Anna Lepistö

CTCF/cohesin-binding sites are frequently mutated in cancer

Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC-binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A•T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase ɛ (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome.

Cumulative failure rate of ileal pouch-anal anastomosis and quality of life after failure.

AbstractPURPOSE: The aim of the study was to calculate the cumulative occurrence of pouch failure among 486 patients who had undergone proctocolectomy and ileoanal anastomosis for ulcerative colitis or familial adenomatous polyposis. The other goal was to compare the quality of life in the failure group of 21 patients, the successful group, and the healthy population. METHODS: Data were collected from patient histories, with the probability of pouch failure being calculated by the Kaplan-Meier method. Patients with pouch failure and controls were sent a Short-Form 36-item quality-of-life questionnaire, and data were analyzed with paired t-test. RESULTS: The overall failure rate was 5.3 percent (26), including 24 pouch excisions and 2 early deaths (0.4 percent). Cumulative probabilities of pouch failure were 1, 5, and 7 percent at 1, 5, and 10 years, respectively. Neither pouchitis, gender, nor diagnosis correlated with pouch failure, but fistula formation (P < 0.001) did. Patients with failure had lower quality-of-life scores for physical function (P < 0.02), social function (P < 0.04), energy (P < 0.02), and physical role function (P < 0.03) than the healthy population. Scores for physical function (P < 0.01), energy (P < 0.01), and physical role function (P < 0.05) were also lower than those of control patients. CONCLUSIONS: The most common cause of pouch failure is fistula, whereas pouch excision is rarely caused by pouchitis. The impaired quality of life of patients in the failure group was caused by impairment of physical function and restrictions in social life.

Outcome of patients after endoluminal stent placement for benign colorectal obstruction

Abstract Objective. Self-expanding metal stents (SEMS) have been successfully used as a “bridge to surgery” or as palliation for acute malignant colorectal obstruction. Little data on the use of stents for benign obstruction exists and the results vary. The purpose of this study was to evaluate the efficacy and safety of SEMS in benign colorectal obstruction. Material and methods. A total of 21 patients with 23 SEMS procedures between the years 1998 and 2008 were retrospectively studied. Eight patients had an obstruction in the surgical anastomosis. In addition, there were two patients with anastomotic strictures due to Crohns disease. In 10 patients the obstruction was caused by diverticular disease and one patient had a stricture after radiation therapy. Results. Technical success was achieved for all the patients. Clinical success was achieved for 76% (16/21) of the patients. The anastomotic strictures were resolved with SEMS in 5 out of 8 cases (63%). Three patients with diverticular stricture (30%) were eventually resolved with SEMS. Nine (43%) patients in 10 out of 23 procedures (43%) had a complication, the majority being in patients with diverticular stricture. Conclusions. SEMS is a good treatment option for patients with anastomotic stricture of the colon and for patients with benign colonic stricture who are unfit for surgery. SEMS can be used as a bridge to surgery in diverticular obstruction but there seems to be a considerable risk of complications. If a SEMS is placed into a diverticular stricture, the planned bowel resection should be performed within a month.

Prevalence of primary sclerosing cholangitis in ulcerative colitis patients undergoing proctocolectomy and ileal pouch-anal anastomosis.

Background: This study aimed to determine the prevalence of primary sclerosing cholangitis (PSC) among patients with ulcerative colitis (UC) needing proctocolectomy. Methods: The study sample included 441 consecutive patients who underwent proctocolectomy with ileal pouch‐anal anastomosis from 1993 to 2004 at the Helsinki University Central Hospital. Liver biopsy samples were taken at operation. Patient groups with and without PSC were compared. Results: PSC was present in 52 (11.8%) patients. Only 19 of these had been diagnosed before surgery; 40 patients with PSC were detected by liver biopsy at the operation, making the sensitivity of perioperative liver biopsy to diagnose PSC 83.3%. The cumulative incidence of colorectal dysplasia or cancer in the UC patients with PSC (19% after 10 years and 43% after 20 years) was not significantly different than that of UC patients without PSC (24% after 10 years and 39% after 20 years). Pouchitis occurred more often in patients with PSC (25 of 52; 48.1% versus 101 of 389, 26.0%; P = 0.001). The failure rate of ileal pouch–anal anastomosis did not significantly differ between the 2 groups. Conclusions: The prevalence of PSC among patients with UC needing proctocolectomy was higher than in patients with UC in general. Liver biopsy can be recommended as a safe adjunct at proctocolectomy for surveillance of any liver effects.

Survival of patients with pseudomyxoma peritonei treated by serial debulking.

Aim  We evaluated the outcome of patients with pseudomyxoma peritonei (PMP) after traditional debulking. PMP is a clinical condition characterized by disseminated intraperitoneal mucinous tumours often accompanied by mucinous ascites derived usually from an appendiceal neoplasm. Patients with PMP have traditionally been treated by serial debulking, but aggressive cytoreduction followed by hyperthermic intraperitoneal chemotherapy is now advocated as standard treatment in PMP.

durability of Kock Continent Ileostomy

AbstractPURPOSE: The purpose of this study was to determine the cumulative success rate of Kock continent ileostomy and the reasons leading to excision and to compare the results with pelvic pouch and ileal pouch-anal anastomosis. METHODS: The data were collected from the histories of 96 patients, who underwent a Kock continent ileostomy operation from 1972 to 2000 at Helsinki University Central Hospital. The failure rate was calculated by the Kaplan-Meier method. RESULTS: Overall, the continent ileostomy was converted to conventional stoma in 21 patients (24 percent). The cumulative success rate was 96 percent at 1 year, 86 percent at 10 years, 77 percent at 15 years, and 71 percent at 29 years. The most common reason for pouch excision was partial or total nipple-valve sliding. Eighty-five re-reconstructions were performed among 57 patients (59 percent), the most common indication being nipple-valve dysfunction. Of these patients, 14 later ended up with pouch excision. The success rate of continent ileostomy was significantly lower than that of ileoanal anastomosis (P < 0.01). CONCLUSION: The durability of continent ileostomy is mainly related to the mechanism of the nipple valve and not to ileitis or other systemic effects of the basic disease. Kock continent ileostomy can offer satisfactory long-term function in more than two-thirds of patients up to 30 years.

Genomic profile of pseudomyxoma peritonei analyzed using next‐generation sequencing and immunohistochemistry

Pseudomyxoma peritonei (PMP) is a relatively rare clinical syndrome characterized by neoplastic epithelial cells growing in the peritoneal cavity and secreting mucinous ascites. Our aim was to explore the molecular events behind this fatal but under‐investigated disease. We extracted DNA from 19 appendix‐derived PMP tumors and nine corresponding normal tissues, and analyzed the mutational hotspot areas of 48 cancer‐related genes by amplicon‐based next‐generation sequencing (NGS). Further, we analyzed the protein expression of V600E mutated BRAF, MLH1, MSH2, MSH6 and p53 from a larger set of PMP tumors (n = 74) using immunohistochemistry. With NGS, we detected activating somatic KRAS mutations in all of the tumors studied. GNAS was mutated in 63% of the tumors with no marked difference between low‐grade and high‐grade tumors. Only one (5.3%) tumor showed oncogenic PIK3CA mutation, one showed oncogenic AKT1 mutation, three (15.8%) showed SMAD4 mutations and none showed an APC mutation. P53 protein was aberrantly expressed in higher proportion of high‐grade tumors as compared with low‐grade ones (31.3 vs. 7.1%, respectively; p = 0.012) and aberrant expression was an independent factor for reduced overall survival (p = 0.002). BRAF V600E mutation was only found in one (1.4%) high‐grade tumor by immunohistochemistry (n = 74). All the studied tumors expressed mismatch repair proteins MLH1, MSH2 and MSH6. Our results indicate that KRAS mutations are evident in all and GNAS mutations in most of the PMPs, but BRAF V600E, PIK3CA and APC mutations are rare. Aberrantly expressed p53 is associated with high‐grade histology and reduced survival.

Risk of cancer in patients with chronic pouchitis after restorative proctocolectomy for ulcerative colitis

Aim  The aim of this study was to evaluate the consequences of chronic pouchitis after restorative proctocolectomy for ulcerative colitis.

Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Background:Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC.Methods:We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls.Results:In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02–1.49, P=0.033), 1.59 (95% CI: 1.08–2.34, P=0.019) and 1.07 (95% CI: 1.03–1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89–1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10–1.44, P=7.7 × 10−4) and 1.40 (95% CI: 1.14–1.72, P=1.2 × 10−3), respectively.Conclusions:These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

Gastric outlet obstruction in gastric cancer: a comparison of three palliative methods.

Gastric outlet obstruction (GOO) commonly occurs in advanced gastric cancer. Our aim was to evaluate the results of endoscopic stenting (ES), palliative resection (PR), and gastrojejunostomy (GJ) as palliation of GOO.