Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM- tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-gamma, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.

Newfoundland has the highest rate of colorectal cancer (CRC) of any Canadian province. In order to investigate the factors, especially genetic components, responsible for CRC we established the Newfoundland Colorectal Cancer Registry. In a 5-year period we examined every case of CRC diagnosed under the age of 75 years and obtained consent from 730 cases. Careful analysis of family history was used to assign a familial cancer risk, based on established criteria. We observed that 3.7% of CRC cases came from families meeting the Amsterdam II criteria and a further 0.9% of cases involved familial adenomatous polyposis (FAP). An additional 43% of cases met one or more of the revised Bethesda criteria and 31% of all cases had a first-degree relative affected with CRC. We compared the Newfoundland data with data from the province of Ontario, where the same recruitment and risk-assessment criteria were used. In all categories, the indicators of familial risk were significantly higher in Newfoundland. These data were also compared to results published from 13 other population-based studies worldwide. In every category the proportion of Newfoundland cases meeting the criteria was higher than in any other population. The mean differences were: 3.5-fold greater for FAP, 2.8-fold higher for Amsterdam criteria, 2.0-fold higher for Bethesda criteria and 1.9-fold higher for the number of affected first-degree relatives. We conclude that the high incidence of CRC in Newfoundland may be attributable to genetic, or at least familial, factors. In the high-risk families we provide evidence for the involvement of founder mutations in the APC and MSH2 genes.

Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America.The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland. Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer^like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1. Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings. Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.

Kallikreins are a family of 15 serine proteases clustered together on the long arm of chromosome 19. Recent reports have linked kallikreins to malignancy. The human kallikrein gene 6 (KLK6) is a newly characterized member of the human kallikrein gene family. Recent work has focused on the possible role of this gene and its protein product as a tumor marker and its involvement in diseases of the central nervous system. In this study, we performed extensive in silico analyses of KLK6 expression from different databases using various bioinformatic tools. These data enabled us to construct and verify the longest transcript for this kallikrein, to identify several polymorphisms among published sequences and to summarize the 21 single-nucleotide polymorphisms of the gene. Our expressed sequence tag (EST) analyses suggest the existence of seven new splice variants of the gene, in addition to the already reported ones. Most of these variants were identified in libraries from cancerous tissues. KLK6 orthologues were identified from three other species with approximately 86% overall homology with rat and mouse orthologues. We also utilized several databases to compare KLK6 gene expression in normal and cancerous tissues. The serial analysis of gene expression and EST expression profiles showed upregulation of the gene in female genital (ovarian and uterine) and gastrointestinal (gastric, colon, esophageal and pancreatic) cancers. Significant downregulation was observed in breast cancers and brain tumors, in relation to their normal counterparts.

Commercial crossbred hogs and gilts, and purebred Landrace boars and gilts were slaughtered after a lairage period of either 2 or 24 h. The meat quality of the carcasses was assessed by measuring the pH of the Longissimus dorsi and adductor muscles at 45 min and 20 hpost mortem. Serum cortisol and thyroid parameters were measured in blood taken at slaughter. The incidence of the pale, soft and exudative (PSE) condition was slightly higher in purebred Landrace pigs killed after a short lairage period than in those held in lairage overnight. The PSE condition tended to be more prevalent in Landrace gilts than boars. The percentage of carcasses classified as dark, firm and dry (DFD) was much greater in both commercial crossbred and purebred Landrace pigs killed after overnight lairage. The incidence of the DFD condition was greater in Landrace boars than gilts, particularly after overnight lairage. Serum cortisol levels were higher and serum total thyroxine (T4) and free thyroxine indices (FTI) lower in pigs killed after a short lairage. Serum total T4 and FTI values at slaughter were lower in boars than gilts.