Neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. Affected individuals develop schwannomas characteristically affecting both vestibular nerves leading to hearing loss and eventual deafness. Rehabilitation with brain stem implants and in some cases cochlear implants is improving this outcome. Schwannomas also occur on other cranial nerves, on spinal nerve roots and peripheral nerves. Meningiomas and ependymomas are other tumour features. In excess of 50% of patients represent de novo mutations and as many as 33% are mosaic for the underlying disease causing mutation. Truncating mutations (nonsense, frameshift insertions/deletions) are the most frequent germline events and cause the most severe disease, whilst single and multiple exon deletions are common and are usually associated with milder NF2. A strategy for detection of the latter is vital for a sensitive genetic analysis. NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy. Surgery remains the focus of current management although watchful waiting and occasionally radiation treatment have a role. We are seeing the advent of tailored drug therapies aimed at the genetic level and these are likely to provide huge improvements for this devastating, life limiting condition.

Development of a scoring system to screen for BRCA1/2 mutations.

Selection for genetic testing for pathogenic mutations in BRCA1 and BRCA2 is an important area of healthcare. While testing costs for mutational analysis are falling, costs of tests in North America remain in excess of $3,000. Most countries state that there should be at least a 10-20% likelihood of detecting a mutation in BRCA1 or BRCA2 within a family before mutational analysis is performed. A number of computer-based models have been developed to assess this likelihood, and these continue to be improved to incorporate mutation frequencies, breast cancer incidence and tumour histology. However, these can be time-consuming and difficult to use in a busy clinic. The Manchester scoring system was developed in 2003, and we have continued to validate its use in Western populations. The scoring system discriminates well at both the 10 and 20% threshold for testing and compares very well with more complex computer-based models. However, it should not be used in its current form in founder populations or populations with low incidence of breast cancer, although a lower points threshold could be used to determine an appropriate cut off. The development of the Manchester score and its comparison with other models will be described in this chapter.

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group.

PURPOSE: Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. PATIENTS AND METHODS: Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. RESULTS: Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. CONCLUSION: Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.