Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.

A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).

Analysis of the genes coding for the BRCA1-interacting proteins, RAP80 and Abraxas (CCDC98), in high-risk, non-BRCA1/2, multiethnic breast cancer cases.

Background Around half of familial breast cancer cases are caused by germ-line mutations in genes which are critically involved in the maintenance of genome stability. Mutations in related genes functioning in DNA repair may account for currently unattributed cases. Two such genes, RAP80 and Abraxas, have recently been identified to be in a complex with BRCA1, and are required for the localization of BRCA1 to DNA damage foci. Methods RAP80 and Abraxas variants were screened for in a cohort of 95 high risk, non-BRCA1/2 breast cancer cases of varying ethnicity: those of Ashkenazi Jewish (n = 35), mixed Canadian (n = 34) and Swiss descent (n = 26). Results We have identified four missense variants, four silent SNPs, three SNPs in the UTRs and seven intronic variants in RAP80. Two of the previously reported RAP80 variants were further investigated. In Abraxas, we have identified two missense, nine intronic and two variants in the 3' UTR. Conclusions Overall, it seems unlikely that moderate to highly penetrant alleles of either RAP80 or Abraxas, confer a significantly high relative risk of breast cancer.

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women.

BACKGROUND: BRCA1 and BRCA2 account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (CHEK2) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance CHEK2 alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population. METHODS: The 14 coding exons of CHEK2 were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques. RESULTS: Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73). CONCLUSION: The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.

GeneNews Limited: bringing the blood transcriptome to personalized medicine.

GeneNews Limited (TSX:GEN) is a molecular diagnostics company, uniquely positioned to deliver on the promise of personalized medicine. GeneNews has developed and patented the Sentinel Principle(®), an innovative approach to identify clinically actionable disease biomarkers from the blood transcriptome. Novel biomarker panels have been identified to address unmet clinical needs in a broad spectrum of malignancy, including those for oncology, cardiovascular, metabolic and neurological related disorders. Currently available products and services from GeneNews are: ColonSentry™, the world's first blood-based molecular test for colorectal cancer, and; the SentinelGX™ Pharmacogenomic and Companion Diagnostic BloodRNA™ services, established to effectively support pharmaceutical partners in their companion diagnostic, development efforts.

Day-to-day variability in acid reflux patterns using the BRAVO pH monitoring system.

BACKGROUND & GOALS: The wireless pH monitoring system such as the BRAVO pH system is a significant advancement in the evaluation of patients with gastroesophageal reflux because of its potentially better tolerability and the ability to record data over a 48-hour period. The aim of our study was to evaluate safety, performance, tolerability, and day-to-day variability in acid reflux patterns using the BRAVO pH system. METHODS: A total of 90 consecutive patients (48 men and 42 women) with persistent reflux symptoms underwent BRAVO pH capsule placement from October 2002 to August 2003 at a tertiary care hospital. The BRAVO pH capsule was deployed 6 cm proximal to the squamocolumnar junction under endoscopic guidance. The pH recordings over 48 hours were obtained after uploading data to a computer from the pager-like device that recorded pH signals from the BRAVO pH capsule. RESULTS: Successful pH data over 48 hours was obtained in 90% of patients. Nearly two thirds of patients experienced a variety of symptoms ranging from a foreign body sensation to chest discomfort or pain. Four patients had severe chest pain, 3 of whom required endoscopic removal of the BRAVO pH capsule. In 74.4% of patients, number of reflux events as well as time (%) pH<4 correlated from the first 24-hour period to the second 24-hour period. However, in 28% of patients, no predictable pattern of (%) time pH<4 in the supine position was reproduced from one 24-hour period to the next 24-hour period. CONCLUSIONS: The BRAVO pH system appears a safe and effective method of recording esophageal acid exposure. It is an acceptable alternative for patients who are unwilling or unable to tolerate nasopharyngeal catheter-based pH studies, and it has a potential advantage of the 2-day recording period.