Clinical study of guided bone regeneration with resorbable polylactide-co-glycolide acid membrane.

The guided bone regeneration (GBR) technique is often applied to provide sufficient bone for ideal implant placement. The objective of this study was to evaluate whether GC membrane®, which has already been used for guided tissue regeneration (GTR), can also be available for GBR. Twenty-three implants in 18 patients were evaluated in the study. All patients underwent implant placement with GBR using GC membrane®. Cone-beam computed tomography was performed at 13-30 weeks after surgery and the amount of augmented bone was assessed. The implant stability quotient (ISQ) was measured at the second operation to evaluate implant stability. Although wound dehiscence was observed at 4 of 23 regions (17.4%), all wounds closed quickly without any events by additional antibiotic administration. GBR-induced bone augmentation of 0.70-2.56 mm horizontally and 0-6.82 mm vertically. Only 0.18 mm of bone recession was observed at 16-24 months after implant placement. GBR with GC membrane® induced sufficient bone augmentation, leading to successful implant treatment. The present results suggest that GC membrane® is available not only for GTR, but also for GBR.

Soft tissue changes after a mandibular osteotomy for symmetric skeletal class III malocclusion.

The soft tissue profile is crucial to esthetics after orthognathic surgery. The aim of this study was to assess the soft tissue changes of the subnasal and submental regions more than 1 year after a sagittal split ramus osteotomy (SSRO) in patients with skeletal class III malocclusion. A total of 22 patients with mandibular prognathism were included in this study. Patients had lateral cephalograms before and more than 1 year after they underwent an isolated SSRO. Soft and hard tissue changes were assessed using the lateral cephalograms. The lower lip, labiomenton, and soft tissue menton moved posteriorly by 85, 89, and 88% compared with the corresponding hard tissue, and the movement of the soft tissue B point and the top of the chin nearly reflected the displacement of the hard tissues, at 96 and 99%, respectively. The labiomenton, stomions, and naso-labial angles were changed after the mandibular set-back and the changes in these angles correlated with either the width of the soft tissue or skeletal displacement. The naso-labial angle could be altered even if an isolated mandibular osteotomy is performed. Changes to the stomions and naso-labial angles were affected by hard tissue movement, while changes to the labiomental angle were affected by the width of the soft tissue after the mandibular osteotomy. It is important to create an accurate preoperative prediction of the esthetic outcomes after a mandibular osteotomy by considering the interrelations between the hard and soft tissues.

A Patient With Aspiration Pneumonia After Mandibular Osteotomy With Genioplasty.

Orthognathic surgery including maxillary osteotomy, mandibular osteotomy, and genioplasty is a reliable treatment strategy for jaw deformity. However, there are some complications associated with these surgeries, including neurovascular damage and abnormal bleeding. The authors present here a patient of aspiration pneumonia after mandibular osteotomy.An 18-year-old female patient underwent sagittal split ramus osteotomy and genioplasty for mandibular prognathism. She began choking and coughing immediately after surgery. She was diagnosed with aspiration pneumonia based on chest radiography and computed tomography findings. Her hyoid bone was shifted 23 mm inferiorly after surgery, and this movement may have caused swallowing dysfunction. She was treated with intravenous antibiotics and discharged on the 18th postoperative day.Although the hyoid bone is transiently shifted inferiorly by mandibular setback with or without genioplasty, this shift does not usually affect swallowing function. Damage to the suprahyoid muscles during genioplasty may cause both an inferior shift and dysmobility of the hyoid bone. Therefore, surgeons must be careful not to damage the suprahyoid muscles at the lingual site osteotomy in genioplasty to avoid this complication.

Bimaxillary Osteotomy for Jaw Deformity With Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a subtype of muscular dystrophies which reduces the muscle strength, especially the regions of scapular, shoulder, and upper arms, progressively. According to progressive muscle weakness in FSHD, postoperative stability of patient with FSHD after orthognathic surgery is not reliably acquired same as healthy subjects. A 32-year-old woman with FSHD underwent orthodontic and orthognathic surgical treatment due to jaw deformity. She has been followed up more than 3 years after surgery and acquired skeletal stability. This patient is the first report that showed long-term skeletal stability after orthognathic surgery in patient with FSHD. This patient report suggests that it is possible to apply orthognathic surgical treatment to patients with FSHD.

Effects of Vertical Movement of the Anterior Nasal Spine on the Maxillary Stability After LeFort I Osteotomy for Pitch Correction.

Few reports have so far evaluated the maxillary stability after LeFort I osteotomy (L-1) for pitch correction. In the current study, the authors assessed the SN-PP (palatal plane) to evaluate the skeletal stability after osteotomy with clockwise or counter-clockwise rotation and investigated the effects of anterior nasal spine (ANS) and posterior nasal spine (PNS) movement on the stability of the SN-PP.The SN-PP and the positions of ANS, PNS, and point A were measured on lateral cephalograms before surgery (T1), immediately after surgery (T2), and more than 1 year after surgery (T3).All measured angle and points were stable in 4 cases of counter-clockwise rotation. In the 16 cases of clockwise rotation, T3-T2 of SN-PP, ANS, and point A was -2.05°, -2.56 mm, and -1.64 mm, when the SN-PP increased more than 4° after osteotomy. When the ANS moved downward more than 3 mm, the ANS and point A relapsed significantly by 2.75 and 2.31 mm, while the SN-PP relapsed 1.61° more than 1 year after surgery.When the SN-PP increased by more than 4° or the ANS moved downward by more than 3 mm, the authors suggest shifting the PNS upward instead of moving the ANS downward.

Oral Rehabilitation With Orthognathic Surgery After Dental Implant Placement for Class III Malocclusion With Skeletal Asymmetry and Posterior Bite Collapse.

Increasing numbers of older patients are seeking orthognathic surgery to treat jaw deformity. However, orthodontic and orthognathic surgical treatment is difficult in cases without occlusal vertical stop. A 55-year-old man presented with Class III malocclusion and mandibular protrusion including esthetic problems and posterior bite collapse. He underwent dental implant treatment to reconstruct an occlusal vertical stop before orthognathic surgery. His occlusal function and esthetic problems improved after surgery, and his skeletal and occlusal stability has been maintained for 6 years. Dental implant placement at appropriate positions could help to determine the position of the proximal segment at orthognathic surgery and could shorten the time required to restore esthetic and occlusal function. This case demonstrates how skeletal and dental stability can be maintained long after surgery in a patient with jaw deformity and posterior bite collapse.

The three-dimensional assessment of dynamic changes of the proximal segments after intraoral vertical ramus osteotomy.

OBJECTIVES: The aim of this study was to assess the positional changes of the proximal segments after intraoral vertical ramus osteotomy (IVRO). METHOD: Fifteen patients underwent IVRO and were followed according to the authors' unique postoperative management regimen. The analyses of the positions and angles of the proximal segments were performed on frontal and lateral cephalograms, which were taken before surgery (T1) and within 3 days (T2), at 4 weeks (T3), and later than 6 months after surgery (T4). The three-dimensional positions of the condylar heads were also assessed by CT images, which were taken before and 1 year after surgery. RESULTS: The proximal segments temporarily swung posteriorly and laterally with a center on the condylar head as a fulcrum point at T2 and T3, compared with T1, and they repositioned at T4. The condylar heads moved inferior approximately 2 mm with lateral rotation one year after surgery, as seen in the CT. DISCUSSION: The condylar heads changed their positions physiologically for newly established jaw movement after IVRO with the authors' post-operative management regimen because the post-operative skeletal stability and the jaw function were good and stable using this method.

A patient with severe maxillary gingival exposure treated with combined compression osteogenesis of the anterior alveolar bone and conventional Le Fort I osteotomy.

Excessive gingival exposure at the maxillary anterior region during not only smiling (a gummy face) but also at rest creates both functional and aesthetic problems for patients. We herein introduce a unique treatment procedure for mandibular retrognathia with a gummy face. This procedure combines conventional Le Fort I osteotomy and following corticotomy at the anterior region of the maxilla. Subsequently, the anterior segment is continuously compressed (compression osteogenesis) in a posterior-superior direction until it reaches an ideal position. This procedure appears to safely and adequately resolve both the aesthetic and functional complaints associated with patients with a gummy face.

[A review of toxicity superselective intra-arterial concurrent chemoradiotherapy(SIACC)for oral cancer].

Superselective intra-arterial concurrent chemoradiotherapy(SIACC)for oral cancer has been favored for its efficacy and ability to not damage organs. SIACC was applied to 13 previously untreated patients with oral cancer for the purpose of avoiding surgical resection of the primary tumor in our hospital from 2007 to 2009. Although a complete response of the primary tumor was achieved in all cases, various adverse events also occurred. All patients experienced leucopenia, and most patients suffered from mucotitis and dry mouth. One patient had dizziness and nausea due to the catheter insertion into the vertebra artery. Although SIACC is an important treatment strategy for oral cancer, careful attention for adverse events should be taken into account during and after treatment.

Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer.

BACKGROUND AND AIMS: Although critical for methylation reactions, how dietary folate and B vitamins affect global DNA methylation level in colorectal cancers is currently unknown. Long interspersed nucleotide element-1 (LINE-1) is an emerging indicator of genome-wide DNA methylation level that has previously been linked to colon cancer survival. METHODS: We examined the association between dietary intake of folate, alcohol and B vitamins and LINE-1 hypomethylation in 609 incident colon cancers, utilising the database of two independent prospective cohort studies. RESULTS: Participants with > or = 400 microg folate intake per day were significantly less likely to develop LINE-1 hypomethylated colon cancers than those reporting <200 microg of folate intake per day (RR=0.57, 95% CI=0.36 to 0.91 for <55% LINE-1 methylated colon tumours; RR=0.74, 95% CI=0.51 to 1.06 for 55-64% LINE-1 methylated colon tumours; and RR=1.08, 95% CI=0.66 to 1.75 for > or = 65% LINE-1 methylated tumours; P(interaction)=0.01). By contrast, high alcohol consumption conferred a higher risk of LINE-1 hypomethylated cancers (> or = 15 g alcohol per day versus none, RR=1.67, 95% CI=1.04 to 2.67 for <55% LINE1 methylated tumours; and RR=1.55, 95% CI=1.10 to 2.18 for 55-64% LINE-1 methylated tumours) but had no association with > or = 65% LINE-1 methylated tumours (RR=1.06, 95% CI=0.69 to 1.62). High intakes of vitamin B(6), B(12) or methionine were not significantly associated with colon cancers, regardless of LINE-1 methylation level. CONCLUSION: The influence of dietary folate intake and alcohol consumption on colon cancer risk differs significantly according to tumoral LINE-1 methylation level.

Germline polymorphisms in the one-carbon metabolism pathway and DNA methylation in colorectal cancer.

Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (> or = 6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32-43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02-14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/ Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer.

CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer.

BACKGROUND: The CpG island methylator phenotype (CIMP), characterised by widespread promoter methylation, is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on prognosis remains uncertain. METHODS: Utilising 649 colon cancers (stage I-IV) in two independent cohort studies, we quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) as well as CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN by using MethyLight technology. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features. RESULTS: After adjustment for other predictors of patient survival, patients with CIMP-high cancers (126 (19%) tumours with >or=6/8 methylated CIMP-specific promoters) experienced a significantly low colon cancer-specific mortality (multivariate HR 0.44, 95% confidence interval (CI) 0.22 to 0.88), whereas the BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI 1.13 to 3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumours (multivariate HR 0.70, 95% CI 0.36 to 1.37). In stratified analyses, CIMP-high tumours were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to prognostic significance. CONCLUSION: CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.

Flower color mutation caused by spontaneous cell layer displacement in carnation (Dianthus caryophyllus).

A change of layer arrangement of shoot apical meristem (SAM) organized by three cell layers (L1, L2 and L3) is thought to be one of the provocations of bud sport, which often induces changes in phenotypic colors in periclinal chimeras. This paper describes a cell layer rearrangement which is the cause of spontaneous flower color mutation by using two carnation (Dianthus caryophyllus L.) cultivars that are presumably periclinal chimeras, 'Feminine Minami' (deep pink flower) and its recessive sport 'Tommy Minami' (pinkish red flower). The genotype of the acyl-glucose-dependent anthocyanin 5-glucosyltransferase (AA5GT) which is responsible for the color change of red to pink, in each cell layer was deduced by genomic analysis using tissues originated from specific cell layer and investigation of partial petal color mutations. In the results, the genotype of the L1 of 'Feminine Minami' was heterozygous for functional AA5GT and non-functional AA5GT carrying retrotransposon Ty1dic1 (AA5GT-Ty1dic1), and its inner cell layer hid red flower genotype, whereas AA5GT-Ty1dic1 of the L1 of 'Tommy Minami' became homogenic in absence of the insertion of a new Ty1dic1. Our outcomes concluded that the L1 of 'Tommy Minami' harboring the recessive AA5GT alleles are attributed to the inner cell layer of 'Feminine Minami' possessing red flower genotype.

LINE-1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer.

The CpG island methylator phenotype (CIMP) with widespread promoter CpG island methylation is a phenotype in colorectal cancer, associated with microsatellite instability (MSI) and BRAF mutation. Genome-wide hypomethylation may also play an important role in genomic instability. However, the relation between global DNA methylation level and methylation in individual CpG islands remains uncertain. Utilizing 869 population-based colorectal cancers, we measured long interspersed nucleotide element-1 (LINE-1) methylation level by Pyrosequencing, which correlates with global DNA methylation level. We quantified DNA methylation in 8 CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) by real-time PCR (MethyLight technology). LINE-1 methylation levels in tumors were approximately normally distributed (mean, 61.4%; median, 62.3%; standard deviation, 9.6%). Among the 869 tumors, 128 (15%) were classified as CIMP-high (>or=6/8 methylated promoters). The mean LINE-1 methylation level was higher in CIMP-high tumors (65.1%, p < 0.0001) than non-CIMP-high tumors (60.7%), and higher in MSI-high tumors (64.7%, p < 0.0001) than non-MSI-high tumors (60.7%). When tumors were stratified by MSI/CIMP status, compared to non-MSI-high non-CIMP-high tumors (mean LINE-1 methylation level, 60.4%), the mean LINE-1 methylation level was higher in MSI-high CIMP-high (64.8%, p < 0.0001), MSI-high non-CIMP-high (64.6%, p = 0.03) and non-MSI-high CIMP-high tumors (66.1%, p = 0.0003). In addition, 18q loss of heterozygosity in non-MSI-high tumors was correlated with LINE-1 hypomethylation (p = 0.004). In conclusion, both CIMP-high and MSI-high are inversely associated with LINE-1 hypomethylation, suggesting that CIMP/MSI and genomic hypomethylation may represent different pathways to colorectal cancer. Our data also support a possible link between global hypomethylation and chromosomal instability.

Cyclooxygenase-2 overexpression is common in serrated and non-serrated colorectal adenoma, but uncommon in hyperplastic polyp and sessile serrated polyp/adenoma.

BACKGROUND: Cyclooxygenase-2 (COX-2, PTGS2) plays an important role in colorectal carcinogenesis. COX-2 overexpression in colorectal cancer is inversely associated with microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). Evidence suggests that MSI/CIMP+ colorectal cancer may arise through the serrated tumorigenic pathway through various forms of serrated neoplasias. Therefore, we hypothesized that COX-2 may play a less important role in the serrated pathway. METHODS: By immunohistochemistry, we assessed COX-2 expression in 24 hyperplastic polyps, 7 sessile serrated polyp/adenomas (SSA), 5 mixed polyps with SSA and adenoma, 27 traditional serrated adenomas, 515 non-serrated adenomas (tubular adenoma, tubulovillous adenoma and villous adenoma), 33 adenomas with intramucosal carcinomas, 96 adenocarcinomas with serration (corkscrew gland) and 111 adenocarcinomas without serration. RESULTS: Strong (2+) COX-2 overexpression was more common in non-serrated adenomas (28% = 143/515) than in hyperplastic polyps (4.2% = 1/24, p = 0.008) and serrated polyps (7 SSAs and 5 mixed polyps) (0% = 0/12, p = 0.04). Furthermore, any (1+/2+) COX-2 overexpression was more frequent in non-serrated adenomas (60% = 307/515) than in hyperplastic polyps (13% = 3/24, p < 0.0001) and serrated polyps (SSAs and mixed polyps) (25% = 3/12, p = 0.03). Traditional serrated adenomas and non-serrated adenomas showed similar frequencies of COX-2 overexpression. Regardless of serration, COX-2 overexpression was frequent (approximately 85%) in colorectal adenocarcinomas. Tumor location was not significantly correlated with COX-2 overexpression, although there was a trend towards higher frequencies of COX-2 overexpression in distal tumors (than proximal tumors) among hyperplastic polyps, SSAs, mixed polyps, traditional serrated adenomas and adenocarcinomas. CONCLUSION: COX-2 overexpression is infrequent in hyperplastic polyp, SSA and mixed polyp with SSA and adenoma, compared to non-serrated and serrated adenoma. COX-2 overexpression becomes more frequent as tumors progress to higher grade neoplasias. Our observations suggest that COX-2 may play a less significant role in the serrated pathway of tumorigenesis; however, COX-2 may still play a role in later stage of the serrated pathway.

Molecular correlates with MGMT promoter methylation and silencing support CpG island methylator phenotype-low (CIMP-low) in colorectal cancer.

BACKGROUND: The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct epigenetic phenotype in colorectal cancer. In contrast, a phenotype with less widespread promoter methylation (CIMP-low) has not been well characterised. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and silencing have been associated with G>A mutations and microsatellite instability-low (MSI-low). AIM: To examine molecular correlates with MGMT methylation/silencing in colorectal cancer. METHODS: Utilising MethyLight technology, we quantified DNA methylation in MGMT and eight other markers (a CIMP-diagnostic panel; CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) in 920 population-based colorectal cancers. RESULTS: Tumours with both MGMT methylation and loss were correlated positively with MSI-low (p = 0.02), CIMP-high (>or=6/8 methylated CIMP markers, p = 0.005), CIMP-low (1/8-5/8 methylated CIMP markers, p = 0.002, compared to CIMP-0 with 0/8 methylated markers), KRAS G>A mutation (p = 0.02), and inversely with 18q loss of heterozygosity (p = 0.0002). Tumours were classified into nine MSI/CIMP subtypes. Among the CIMP-low group, tumours with both MGMT methylation and loss were far more frequent in MSI-low tumours (67%, 12/18) than MSI-high tumours (5.6%, 1/18; p = 0.0003) and microsatellite stable (MSS) tumours (33%, 52/160; p = 0.008). However, no such relationship was observed among the CIMP-high or CIMP-0 groups. CONCLUSION: The relationship between MGMT methylation/silencing and MSI-low is limited to only CIMP-low tumours, supporting the suggestion that CIMP-low in colorectal cancer may be a different molecular phenotype from CIMP-high and CIMP-0. Our data support a molecular difference between MSI-low and MSS in colorectal cancer, and a possible link between CIMP-low, MSI-low, MGMT methylation/loss and KRAS mutation.

Physiological positioning strategy alters condylar position after mandibular ramus sagittal split osteotomies for mandibular prognathism.

OBJECTIVE: The aim of this study was to elucidate the physiological position of the proximal segment for postoperative jaw movement in patients with mandibular prognathism. METHODS: Twenty-two patients with mandibular prognathism were treated by orthognathic surgery using bilateral mandibular sagittal split ramus osteotomies (SSRO) with a physiological positioning strategy. The skeletal stability was assessed, and the movement of the proximal segment was evaluated by cephalography and computed tomography performed preoperatively, immediately postoperatively, and one year postoperatively. RESULTS: The patients were divided into two groups: the stable group (SNB relapse <1.5°) and the relapse group (SNB relapse ≥1.5°). In the stable group at one year postoperatively, the average SNB relapse was only 0.29° (7%), the condylar head had moved posteriorly by 0.75 mm, and the proximal segment had rotated counterclockwise by 1.2°. CONCLUSION: This new physiological positioning strategy improves the position of the condyle compared with the preoperative position in patients with mandibular prognathism.

Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample.

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by an independent, large dataset. Using MethyLight assays on 920 colorectal cancers from two large prospective cohort studies, we quantified DNA methylation in eight CIMP-specific markers [the above five plus CDKN2A (p16), CRABP1, and MLH1]. A CIMP-high cutoff was set at > or = 6/8 or > or = 5/8 methylated promoters, based on tumor distribution and BRAF/KRAS mutation frequencies. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated > or = 85% sensitivity and > or = 80% specificity, indicating overall good concordance in methylation patterns and good performance of these markers. Based on sensitivity, specificity, and false positives and negatives, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1, and CDKN2A. In conclusion, a panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP-high.

Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype.

Cytoplasmic mislocalization of p27 (CDKN1B/KIP1) is caused by activated AKT1 and has been associated with poor prognosis in various cancers. CIMP in colorectal cancer is characterized by extensive promoter methylation and is associated with MSI-MSI-H and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in 8 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) in 853 colorectal cancer samples obtained from 2 large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 (P < .0001), CIMP-high (P < .0001), MSI-H (P < .0001), and BRAF mutations (P < .0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS/BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.