Molecular Basis of Disease

Breast Cancer

Breast cancer is the most common cancer among women in Western countries, with about 180,000 new cases and 40,000 deaths occurring annually in the United States. Epidemiologic factors consistently associated with breast cancer risk include a family history of breast cancer, breast biopsy features, and hormonal risk factors such as age at menarche, parity, and age at first live birth. After female gender and age, family history of breast cancer is the most significant risk factor. In a meta-analysis of family history of breast cancer as a risk factor, the relative risk ranged from 1.5 for a second-degree relative to 3.6 for a mother and sister with breast cancer.1 Relative risks are significantly influenced by the degree of relationship of affected relatives and their age of breast cancer onset, with closer degrees of relationship and younger age of onset conveying higher risks. An analysis of family history as a risk factor using data from the Swedish Family-Cancer Database showed a population-attributable fraction of about 11%.2

Breast cancer is a complex disease, resulting from an incompletely characterized interplay of genetic and environmental factors. In the majority of cases, the level of genetic analysis currently available cannot be used to stratify risk. However about 5% to 10% of breast cancer is hereditary, that is, due to the transmission of highly penetrant mutations in breast cancer-predisposing genes. Within hereditary breast cancer families, mutation status is the overriding risk factor, and genetic analysis can be used to clarify risk and guide medical management in a highly effective way. Genetic risk assessment consists of evaluating the pattern of cancers in the family, judging which of the known hereditary breast cancer syndromes fits the pattern, and pursuing genetic analysis.3

A specific genetic syndrome can be elucidated in about half of hereditary breast cancer families. Additional genes remain to be described.4 Risk-conferring alleles are conceptualized as high-penetrance genes with low prevalence

(e.g., BRCA1 and BRCA2 [hereditary breast-ovarian cancer (HBOC) syndrome], TP53 [Li-Fraumeni syndrome],PTEN [Cowden syndrome], LKB1 [Peutz-Jeghers syndrome]) or low-penetrance genes with high prevalence (possibly CHEK2,5 ATM,6 and the TGFBR1*6A allele7). The latter category may have small effects in individuals, but large aggregate effects in populations because they are common.

Using data from the Anglian Breast Cancer Study, Pharoah et al.8 found that the best-fitting genetic model hypothesized that susceptibility to breast cancer is due to several loci, each conferring a modest independent risk. Assuming that all the susceptibility genes could be identified, they showed that the half of the population at highest risk would account for 88% of all affected individuals. Clinical testing for one or a few low-penetrance genes at a time would be unsatisfying in many respects. Mutations are found in many individuals but convey small risks, and gene-gene and gene-environment interactions are unknown, limiting clinical utility. Ultimately, whole genome screening might be used in combination with knowledge about such interactions to achieve higher predictive power and allow for efficient breast cancer risk stratification.

BRCA1 and BRCA2

Newman et al. published the first study providing quantitative evidence for an autosomal dominant breast cancer susceptibility allele, accounting for an estimated 4% of breast cancer families and conveying an 82% lifetime risk of breast cancer.9 Following the report by Hall et al. of linkage to chromosome 17q21 for early-onset hereditary breast cancer,10 BRCA1 was isolated using a positional cloning strategy in 1994.11 Subsequently, BRCA2, a second breast-ovarian cancer susceptibility gene, was localized to chromosome 13q12-q13 and cloned.12,13 GenBank, the National Institutes of Health genetic sequence database, lists entries for BRCA1 and BRCA2 as U14680 and U43746, respectively (http://www.ncbi.nlm.nih.gov/Genbank/).

Elucidation of the functions of BRCA1 and BRCA2 has lagged behind the technical capability of carrier detection, delineation of the clinical syndrome, and demonstration of the efficacy of medical management strategies. The manifold functions of BRCA1 and BRCA2 are incompletely characterized. BRCA1 and BRCA2 encode very large proteins with 1863 and 3418 amino acids, respectively; each bears little homology to other known proteins or to each other. BRCA1 appears to play a role in numerous cellular functions including transcriptional regulation and influence of estrogen receptor activity, chromatin remodeling, DNA damage repair (homologous recombination and repair of transcription-coupled oxidation-induced DNA damage), centrosome duplication, cell growth, apop-tosis, and cell cycle checkpoint control.14 BRCA1 contains an N-terminal RING domain that interacts with BARD1. Two BRCA1 C-terminal (BRCT) domains are present, which are found in proteins involved in DNA repair and control of the cell cycle. BRCA2 contains eight highly conserved BRC repeats of 30 to 40 residues in exon 11, which bind to RAD51, a key recombinational repair protein. After exposure of cells to DNA damage, BRCA1 relocalizes from nuclear foci to sites of DNA synthesis and becomes hyper-phosphorylated. BARD1, BRCA2, and RAD51 all relocalize with BRCA1.15

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