BRCA1 and BRCA2 Cancer Risks
http://www.100md.com
《临床肿瘤学》
Cancer Research United Kingdom Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Cancer Research United Kingdom Human Cancer Genetics Group, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, United Kingdom
The recent analysis of penetrance obtained from high-risk families in North America gives rise to some concern, as it purports to provide useful information to women undertaking genetic testing today.1 Chen et al1 reported that "it is important to assess the future cancer risks for a cancer free counselee" and that a "counselee can directly read her prospective risks" from one of the tables and curves in the report. A series of 1,948 families were tested for BRCA1/2 mutations in more than eight centers. Two hundred eighty-three BRCA1 mutation families and 143 BRCA2 mutation families were identified. Chen et al used statistical modeling to arrive at penetrance figures by age 70 years of 46% (95%CI, 39% to 54%) for BRCA1 and 43% (95%CI, 36% to 51%) for BRCA2. Previous studies have found evidence that genetic or environmental modifiers that cluster in families may modify the risk of breast cancer conferred by BRCA1 and BRCA2 mutations or risks may vary the site and type of mutation.2,3 Given the study design of Chen et al, one would therefore expect their penetrance estimates to be on average higher than estimates from population based studies, whereas in fact they are lower.2,4
A possible explanation for the low breast cancer risk estimates found in this study is that they may be biased by the failure to account for other genes. In their analysis, Chen et al used all ascertained families, both mutation positive and mutation negative, and modeled the probability of the genetic test result conditional on the family phenotypes and the genetic model (retrospective likelihood) or the probability of the test result and family phenotypes conditional on the genetic model (prospective likelihood). However, they assumed a model where all genetic susceptibility to breast cancer is due to BRCA1 and BRCA2 only. BRCA1 and BRCA2 mutations account for only 15% to 20% of the observed familial relative risk among first degree relatives, and other genes, probably conferring lower risks, are likely to explain the residual familial clustering.5 In the analysis of Chen et al, a proportion of mutation negative families with evidence of familial aggregation will be assumed to be due to BRCA1 and BRCA2, so that the resulting penetrance estimates represent a weighted average of the risks from both mutation positive and mutation negative families. As a result, Chen et al may have underestimated the breast cancer risks in their sample of BRCA1 and BRCA2 mutation positive families. This effect was demonstrated in the segregation analysis results of Antoniou et al6 where the authors modeled the simultaneous effects of BRCA1, BRCA2, and other hypothetical genes. When all genetic susceptibility was assumed to be due to BRCA1 and BRCA2, the breast cancer risks conferred by the mutations were estimated to be much lower than when a third major gene, or a polygenic component, was allowed into the model.
We are also concerned about the adjustments for the effects of bilateral oophorectomy presented in Table 8. Evidence from population-based studies indicate that the effects of oophorectomy are predominantly, if not completely, due to the effect of an earlier menopause, and that the effect depends strongly on the age at menopause.7 Although this has not been shown clearly in BRCA1/2 carriers, it seems implausible that an oophorectomy at age 50 has the same effect as one at age 35. This effect needs to be kept in mind during counseling.
Finally, we would like to caution against the presumption that there are a single set of risk estimates for BRCA1/2 carriers that are appropriate in all situations. There is strong evidence that these risks are influenced by both genetic and lifestyle risk factors. In particular, the risks are expected to be correlated with family history, and clinicians should be aware of this when counseling at-risk women.
REFERENCES
Chen S, Iversen ES, Friebel T, et al: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24:863-871, 2006
Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003
Thompson D, Easton D: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410-419, 2001
Begg CB: On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 94:1221-1226, 2002
Thompson D, Easton D: The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia 9:221-236, 2004
Antoniou AC, Pharoah PD, McMullan G, et al: A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76-83, 2002
Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047-1059, 1997(Antonis C. Antoniou , Pau)
Cancer Research United Kingdom Human Cancer Genetics Group, Department of Oncology, University of Cambridge, Cambridge, United Kingdom
CR-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Academic Unit of Medical Genetics and Regional Genetics Service, St Mary's Hospital, Manchester, United Kingdom
The recent analysis of penetrance obtained from high-risk families in North America gives rise to some concern, as it purports to provide useful information to women undertaking genetic testing today.1 Chen et al1 reported that "it is important to assess the future cancer risks for a cancer free counselee" and that a "counselee can directly read her prospective risks" from one of the tables and curves in the report. A series of 1,948 families were tested for BRCA1/2 mutations in more than eight centers. Two hundred eighty-three BRCA1 mutation families and 143 BRCA2 mutation families were identified. Chen et al used statistical modeling to arrive at penetrance figures by age 70 years of 46% (95%CI, 39% to 54%) for BRCA1 and 43% (95%CI, 36% to 51%) for BRCA2. Previous studies have found evidence that genetic or environmental modifiers that cluster in families may modify the risk of breast cancer conferred by BRCA1 and BRCA2 mutations or risks may vary the site and type of mutation.2,3 Given the study design of Chen et al, one would therefore expect their penetrance estimates to be on average higher than estimates from population based studies, whereas in fact they are lower.2,4
A possible explanation for the low breast cancer risk estimates found in this study is that they may be biased by the failure to account for other genes. In their analysis, Chen et al used all ascertained families, both mutation positive and mutation negative, and modeled the probability of the genetic test result conditional on the family phenotypes and the genetic model (retrospective likelihood) or the probability of the test result and family phenotypes conditional on the genetic model (prospective likelihood). However, they assumed a model where all genetic susceptibility to breast cancer is due to BRCA1 and BRCA2 only. BRCA1 and BRCA2 mutations account for only 15% to 20% of the observed familial relative risk among first degree relatives, and other genes, probably conferring lower risks, are likely to explain the residual familial clustering.5 In the analysis of Chen et al, a proportion of mutation negative families with evidence of familial aggregation will be assumed to be due to BRCA1 and BRCA2, so that the resulting penetrance estimates represent a weighted average of the risks from both mutation positive and mutation negative families. As a result, Chen et al may have underestimated the breast cancer risks in their sample of BRCA1 and BRCA2 mutation positive families. This effect was demonstrated in the segregation analysis results of Antoniou et al6 where the authors modeled the simultaneous effects of BRCA1, BRCA2, and other hypothetical genes. When all genetic susceptibility was assumed to be due to BRCA1 and BRCA2, the breast cancer risks conferred by the mutations were estimated to be much lower than when a third major gene, or a polygenic component, was allowed into the model.
We are also concerned about the adjustments for the effects of bilateral oophorectomy presented in Table 8. Evidence from population-based studies indicate that the effects of oophorectomy are predominantly, if not completely, due to the effect of an earlier menopause, and that the effect depends strongly on the age at menopause.7 Although this has not been shown clearly in BRCA1/2 carriers, it seems implausible that an oophorectomy at age 50 has the same effect as one at age 35. This effect needs to be kept in mind during counseling.
Finally, we would like to caution against the presumption that there are a single set of risk estimates for BRCA1/2 carriers that are appropriate in all situations. There is strong evidence that these risks are influenced by both genetic and lifestyle risk factors. In particular, the risks are expected to be correlated with family history, and clinicians should be aware of this when counseling at-risk women.
REFERENCES
Chen S, Iversen ES, Friebel T, et al: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24:863-871, 2006
Antoniou A, Pharoah PD, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003
Thompson D, Easton D: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68:410-419, 2001
Begg CB: On the use of familial aggregation in population-based case probands for calculating penetrance. J Natl Cancer Inst 94:1221-1226, 2002
Thompson D, Easton D: The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia 9:221-236, 2004
Antoniou AC, Pharoah PD, McMullan G, et al: A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76-83, 2002
Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormone replacement therapy: Collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 350:1047-1059, 1997(Antonis C. Antoniou , Pau)