COL11A1 in FAP polyps and in sporadic colorectal tumors

BACKGROUND: We previously reported that the α-1 chain of type 11 collagen (COL11A1), not normally expressed in the colon, was up-regulated in stromal fibroblasts in most sporadic colorectal carcinomas. Patients with germline mutations in the APC gene show, besides colonic polyposis, symptoms of stromal fibroblast involvement, which could be related to COL11A1 expression. Most colorectal carcinomas are suggested to be a result of an activated Wnt- pathway, most often involving an inactivation of the APC gene or activation of β-catenin. METHODS: We used normal and polyp tissue samples from one FAP patient and a set of 37 sporadic colorectal carcinomas to find out if the up-regulation of COL11A1 was associated with an active APC/β-catenin pathway. RESULTS: In this study we found a statistically significant difference in COL11A1 expression between normal tissue and adenomas from one FAP patient, and all adenomas gave evidence for an active APC/β-catenin pathway. An active Wnt pathway has been suggested to involve stromal expression of WISP-1. We found a strong correlation between WISP-1 and COL11A1 expression in sporadic carcinomas. CONCLUSIONS: Our results suggest that expression of COL11A1 in colorectal tumors could be associated with the APC/β-catenin pathway in FAP and sporadic colorectal cancer

Heritable breast cancer in twins

Known major mutations such as BRCA1/2 and TP53 only cause a small proportion of heritable breast cancers. Co-dominant genes of lower penetrance that regulate hormones have been thought responsible for most others. Incident breast cancer cases in the identical (monozygotic) twins of representative cases reflect the entire range of pertinent alleles, whether acting singly or in combination. Having reported the rate in twins and other relatives of cases to be high and nearly constant over age, we now examine the descriptive and histological characteristics of the concordant and discordant breast cancers occurring in 2310 affected pairs of monozygotic and fraternal (dizygotic) twins in relation to conventional expectations and hypotheses. Like other first-degree relatives, dizygotic co-twins of breast cancer cases are at higher than usual risk (standardised incidence ratio (SIR)=1.7, CI=1.1–2.6), but the additional cases among monozygotic co-twins of cases are much more numerous, both before and after menopause (SIR=4.4, CI=3.6–5.6), than the 100% genetic identity would predict. Monozygotic co-twin diagnoses following early proband cancers also occur more rapidly than expected (within 5 years, SIR=20.0, CI=7.5–53.3). Cases in concordant pairs represent heritable disease and are significantly more likely to be oestrogen receptor-positive than those of comparable age from discordant pairs. The increase in risk to the monozygotic co-twins of cases cannot be attributed to the common environment, to factors that cumulate with age, or to any aggregate of single autosomal dominant mutations. The genotype more plausibly consists of multiple co-existing susceptibility alleles acting through heightened susceptibility to hormones and/or defective tumour suppression. The resultant class of disease accounts for a larger proportion of all breast cancers than previously thought, with a rather high overall penetrance. Some of the biological characteristics differ from those of breast cancer generally

Univariate and bivariate analyses of cholesterol and triglyceride levels in pedigrees

A multivariate normal model for pedigree analysis is applied to fasting total serum cholesterol and total serum triglyceride measurements on 771 individuals in 95 pedigrees from Rochester, MN. Univariate and bivariate analyses are carried out to determine to what extent the aggregation and coaggregation in families of these two traits may be attributed to shared genetic and environmental factors. Pedigrees were ascertained through a sample of schoolchildren enriched for those with serum cholesterol levels in the highest and lowest deciles of their age- and sex-specific distributions. Ascertainment is corrected for by conditioning the likelihood on the trait values of the probands. Univariate results confirm the findings of previous studies indicating that familial aggregation of serum cholesterol and triglyceride levels is due both to shared genes and to shared environmental factors. Results of the bivariate analyses suggest that the coaggregation of cholesterol and triglyceride levels in these families is strongly influenced by both shared genes (pleiotropy) and shared environmental factors. These findings are consistent with our understanding of lipid metabolism and of specific environmental factors known to influence both traits.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38240/1/1320230306_ftp.pd

The effects of generation and gender on the joint distributions of lipid and apolipoprotein phenotypes in the population at large

The generation and gender effects on the joint distributions of total plasma cholesterol (Total-C), 1n triglycerides (1nTrig), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), apolipoproteins AI (Apo AI), AII (Apo AII), and E (1nApo E) were studied in 184 male grandparents (MGP), 242 female grandparents (FGP), 237 male parents (MP), 235 female parents (FP), 202 male children (MC), and 200 female children (FC). Homogeneity of variance tests revealed that lipid variances were gender and/or generation specific while apolipoprotein variances were homogeneous across strata. In the absence of heterogeneity of variance, significant heterogeneity in LDL:1nTrig and 1nTrig:Apo AII covariation was found between genders in the parental generation. In the presence of heterogeneity of variance, significant heterogeneity of correlation between genders and/or across generations was found for the HDL-C: LDL-C, Total-C:LDL-C, Total-C: 1nTrig, 1nTrig:LDL-C, Total-C: 1nApo E and HDL-C:1nApo E bivariate distributions. Analyses of principal components revealed that the generation and gender specific cohorts have similar eigenvalues but distinct eigenvectors for the first two principal components underlying the seven dimensional lipid and apolipoprotein distribution. We conclude that the amount of variability explained by the first two principal components is the same across cohorts but how the interindividual variability is distributed among the lipid and apolipoprotein traits is generation and gender specific. This study documents the role that variance and covariance might play in determining risk of disease for special subgroups of the population at large. It also demonstrates how variances and covariances between risk factors traits characterize life processes of aging and sexual dimorphism. This study argues that future biometrical genetic and epidemiological studies of coronary artery disease must take into account age and gender effects on interindividual variability and covariability of risk factors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28926/1/0000763.pd