros K, Stanier P, Mazis D, Kritikos N, Rozis M, Anesidis E, Antoniou C, Stamatakos M
MKI67 (marker of proliferation Ki-67);
Atlas Genet Cytogenet Oncol Haematol. May 2014
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URL : http://AtlasGeneticsOncology.org/Genes/MKI67ID41369ch10q26.html

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