Clinical characterization and mutation spectrum in Hispanic families with adenomatous polyposis syndromes.

Several genetically defined hereditary colorectal cancer (CRC) syndromes are associated with colonic polyposis including familial adenomatous polyposis (FAP) and MUTYH adenomatous polyposis (MAP). Limited data exists on the clinical characterization and genotypic spectrum of polyposis syndromes among Hispanics. To describe the phenotype and genotype of Puerto Rican Hispanic patients with FAP and MUTYH and compare with other ethnic and racial groups. Probands were identified from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Recruited individuals completed risk factors, medical, and family history questionnaires and underwent genetic testing for genotype analysis. Frequency analysis, Chi square, Fisher's exact and Wilcoxon rank-sum tests were used for statistical analysis methods. A total of 31 FAP (from 19 families) and 13 MAP (from 13 families) Hispanic patients recruited from the PURIFICAR were evaluated. Among the FAP cases, mean age at diagnosis was 27.6 (range 9-71 years); 67.7 % cases had more than 100 polyps and 41.9 % had upper gastrointestinal polyps. Among the 19 FAP families, there were 77 affected FAP individuals and 26 colorectal cancer cases. Genetic mutations were available for 42.2 % of FAP families; all mutations identified were unique. Surgeries were reported in 31 cases; 14 (45.2 %) prophylactic surgeries and 6 (19.4 %) therapeutic surgeries for management of CRC. Among MAP cases, mean age at diagnosis was 53 (range 34-76 years). Genetic analysis revealed homozygous biallelic mutations (G382D) in 53.8 %, compound heterozygous mutations (G382/Y165C) in 23 %, and non-G382/Y165C monoallelic mutations in 23 %. Familial cancer registries should be promoted as vehicles for detection, education and follow up of families at-risk of acquiring familial cancers. PURIFICAR is the first and only familial cancer registry in Puerto Rico providing these services to families affected with familial cancer syndromes promoting education, testing and surveillance of at-risk family members, and focusing on cancer prevention efforts. The fact that only 40 % of FAP patients had access to genetic testing stresses the need to promote the establishment of policies supporting genetic testing coverage by medical insurance companies in order to provide patients with the highest standard of care to prevent cancer. Furthermore, our results suggest that Hispanics may have uncommon mutations in adenomatous polyposis related genes, which emphasize the need for full gene sequencing to establish genetic diagnosis.

Ethnic and sex disparities in colorectal neoplasia among Hispanic patients undergoing screening colonoscopy.

BACKGROUND & AIMS: Colorectal cancer (CRC) has a high prevalence among the US Hispanic population. In Puerto Rico, CRC is the third leading cause of cancer death in men and the second in women. There are limited published data on the prevalence of colorectal neoplasia (CRN) among the US Hispanic population. We determined the prevalence of CRN (colorectal adenomas and cancer) among asymptomatic, Hispanic subjects who were screened in Puerto Rico and evaluated risk factors associated with CRN. METHODS: We performed a retrospective review of the medical, endoscopic, and pathology records of individuals who underwent first-time screening colonoscopies at an ambulatory gastroenterology practice from January 1, 2008, to December 1, 2009. The prevalence of CRN (overall and advanced), documented by colonoscopy and pathology reports, was calculated for the complete cohort and by sex. RESULTS: Of the 745 Hispanic individuals who underwent screening colonoscopies during the study period, the prevalence for overall CRN was 25.1% and for advanced CRN (≥ 1 cm and/or with advanced histology) was 4.0%. The prevalence of CRN was higher for men than women (32.0% vs 20.6%; P = .001; odds ratio, 1.92; 95% confidence interval, 1.4-2.6). CRN was more frequently located in the proximal colon (67.7% proximal vs 32.3% distal). A family history of CRC was associated with advanced CRN (odds ratio, 2.73; 95% confidence interval, 1.10-6.79). CONCLUSIONS: CRN was more common among Hispanic men than women and increased with age. CRNs among Hispanic individuals were predominantly located in the proximal colon. These findings indicate that there are ethnic and sex disparities in patterns of CRN that might be related to genomic admixture and have important implications for screening algorithms for Hispanic individuals.

Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons.

Cisplatin is a platinum-based chemotherapeutic agent that induces peripheral neuropathy in 30% of patients. Peripheral neuropathy is the dose limiting side effect, which has no preventative therapy. We have previously shown that cisplatin induces apoptosis in dorsal root ganglion (DRG) sensory neurons by covalently binding to nuclear DNA (nDNA), resulting in DNA damage, subsequent p53 activation and Bax-mediated apoptosis via the mitochondria. We now demonstrate that cisplatin also directly binds to mitochondrial DNA (mtDNA) with the same binding affinity as nDNA. Cisplatin binds 1 platinum molecule per 2166 mtDNA base pairs and 1 platinum molecule per 3800 nDNA base pairs. Furthermore, cisplatin treatment inhibits mtDNA replication as detected by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and inhibits transcription of mitochondrial genes. The relative reduction in mtDNA transcription is directly related to the distance the gene is located from the transcription initiation point, which implies that randomly formed platinum adducts block transcription. Cisplatin treated DRG neurons exhibit mitochondrial vacuolization and degradation in vitro and in vivo. Taken together, this data suggests that direct mtDNA damage may provide a novel, distinct mechanism for cisplatin-induced neurotoxicity separate from the established nDNA damage pathway.

The neurosteroid 3alphaDIOL modulates place preference when infused in the basolateral amygdala according to sex.

Three different behavioral tasks were used to study the role of the neurosteroid 5alpha -androstane-3alpha, 17beta-diol (3alphaDIOL) in affective components of behavior when infused into the basolateral amygdala (BLA) of both sexes. Female rats were ovariectomized; half received implants containing estradiol benzoate (OVX-EB), whereas the other half received empty implants (OVX). Male rats were gonadally intact. No differences were noted in male behavior according to the conditioned place preference (CPP) test, the modified Vogel conflict test (VCT), or the elevated plus maze (EPM) upon infusion of 3alphaDIOL. In contrast, 3alphaDIOL modulated CPP and VCT performance among female rats. Therefore, the authors propose that 3alphaDIOL modulates affect through the BLA via a sex-specific mechanism.