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BACKGROUND To evaluate their relative activity and specificity for prostate cells promoter and regulatory regions from three prostate-expressed genes–prostate-specific antigen (PSA), probasin, and relaxin H2–have been compared in prostate cell lines and in lines of breast, bladder, liver, kidney, lung, and ovarian origin. METHODS After transfection into different cell types, the activity of promoters was assayed using linked reporter genes and normalized against that of the Rous sarcoma virus. Activity was measured both in the presence and in the absence of co-transfected androgen receptor (AR). RESULTS PSA and probasin regulatory regions showed strong responsiveness to co-transfection of the AR in most cell types. The core PSA promoter region showed low activity and specificity, but the specificity and level of expression were substantially increased by inclusion of upstream sequences, particularly the enhancer region. Probasin promoter fragments showed specificity of expression for prostate cell lines but required AR for significant levels of expression. Relaxin promoter fragments directed significant AR-inducible expression in prostate cells but showed little specificity and variable AR responsiveness in other cell types. CONCLUSIONS Of regulatory regions tested, a 430-base pair probasin promoter and PSA enhancer/core promoter showed the best combination of AR-stimulated prostate cell expression with limited expression in other cell types. Prostate 35:18–26, 1998. © 1998 Wiley-Liss, Inc.

Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (P

Anna Abuli, Ceres Fernandez-Rozadilla, Virginia Alonso-Espinaco, Maria DoloresGiraldez, Jenifer Munoz, Xavier Bessa, Xavier Llor, Rodrigo Jover, Luis Carvajal-Carmona,Ian Tomlinson, Victor Moreno, Angel Carracedo, Antoni Castells, Montserrat Andreu,Clara Ruiz-Ponte, Sergi Castellvi-BelColorectal cancer (CRC) is the second most common cancer in Spain. Although the majorityof CRC is sporadic, inherited susceptibility is relevant in about 30-35% of cases, being dueto hereditary mutations in less than 5%. Much of the remaining genetic risk may beattributabletoalarge numberofcommon,low-penetrancegeneticvariants. ThereispreviousevidenceingeneticsusceptibilitytoCRCoftheinvolvementofgenesthatbelongtocolorectalcarcinogenesis pathways, genes involved in CRC susceptibility by studies in mice, and geneslocated on chromosomal regions (9q22 and 3q22) identified by genetic linkage analysis inCRC families. Objectives. To select genes from CRC pathways, mouse susceptibility studiesor chromosomal regions 9q22 and 3q22 with potential implications in CRC and its poly-morphisms with a putative functional effect, and to assess their implication in geneticsusceptibility toCRC by acase-control associationstudy. Patients andmethods. Case-controlgenetic association study in 2 stages in the EPICOLON cohort (stage 1, 515 cases vs.515 controls; replication stage 2, 900 cases vs. 900 controls). Results. We assessed 400polymorphisms in stage 1. Ten per cent showed significant association with CRC. In orderto validated these statistically significant associations, we replicated 42 polymorphisms inan independent cohort (stage 2), and 5 of them showed significant findings in both stages:[rs1444601, OR=0,85 (0,75-0,95, p=0,006); rs2071387, OR=0,56 (0,36-0,88, p=0,009);rs13088006, OR=0,67 (0,48-0,93, p=0,017); rs2297155, OR=0,35 (0,14-0,9, p=0,019);rs939453,OR=0,89(0,81-0,99,p=0,038)].Conclusions.Fivepolymorphismsshowedstatist-ically significant differences in both independent CRC cohorts, and they may correspondto new low-penetrance genetic components for CRC.