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Carotid body and vagal paragangliomas, although considered indolent tumors, represent a challenge for the treating physician. This is mainly because of their peculiar localization, in close proximity with important anatomical structures. In addition, there is no chemotherapy available for these

Background and Aims Germline variation in allele-specific expression (ASE) is associated with highly penetrant familial cancers, but its role in common sporadic cancers is unclear. ASE of the adenomatous polyposis coli (APC) gene plays a role in familial adenomatous polyposis coli. We hypothesized that moderate ASE variation in APC contributes to common forms of colorectal cancer (CRC). Methods Denaturing high performance liquid chromatography (DHPLC) was employed for germline APC ASE analysis in CRC cases (n=53) and controls (n=68). Means, medians, and variances of ASE were compared. Mutation analysis and SNP genotyping were performed. Results ASE distributions differed significantly between groups; cases had a significantly larger variance than controls (p = 0.0004). Importantly, CRC risk increased proportionally with the degree of deviation from the mean. Individuals with ASE deviating more than 1 SD from the mean had an odds ratio (OR) of 3.97 (1.71, 9.24 95% CI; p = 0.001); those deviating more than 1.645 SDs had an OR of 13.46 (1.76, 609.40 95% CI; p = 0.005). In support of these findings, sequence analysis revealed that a patient with marked ASE, who was negative for CRC family history, carried a nonsense APC mutation (p.Arg216X). Furthermore, APC genotyping showed that multiple SNPs were associated with ASE values and/or ASE variance in cases, but not in controls. Thus, cis variants may explain at least some of the ASE results. Conclusion Our results indicate that imbalanced germline ASE of APC is more frequent in CRC patients than controls, and represents an indicator of risk for common forms of CRC.

Genomic instability plays a key role in hereditary nonpolyposis colorectal cancer and in a significant sub-set of non-hereditary colorectal tumors. Recent evidence suggests that microsatellite instability also occurs in various sub-sets of common, non-hereditary forms of extra-colorectal carcinoma. To investigate the role of microsatellite instability in breast cancer, and to correlate this type of alteration with clinico-pathological characteristics, including tumor proliferative activity, we analyzed the status of 8 different microsatellite loci in 28 cases of primary mammary carcinoma. For this purpose, microsatellite banding patterns were compared in paired breast-cancer/peripheral-blood DNA samples. Microsatellite instability was observed in 6/28 (21%) of the cases. Four of the 6 tumors had low proliferative activity, one had high proliferative activity, and in one case proliferative activity values were not available. All chromosomal loci investigated demonstrated microsatellite instability in one or more representative tumors of the series. Shifts in length larger than 2 bp were the most frequent change. Microsatellite instability significantly correlated with the lobular histotype, and with lymph-node involvement. A trend was also observed associating microsatellite instability and large tumor size.

Analysis of genotype-phenotype correlations in familial adenomatous polyposis (FAP) patients demonstrated that the phenotypic heterogeneity of FAP is partly related to the mutation site. We investigated the molecular basis for the difference in severity of colorectal disease observed comparing FAP patients from two kindreds with neighbouring germline mutations in exon 9 of the APC gene. Patients from one kindred presented with a attenuated form of FAP, characterized by a low number of colorectal adenomas (up to 22). In FAP patients from this kindred, the APC gene mutation was localized at codon 367, in the portion of exon 9 that is alternately spliced. This is expected to result in the splicing-out of the mutation site in a fraction of mRNA molecules and in the residual production of wild-type transcripts from the mutant APC allele. Patients from the other kindred manifested a FAP phenotype characterized by hundreds of colorectal adenomas (320 to > 500). In these patients, the APC gene mutation abolished the donor site of exon 9a, used in both alternately spliced isoforms of the exon. The analysis of the relative levels of mutant and wild-type transcripts in unaffected colonic mucosa demonstrated that the mutant allele was not expressed. The model offered by our FAP patients with neighbouring exon 9 APC mutations supports the view that in addition to the mutation site, the type of mutation and transcript dosage effects contribute to the heterogeneity of disease phenotypes.