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Heritable breast cancer in twins
T M Mack1, A S Hamilton, M F Press
1Department of Preventive Medicine, University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, 1441 Eastlake Avenue MC9175, Los Angeles, California, CA 90089-9175, USA. tmack@usc.edu
British Journal of Cancer
|August 15, 2002
Summary
Most heritable breast cancers are not caused by major mutations like BRCA1/2. Instead, a complex genetic profile involving multiple susceptibility alleles likely drives hormone-related breast cancer risk.
Area of Science:
- Genetics
- Oncology
- Epidemiology
Background:
- Major gene mutations (e.g., BRCA1/2, TP53) explain only a small fraction of hereditary breast cancers.
- Hormone-regulating genes with lower penetrance are hypothesized to contribute to the majority of other cases.
- Identical twin studies offer a comprehensive model to study the full spectrum of genetic alleles influencing breast cancer risk.
Purpose of the Study:
- To investigate the descriptive and histological characteristics of breast cancers in monozygotic (MZ) and dizygotic (DZ) twins.
- To compare concordant and discordant breast cancer cases within twin pairs against conventional hypotheses.
- To elucidate the genetic underpinnings of breast cancer beyond known high-penetrance mutations.
Main Methods:
- Analysis of breast cancer concordance and discordance in 2310 affected MZ and DZ twin pairs.
- Comparison of standardized incidence ratios (SIR) for breast cancer in co-twins.
- Histological and receptor status (oestrogen receptor-positive) analysis of tumors in concordant vs. discordant pairs.
Main Results:
- MZ co-twins of breast cancer cases exhibit a significantly higher risk (SIR=4.4) than predicted by genetic identity alone.
- Breast cancer diagnoses occur more rapidly in MZ co-twins of early-onset cases (within 5 years, SIR=20.0).
- Tumors in concordant twin pairs are more likely to be oestrogen receptor-positive than those in discordant pairs.
Conclusions:
- The increased risk in MZ co-twins suggests a genetic model beyond common environmental factors or single dominant mutations.
- A genotype involving multiple interacting susceptibility alleles, potentially affecting hormone regulation or tumor suppression, is a more plausible explanation.
- This complex genetic profile accounts for a substantial proportion of all breast cancers, exhibiting higher penetrance than previously recognized, with some distinct biological characteristics.
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