INHERITED BREAST CANCER - 11/09/11
Résumé |
It has been recognized for many years that family history is an important risk factor for the development of carcinoma of the breast.54 Several autosomal dominant syndromes confer an increased risk of breast cancer. The autosomal dominant transmission can be inferred from the appearance of breast cancer in multiple generations, with multiple family members being affected. As with all autosomal dominant conditions, children of an affected parent have a 50% risk of inheriting the mutated allele. The term familial breast cancer is used to describe the appearance within a family of multiple cases of breast cancer, but with insufficient evidence for autosomal dominant transmission.
With the recent cloning of one of the breast cancer predisposition genes (BRCA1), 61 a great deal of media attention has been generated. Patients are more aware of the influence of family history, are likely to ask their physicians for up-to-date information, and may request genetic testing. Because the surgeon may be one of the first health care providers to assess an individual's risk, it is timely to review the current understanding of inheritance of breast cancer and availability of genetic testing. Genetic testing refers to the analysis of genetic risk in individuals who are perceived to be at high risk due to their family history. This is distinct from genetic screening, which describes population-based genetic testing without regard to the phenotype or clinical indications.
Approximately 5% to 10% of all breast cancer results from the autosomal dominant inheritance of a mutated gene, 17, 42 the vast majority of breast cancer being sporadic. Inherited breast cancer therefore accounts for 9,000 to 18,000 cases per year in the United States. Most cancers are not inherited, however, as characterized by genetic changes in the germline cells of patients. All cancers are genetic at the cellular level in that they result from the accumulation of genetic abnormalities that lead to genome instability and loss of normal growth regulation in the tumor cell. Epidemiologic evidence suggests that the accumulation of three to six mutations is required for the development of sporadic solid tumors.43 Several classes of genes have been identified which are mutated in this progressive accumulation: proto-oncogenes, tumor suppressor genes, and mismatch repair genes. Several proto-oncogenes show increased expression in both invasive and in situ breast cancer, for example c- erbB2 (Her-2/neu), c- myc and int-2.93 The proto-oncogene RET is mutated in the germline of patients with multiple endocrine neoplasia type 2.10, 15, 63
Tumor suppressor genes (TSG), as their name implies, encode protein products that normally control cell growth and regulation. A lack of activity of the TSG then contributes to oncogenesis by allowing unrestricted growth. Knudson's 44 hypothesis states that both alleles at a tumor suppressor locus must be mutated to allow tumor formation. In sporadic breast cancers both these mutations occur in the breast epithelial cells. In inherited breast cancers one mutation is carried in the germline, and the second mutation then occurs at the TSG locus in the target organ. Because every cell already contains one mutation in these autosomal dominant conditions, they are “primed” or predisposed to become malignant. Therefore, inherited cancers occur at a younger age than sporadic cancers and are much more likely to be bilateral and/or multifocal. Marcus et al 59 state that 36% to 85% of breast cancers diagnosed before age 30 are inherited. Many TSG loci are inactivated in sporadic invasive breast cancer, and at least seven loci in ductal carcinoma in situ.75
In the past few years another class of genes has been identified which contributes to colon cancer formation. Mutations of mismatch repair genes result in a lack of fidelity of DNA replication. This is evidenced by replication errors and genomic instability throughout the genome. Hereditary non–polyposis coli (HNPCC) is attributed to the inheritance of mutated mismatch repair genes. Genetic heterogeneity is observed in this syndrome in that mutations in several different genes can result in the same phenotype.1, 2, 27, 47, 52, 56, 68, 69, 70, 71
Genetic testing for inherited disease can be performed in a direct or indirect manner. Indirect testing involves the analysis of genetic linkage within the context of a family. Polymorphic markers are chosen which flank the chromosomal region that segregates with the trait or disease. DNA from family members is assayed using several closely linked markers. The co-inheritance of a chromosomal region with the disease establishes linkage. Asymptomatic individuals can be tested with the same markers to determine if they carry the same pattern of markers and therefore can be placed in a high-risk or low-risk group and counseled appropriately. To obtain meaningful information from this analysis, DNA should be obtained from at least four affected individuals representing multiple generations and from several unaffected first-degree relatives in the family. When key family members are deceased, it may be possible to obtain DNA from archival pathology specimens to establish the pattern of inheritance of the linkage markers. DNA recombination between linked markers and the position of the candidate gene confounds linkage analysis. The rate of recombination increases with distance; thus, closely linked polymorphic markers are key to performing indirect mutation analysis.
Once a disease gene has been cloned and the mutations have been characterized, testing for mutations can be performed via the direct analysis of an individual's DNA. The most comprehensive but also most laborious strategy is direct sequencing of the DNA. Other methods are based on the difference in electrophoretic mobility of the mutated versus the normal (wild-type) DNA fragments. Examples of these assays include single-stranded conformational polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), and heteroduplex analysis.31, 39 The sensitivity of SSCP for detection of a germline mutation is 85% in DNA fragments of 200 bp or less.92 When a particular mutation produces the disease in a family, allele-specific oligonucleotide hybridization (ASO) of the at-risk individual's DNA can be devised in which detection of both normal (wild-type) and mutant alleles is distinguished by their specific DNA sequences.31 Exact sequence information is required for ASO. SSCP analysis detects mutations but does not localize them within a fragment or reveal the nature of the sequence alteration.
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Vol 76 - N° 2
P. 205-220 - avril 1996 Retour au numéro
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- PREFACE
- MARVIN J. LOPEZ
- THE WOMAN AT HIGH RISK FOR BREAST CANCER : Importance of Hyperplasia
- David L. Page
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