High cyclin B1 expression is associated with poor survival in breast cancer.

Cyclin B1 regulates the G(2)-M transition of the cell cycle. Cyclin B1 expression is higher in premalignant and malignant than normal breast lesions. Correlation of cyclin B1 expression with other histopathological variables and prognostic role in breast cancer are not fully understood. Traditionally used prognostic criteria identify large subset of patients to receive adjuvant chemotherapy and to be exposed to adverse effects. A reliable and simple method helping prognostic evaluation in breast cancer is needed. We analysed cyclin B1 expression on 1348 invasive breast cancers and studied correlations with other histopathological variables and survival. High cyclin B1 correlated with high tumour grade, large tumour size and positive nodal status, oestrogen and progesterone receptor negativity, positive HER2 and p53 status, young age at diagnosis, and high cyclin E, cyclin A and Ki67 expression. Among patients not given adjuvant chemotherapy high cyclin B1 was a strong predictor of shorter overall and metastasis-free survival (RR 3.74, P<0.0005 and RR 3.51, P<0.0005, respectively), and remained as an independent prognostic factor also in multivariate analysis (RR 1.80, P=0.04 and RR 2.31, P=0.02, respectively). This study suggests high cyclin B1 associates with aggressive phenotype and is an independent prognostic factor in breast cancer.

No MSH6 germline mutations in breast cancer families with colorectal and/or endometrial cancer.

BACKGROUND: The genetic background in breast cancer families with colorectal and/or endometrial cancer is mostly unknown. The functional connection between MSH6 and the known breast cancer predisposition gene product BRCA1 suggests that the MSH6 gene may also play a role in breast cancer predisposition. METHODS: We analysed 38 breast cancer families with colorectal and/or endometrial cancer for germline mutations in MSH6. RESULTS: No disease associated mutations were detected among the breast cancer families. However, mutation analysis revealed a Glu995STOP mutation in an atypical HNPCC family. The same mutation was found in a patient with both breast and colorectal carcinoma in our previous study, and haplotype analysis confirmed a common ancestral origin. The Glu995STOP mutation was further examined in an extensive series of 245 colorectal and 142 breast carcinoma patients with a family history of breast, colorectal, and/or endometrial carcinoma, and in 268 healthy population controls, but none was found to carry the mutation. CONCLUSIONS: Our results suggest that MSH6 may not be the underlying gene in breast cancer families with a history of colorectal and/or endometrial cancer. The Glu995STOP founder mutation is not a familial breast cancer predisposition allele and makes only a limited contribution to colorectal cancer burden in Finland.

p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.

Germ-line mutations in the p53 gene predispose individuals to Li-Fraumeni syndrome (LFS). The cell cycle checkpoint kinases CHK1 and CHK2 act upstream of p53 in DNA damage responses, and recently rare germ-line mutations in CHK2 were reported in LFS families. We have analyzed CHK1, CHK2, and p53 genes for mutations in 44 Finnish families with LFS, Li-Fraumeni-like syndrome, or families phenotypically suggestive of LFS with conformation-sensitive gel electrophoresis. Five different disease-causing mutations were observed in 7 families (7 of 44 families; 15.9%): 4 in the p53 gene (5 of 44 families; 11.4%) and 1 in the CHK2 gene (2 of 44 families; 4.5%). Interestingly, the other CHK2-mutation carrier also has a mutation in the MSH6 gene. The cancer phenotype in the CHK2-families was not characteristic of LFS, and may indicate variable phenotypic expression in the rare families with CHK2 mutations. No mutations in the CHK1 gene were identified. Additional work is necessary to completely unravel the molecular background of LFS.

BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients.

Germline mutations of BRCA1 and BRCA2 predispose to hereditary breast-ovarian cancer syndrome. In Finland, 20 different BRCA1/2 mutations have been identified, and 13 of them are founder mutations that account for the vast majority of Finnish BRCA1/2 families. The purpose of our study was to determine the prevalence of BRCA1/2 mutations in unselected Finnish ovarian carcinoma patients and to evaluate the relationship between mutation carrier status and personal/family history of cancer. Two hundred and thirty-three patients were screened for all the 20 BRCA1/2 mutations known in the Finnish population. Additionally, a subgroup of patients with personal history of breast cancer and/or family history of breast and/or ovarian cancer was screened for novel BRCA1/2 mutations. Thirteen patients (5.6%) had mutations: eleven in BRCA1 and two in BRCA2. All the mutation-positive patients were carriers of the previously known Finnish BRCA1/2 mutations, and seven recurrent founder mutations accounted for 12 of the 13 mutations detected. A logistic regression analysis was used to determine the odds of mutation for ovarian carcinoma patients. The most significant predictor of a mutation was the presence of both breast and ovarian cancer in the same woman, but family history of breast cancer was also strongly related to mutation carrier status. Although BRCA1/2 mutation testing is not warranted in the general Finnish ovarian cancer patient population, patients who have also been diagnosed with breast cancer or have family history of breast or breast and ovarian cancer could benefit from referral to genetic counselling and mutation testing.

ERCP procedures in a Finnish community hospital: a retrospective analysis of 1207 cases.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure with a risk of serious and life-threatening complications. The most common complications are pancreatitis, haemorrhage, perforation and cholangitis. The aim of this study was to determine indications, success rates and complications in a low-volume ERCP unit in Kanta-Häme Central Hospital (KHCH). MATERIAL AND METHODS: Data on 1207 consecutive ERCPs performed in KHCH between 2002 and 2009 was collected retrospectively from patient histories. Complications were classified according to need for intervention and length of hospitalisation. RESULTS: Cannulation of the desired duct was successful in 89.2% of 825 ERCPs with no earlier sphincterotomy. Complete stone removal was achieved in 91.3% of procedures. Standard biliary sphincterotomy was performed in 73.8% and precut sphincterotomy in 12.0 % of cases. Cholangitis developed in 2.1%, bleeding in 1.9%, pancreatitis in 1.9%, perforation in 1.0% and cardio-pulmonary or miscellaneous complications in 4.2% of cases. The majority of complications could be managed conservatively. In procedures with no earlier sphincterotomy ERCP-related 30-day mortality was 0.2% (n=2) and overall 30-day mortality was 3.3% (n=27). CONCLUSIONS: ERCP indications and success rates, as well as morbidity and mortality were comparable to those re-ported earlier. Although the success rate of cannulation and thereby ERCP procedures seem to be somewhat lower than in tertiary referral centres, ERCP procedures can be safely performed in a low-volume ERCP unit by concentrating procedures on a few experienced endoscopists. The success rates may be further improved with the latest cannulation techniques, used selectively in the last years of the study period.

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families.

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast and ovarian cancer. Our aim was to find associations between the clinical characteristics and positive mutation status in 148 breast cancer families in order to predict the probability of finding a BRCA mutation in a family. Several factors were associated with mutations in univariate analysis, whereas in multivariate analysis (logistic regression with backward selection) only the age of the youngest breast cancer patient and the number of ovarian cancer cases in a family were independent predictors of BRCA mutations. A logistic model was devised to estimate the probability for a family of harbouring a mutation in either BRCA1 or BRCA2. Altogether, 63 out of 148 families (43%) and 28 out of 29 (97%) mutation carrier families obtained probabilities over 10%. The mean probability was 55% for mutation-positive families and 11% for mutation-negative families. The models by Couch et al (1997) and Shattuck-Eidens et al (1997) previously designed for BRCA1 were also tested for their applicability to distinguish carrier families with mutations in either gene. The probability model should be a useful tool in genetic counselling and focusing the mutation analyses, and thus increasing also the cost-effectiveness of the genetic screening.