Breast And Ovarian Analysis Of Disease Incidence And Carrier Estimation Algorithm Boadicea

BOADICEA is one of the latest of the carrier prediction models to be developed (25). It used a U.K. population-based series of 2200 breast cancer cases, 156 multiple case families, and 429 BRCA1I2 carrier families. All were tested for BRCA1I2 mutations. The complex segregation analysis used resulted in a model that allows for the simultaneous effects of BRCA1 and BRCA2. It also takes into account the effect of many low-penetrance genes that are likely to have multiplicative effects on the...

Methods Relying on Gel Electrophoresis to Resolve Heteroduplexes from Homoduplexes

Two somewhat distinct families of mutation-screening techniques rely on gel electro-phoresis to resolve heteroduplexes from homoduplexes. The first family is based on electrophoresis of samples in a denaturing gradient, and its basic implementation is referred to as denaturing gradient gel electrophoresis (DGGE). The second relies on the gel matrix itself to achieve separation between homoduplexes and heteroduplexes. Its basic implementation is referred to as conformation-sensitive gel...

Mucocutaneous Manifestations

The mucocutaneous manifestations of CS are the most common, yet the most difficult to recognize, with an estimated penetrance of 99 by the end of the third decade (17). The characteristic skin lesions of CS are trichilemmomas and papillomatous papules (25). Trichilemmomas are hamartomas of the infundibulum of the hair follicle and are characteristically found at or near the hairline while papillomatous papules are condyloma-like lesions occurring frequently on the face, hands, feet, or oral...

Shattuckeidens Model

This model was one of many developed by Myriad Genetics, Inc., (Salt Lake City, U.S.A.) to predict the likelihood of a given individual having a mutation in one of the breast cancer predisposing genes BRCA1 or BRCA2. This was one of the earliest such models to be developed (17,18), and it only involved prediction of mutations in BRCA1. The authors used full sequencing data from 798 unrelated individuals, who had been selected for testing because of a family history comprising multiple cases of...

Genetic Testing Complexitieswhere To Start

Careful assessment of the cancer pedigree allows the selection of the most appropriate candidate in whom to initiate testing. If possible, it is preferable to initially test a living affected family member (i.e., has had breast or ovarian cancer or a component tumor associated with the particular suspected syndrome) and select the individual who has the highest chance of having a detectable mutation. If a disease-conferring mutation is found in a family, then the source of cancer risk in the...

Penetrance of BRCA1 and BRCA2 Mutations

The cancer risks associated with BRCA1 and BRCA2 mutations are critical for genetic counseling and have been the subject of considerable controversy. Ultimately, estimates of penetrance based on prospective followup of unaffected carriers should become available, but current estimates are derived from retrospective data. Penetrance estimates have been derived from high-risk families (the so-called maximum logarithm of (LoD score) odds score approach) and from population-based studies based on...

Contribution Of Known Genes To Familial Breast Cancer

An important question is the extent to which the known susceptibility genes can explain the familial aggregation of breast cancer. The simplest assessment of this is the proportion of the familial risk to first-degree relatives of cases that is explicable by each gene. We might term this the familial attributable fraction of each gene. These estimates can then be added over genes, on the assumption that the genes interact either additively or combined on a log scale, if the genes interact...

Claus Model

This was one of the first of the risk prediction models to be developed. It was derived from the Cancer and Steroid Hormone (CASH or Claus) study (16). This was a study of 4700 women with breast cancer, who had their family history taken. A statistical model (Claus model, named after the author of the study) was developed that estimated the chance that a cancer-predisposition gene was present in a family. The model dates from before the BRCA1 and BRCA2 genes were identified. The complex...

Contributors

Akslen The Gade Institute, Section for Pathology, Haukeland University Hospital, University of Bergen, Bergen, Norway Antonis C. Antoniou Cancer Research U.K. Genetic Epidemiology Unit, University of Cambridge, Cambridge, U.K. Merav A. Ben-David Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, U.S.A. Lawrence C. Brody Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, Bethesda,...

Examples Of These Models In

For the examples below, we have decided to use some of the models discussed on three sample pedigrees. The pedigrees are not real pedigrees but are based on real histories given by families seen in our cancer genetics clinics, and the mutation status of each family is known. They have been selected to illustrate the various strengths and weaknesses of the models. We have, in addition to the models themselves, incorporated an assessment by an experienced clinician. This reflects the opinion of a...

References

Peutz-Jeghers syndrome clinicopathology and molecular alterations. Cell Mol Life Sci 2006 63 2135-2144. 2. Hemminki A, Markie D, Tomlinson I, et al. A serine threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998 391 184-187. 3. Mehenni H, Gehrig C, Nezu J, et al. Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. Am J Hum Genet 1998 63 1641-1650. 4. Olschwang S, Markie D, Seal S, et al....

Cancers Other Than Breast and Ovarian Cancer

Table 1 groups studies, by type, that have examined the association of cancers other than breast and ovarian FT cancers with BRCA1 2 mutations, or in families with breast and or ovarian cancer. Inclusion in the table was restricted to claims of statistically significant findings. Early linkage studies and family-based studies in which there was no genotyping of colorectal cancer cases observed significant associations between BRCA1 2 mutations Table 1 Genotype Phenotype Correlation Studies,...

Manchester

The Manchester scoring system was developed by Evans et al. in 2004. Its aim was to provide a quick accurate method of assessing whether genetic testing for BRCA1 or BRCA2 is appropriate given a family history of breast and ovarian cancer, and if so, which of the two genes should be tested first. Development of the scoring system used a dataset of 422 non-Jewish families with a history of breast and or ovarian cancer. These were subsequently screened for mutations in BRCA1, and a subset was...