Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors.

BACKGROUND: Trichilemmoma (TL) can occur as a solitary sporadic lesion usually on the face or as multiple facial lesions almost invariably associated with Cowden syndrome (CS). CS is a multisystem disorder caused by a germline inactivating mutation in PTEN (10q23.31), a tumor suppressor gene. We sought to identify PTEN loss by immunohistochemistry (IHC) in sporadic and CS-associated TL to determine whether IHC is a useful tool to assess an individual for CS. METHODS: Six TL biopsies associated with CS and 33 biopsies without CS were retrieved. IHC for PTEN was performed. RESULTS were scored as positive (reactivity in TL cells) or negative (no reactivity in TL cells); normal squamous epithelium and vascular endothelium served as internal positive controls. RESULTS: Complete PTEN loss was noted in 5/6 (83%) CS-associated TL and 1/33 (3%) sporadic (non-CS) TL. CONCLUSION: Demonstration of complete PTEN loss in TL by IHC is strongly suggestive of association with CS, but retention of PTEN staining does not entirely exclude CS. Therefore, PTEN IHC in TLs may be helpful in screening TL for association with CS, but should be used in context with other established clinical criteria, and possibly germline PTEN genotyping to confirm a diagnosis of CS.

Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients.

BACKGROUND: We conducted a study to determine the prevalence and factors associated with hepatic steatosis in human immunodeficiency virus (HIV)-seropositive patients with hepatitis C and to investigate whether steatosis is associated with liver fibrosis. METHODS: Retrospective chart reviews were conducted in 4 hospitals that serve community-based and incarcerated HIV-infected patients who had undergone a liver biopsy for evaluation of hepatitis C virus (HCV) infection during the period of 2000-2003. Demographic characteristics and medication and laboratory data were collected from the time of the biopsy. A pathologist blinded to all clinical data evaluated the specimens. The primary outcome was presence or absence of steatosis. RESULTS: Of 260 HIV-HCV-coinfected patients, 183 met inclusion criteria and had a biopsy specimen adequate for review. Steatosis was present in 69% of patients (graded as minimal in 31%, mild in 27%, moderate in 18%, and severe in 1%). Factors associated with steatosis included use of dideoxynucleoside analogues, such as didanosine and stavudine (odds ratio [OR], 4.63; 95% confidence interval [CI], 1.55-13.82). There was a trend toward presence of steatosis and use of other nucleoside analogues or infection with HCV genotype 3 (OR, 2.65 [95% CI, 0.95-7.41] and 3.38 [95% CI, 0.86-13.28], respectively). The presence of steatosis was associated with fibrosis (OR, 1.37; 95% CI, 1.03-1.81). CONCLUSIONS: In this multiracial population of HIV-HCV-coinfected patients, steatosis was prevalent and was associated with severity of liver fibrosis. Use of nucleoside analogues (particularly didanosine and stavudine) and HCV genotype 3 infection were associated with hepatic steatosis. The development of steatosis is multifactorial in nature and may play a contributory role in the progression of liver disease in HIV-infected patients.

Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis.

Folate depletion and aging are risk factors for colorectal cancer. We investigated the effects of folate status and aging on gene expression in the rat colon. Young (weanling) and older (12 month) rats were fed folic acid depleted (0 mg/kg) and supplemented (8 mg/kg) diets for 20 weeks. Gene expression was measured in colonic mucosal scrapings (n = 3 per group) using oligonucleotide arrays (Affymetrix U34A). Folate depletion induced the up-regulation of immune-related genes, urokinase and inducible nitric oxide synthase and the down-regulation of adhesion molecules (protocadherin-4, nidogen and integrin alphaV) and vascular endothelial growth factor in young rats. The abbreviated response to depletion in old rats (62 changes versus 136 in the young) included up-regulation of caspase-2 and deleted in colon cancer. Gene expression changes due to aging were more abundant in folate depleted than supplemented rats (38 versus 119 genes, respectively). In folate-deficient rats, aging induced the down-regulation of immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3 and vav-1 oncogene. In folate supplemented rats, aging induced the down-regulation of vascular endothelial growth factor and caspase-2. Lower expression of adhesion molecules and higher expression of urokinase with folate depletion in young rats may indicate that cell detachment and migration, cancer-related processes, may be modulated by folate status. An age-related decline in p53 and IGF-BP3 expression was only observed in folate depleted animals, indicating that folate supplementation may reduce the risk for age-associated cancers by suppressing deleterious changes in the expression of certain genes.

Gene mutations in advanced colonic polyps: potential marker selection for stool-based mutated human DNA assays for colon cancer screening.

The detection and removal of advanced colonic polyps (ACPs) can help prevent the development of colorectal cancer. A set of DNA mutations known to be associated with colorectal carcinoma was tested against resected ACPs to determine the set s potential utility as a marker panel for ACPs. A sensitive mutation marker panel could be used by stool-based assays that look for mutated human DNA to detect the presence of ACPs. DNA from 32 ACPs = 1.0 cm in diameter was amplified and tested for 19 colorectal cancer associated DNA mutations and for deletions in BAT-26 (microsatellite instability). One or more mutations were identified by microsequencing in 28 of the 32 ACPs (88%). Mutations were identified in k-ras (59%), APC (33%), and p53 (22%). BAT-26 mutation, a marker for microsatellite instability, was not identified. Stool DNA based assays that can identify these mutations may significantly increase the identification of patients with potentially premalignant ACPs for evaluation and treatment by colonoscopy.