Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis.

Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC-associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K-ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors.

Expression of activation-induced cytidine deaminase in ulcerative colitis-associated carcinogenesis.

AIMS: Activation-induced cytidine deaminase (AID) is a DNA/RNA-editing enzyme that is essential for hypermutation and class-switch recombination in immunoglobulin genes. The aim of this study was to investigate the expression of AID and its association with p53 mutation in ulcerative colitis (UC)-associated carcinogenesis. METHODS AND RESULTS: The expression of AID was examined in 25 patients with UC-associated neoplasia, 20 UC patients without neoplasia, 18 patients with non-inflamed colorectal mucosa unaffected by UC, and 19 patients with sporadic colorectal cancer, by immunohistochemistry and quantitative reverse transcription polymerase chain reaction analysis. Mutational analysis and immunohistochemistry for p53 were also performed. The degree of AID expression was not different between UC-associated neoplasia and sporadic colorectal cancer. However, AID was expressed in both UC-associated neoplasia and UC without neoplasia. Whereas AID expression in UC-associated neoplasia was not correlated with the grade of dysplasia, expression in non-neoplastic mucosa of UC was correlated with the histological grade of inflammation. In UC-associated neoplasia, there was no significant correlation between AID expression and p53 mutation. CONCLUSIONS: AID is associated with inflammation in UC, whereas it may not specifically contribute to carcinogenesis in UC.

Sessile serrated adenoma with early neoplastic progression: a clinicopathologic and molecular study.

Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, ß-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high-grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of ß-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear ß-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and ß-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma.

Mucin core protein expression in serrated polyps of the large intestine.

Sessile serrated adenoma (SSA) has been proposed as a precursor to microsatellite-unstable colorectal carcinoma. However, histological criteria dictating how to differentiate serrated lesions have not been completely established, and a histological overlap exists between SSA and hyperplastic polyps (HPs), particularly the microvesicular type. In this study, based on a critical review of histology, we aimed to elucidate the potential utility of the mucin phenotype in the identification of SSA. We evaluated mucin core protein expression (MUC2, MUC5AC, and MUC6) by immunohistochemical stain in 65 cases of microvesicular-type HPs, 51 SSAs, and 72 traditional serrated adenomas (TSAs). SSAs had clinicopathological and morphological features distinct from those of HPs and TSAs. MUC6 was more frequently positive in SSAs (39%) than in TSAs (4%) and HPs (19%) (P < 0.001 and P = 0.0107, respectively). Right-sided HPs more frequently expressed MUC6 than did left-sided HPs (60% vs. 4%, respectively; P < 0.0001), but SSAs and TSAs showed no regional differences. These findings suggest that determination of mucin core protein expression is insufficient for differentiating SSAs from other types of serrated polyps, and that microvesicular-type HPs of the right colon and SSAs may belong to the same mucin spectrum.

Altered expression of MUTYH and an increase in 8-hydroxydeoxyguanosine are early events in ulcerative colitis-associated carcinogenesis.

8-Hydroxy-guanine (8-OH-G) mismatches readily with adenine residues, leading to a G : C to T : A transversion mutation. The human mutY homologue (MUTYH) excises adenine misincorporated opposite 8-OH-G during replication and suppresses mutations caused by reactive oxygen species. We defined the expression of 8-hydroxydeoxyguanosine (8-OHdG) and MUTYH in ulcerative colitis (UC)-associated neoplasia by immunohistochemistry and compared this with expression in UC patients without neoplasia and patients unaffected by UC. We also performed mutation analyses for MUTYH and K-ras. 8-OHdG was expressed more intensely in the mucosa of UC-associated neoplasia and UC without neoplasm than in the mucosa unaffected by UC. Immunohistochemistry with two different types of MUTYH antibody showed that UC-associated neoplasia and UC without neoplasia exhibited strong cytoplasmic expression and attenuated nuclear expression of MUTYH when compared with patients unaffected by UC. No pathological MUTYH mutations were detected in any of the UC-associated neoplasia cases. However, K-ras mutation was detected in two cases, one of which showed G : C to T : A transversion mutation and attenuated nuclear staining of MUTYH. In conclusion, inflamed mucosa of UC is exposed to oxidative damage. An increase in cytoplasmic MUTYH, rather than its mutation, may contribute to the promotion of carcinogenesis in UC.

Linear mucosal defect may be characteristic of lansoprazole-associated collagenous colitis.

BACKGROUND: Although some cases of collagenous colitis have been induced by lansoprazole (LPZ), the clinicopathologic features of LPZ-associated collagenous colitis have not been elucidated. OBJECTIVE: To elucidate the clinical, endoscopic, and histopathologic features of LPZ-associated collagenous colitis. DESIGN: Retrospective case study. PATIENTS: The subjects were 13 patients with collagenous colitis diagnosed during a period from 2002 to 2007. MAIN OUTCOME MEASUREMENTS: The colonoscopic and histopathologic findings were compared retrospectively between 9 cases of LPZ use (LPZ group) and 4 cases without the use of LPZ (non-LPZ group). RESULTS: A colonoscopy revealed a linear mucosal defect more frequently in the LPZ group (7 of 9 cases [78%]) than in the non-LPZ group (0 of 4 cases [0%], P = .02). Friable mucosa was also noted in 4 patients (44%) in the LPZ group but none in the non-LPZ group. The colonoscopic finding in the non-LPZ group was either normal mucosa or nonspecific minimal abnormalities, whereas patients in the LPZ group had either a linear mucosal defect, mucosal bleeding, or both (P = .001). On histologic examination, the subepithelial collagen band was thicker in patients in the LPZ group than in those in the non-LPZ group (median 45 vs 26.3 mum). All patients in the LPZ group recovered from diarrhea after discontinuance of LPZ. LIMITATION: A small number of patients. CONCLUSIONS: Linear mucosal defects and friable mucosa may be characteristic colonoscopic findings in cases of LPZ-associated collagenous colitis.

GRAFT infection of thoracic aorta due to group C beta-hemolytic streptococcus--a case report.

A fatal case of late-onset graft infection of the thoracic aorta due to group C beta-hemolytic streptococcus is described. A 37-year-old male patient, who had a history of total aortic arch replacement for acute aortic dissection 8 years before, was admitted to the department. He suffered from toxic shock syndrome, disseminated intravascular coagulation (DIC), and acute renal failure. Group C beta-hemolytic streptococcus was detected from his blood; however, echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) failed to detect the focus of the infection. In spite of intensive care, including antibiotic therapy, artificial ventilation, and continuous hemodiafiltration, he died on the 18th day of hospitalization. Autopsy revealed that a small abscess was present at the proximal anastomotic segments of the patient's graft. A bite inflicted by his dog, 14 days before admission, was suspected to be the source of this bacterium. A rare case of graft infection of thoracic aorta in terms of causative organism, long period from graft replacement to graft infection, and site of infection is presented and discussed.