Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers

Grupo de Epidemiología Genética y Molecular, Programa de Genética del Cáncer Humano, Centro Nacional de Investigaciones Oncológicas (CNIO), C/Melchor Fernández Almagro, Madrid, Spain.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 04/2009; 119(1):221-32. DOI: 10.1007/s10549-009-0394-1
Source: PubMed


Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre. The results for ever being parous and number of live-births were very similar for carriers of mutations in both genes. For all mutation carriers combined, the estimated HR associated with ever having had a live-birth was 0.74 (95% confidence interval [CI] = 0.55-1.01, P = 0.06), and that associated with each live-birth was 0.87 (95%CI = 0.77-0.98, P = 0.02). The latter association was observed only in women aged 40 and above (HR = 0.81, 95%CI = 0.70-0.94, P = 0.004 vs. HR = 0.99, 95%CI = 0.83-1.18, P = 0.9 for women under age 40), and this trend was highly consistently observed for carriers of mutations in each gene. There was no evidence of an association between breast cancer risk and age at first birth for parous BRCA1 or BRCA2 mutation carriers (P-trend >or= 0.3). The power to detect associations with ovarian cancer risk was much lower, especially for BRCA2 mutation carriers. Nevertheless, having a live-birth was associated with protection for BRCA1 mutation carriers (HR = 0.41, 95%CI = 0.18-0.94, P = 0.03), and a strong and consistent protective effect of age at first birth was observed for parous carriers of mutations in both genes (HR = 0.65, 95%CI = 0.52-0.83, P < 0.001). This is the third independent study to find that, as in the general population, parity appears to be associated with protection from breast cancer in women with mutations in BRCA1 and BRCA2. Parity appears to be protective for ovarian cancer in BRCA1 mutation carriers, but its role in BRCA2 mutation carriers remains unclear. Whether later age at first birth is also protective for ovarian cancer in mutation carriers requires further confirmation.

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Available from: Eladio Andrés Velasco,
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    • "A cohort effect, alternatively an anticipation effect, has also been reported to influence the age at diagnosis in BRCA1/2 mutation carriers (Litton et al., 2012; Martinez-Delgado et al., 2011; Narod, 2011). Parity, the age at first full-term pregnancy, and breastfeeding habits are other factors that influence the age at cancer diagnosis (Jernstr€ om et al., 1999, 2004; Cullinane et al., 2005; McLaughlin et al., 2007; Fishman, 2010; Milne et al., 2010; Kotsopoulos et al., 2012). There are also several low-penetrance genes that may modify the penetrance of BRCA1/2 mutations (Barnes and Antoniou, 2012; Couch et al., 2013). "
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    ABSTRACT: Three studies have reported that BRCA1/2 mutations of paternal origin confer an earlier age at breast cancer diagnosis compared with maternal origin. The primary aim of this study was to investigate the impact of parental origin of BRCA1/2 mutations on age at breast and ovarian cancer diagnosis. This study included 577 female BRCA1/2 mutation carriers. All BRCA1/2 mutation carriers belonged to families registered between 1993 and 2011 at the Oncogenetic Clinic at Skånes University Hospital, Lund, Sweden. Cox proportional hazard ratios were used to analyze time to breast or ovarian cancer diagnosis. A novel finding was that carriers of BRCA1 mutations of paternal origin were 4 years older at age of ovarian cancer (P = 0.009) compared with those carrying a BRCA1 mutation of maternal origin. BRCA1 carriers with mutations of paternal origin were 4 years younger at breast cancer diagnosis (P = 0.017) compared with those carrying a BRCA1 mutation of maternal origin, which is in agreement with three previous studies. Both findings were adjusted for of year of inclusion, birth date, and oral contraceptive pill use. No associations between parental origin of BRCA2 mutations and time to breast or ovarian cancer diagnosis were found. An attempt to handle a potential selection bias regarding use of oral contraceptives was made using multiple imputations by chained equations. The observed age difference may allow a greater understanding of mechanisms associated with the differences in cancer penetrance in BRCA1/2 mutation carriers, some of which may depend on paternal origin. © 2014 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 01/2015; 54(1). DOI:10.1002/gcc.22217 · 4.04 Impact Factor
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    • "Reproductive factors including parity and breastfeeding practices have been associated with risk reduction in BRCA mutation carriers similar to that of the general population [29,30], suggesting that modifiable risk factors can attenuate risk in this group. However, our understanding of the potential for risk reduction for the majority of modifiable of risk factors in this high risk group remains unknown. "
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    ABSTRACT: Background Breast cancer is the most common female cancer worldwide. The lifetime risk of a woman being diagnosed with breast cancer is approximately 12.5%. For women who carry the deleterious mutation in either of the BRCA genes, BRCA1 or BRCA2, the risk of developing breast or ovarian cancer is significantly increased. In recent years there has been increased penetrance of BRCA1 and BRCA2 associated breast cancer, prompting investigation into the role of modifiable risk factors in this group. Previous investigations into this topic have relied on participants recalling lifetime weight changes and subjective methods of recording physical activity. The influence of obesity-related biomarkers, which may explain the link between obesity, physical activity and breast cancer risk, has not been investigated prospectively in this group. This paper describes the design of a prospective cohort study investigating the role of predictive and modifiable risk factors for breast cancer in unaffected BRCA1 and BRCA2 gene mutation carriers. Methods/design Participants will be recruited from breast cancer family risk clinics and genetics clinics. Lifestyle risk factors that will be investigated will include body composition, metabolic syndrome and its components, physical activity and dietary intake. PBMC telomere length will be measured as a potential predictor of breast cancer occurrence. Measurements will be completed on entry to the study and repeated at two years and five years. Participants will also be followed annually by questionnaire to track changes in risk factor status and to record cancer occurrence. Data will be analysed using multiple regression models. The study has an accrual target of 352 participants. Discussion The results from this study will provide valuable information regarding the role of modifiable lifestyle risk factors for breast cancer in women with a deleterious mutation in the BRCA gene. Additionally, the study will attempt to identify potential blood biomarkers which may be predictive of breast cancer occurrence.
    BMC Cancer 03/2013; 13(1):138. DOI:10.1186/1471-2407-13-138 · 3.36 Impact Factor
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    • "Segregation analysis models have also quantified the extent of variation in risk between and within families (Antoniou et al., 2008a; Begg et al., 2008). Lifestyle factors such as parity may influence risk (Andrieu et al., 2006; Cullinane et al., 2005; Milne et al., 2010). However, the higher risk in mutation carriers with a strong family history of the disease suggests that genetic modifiers of BRCA1 and BRCA2 also influence the risk of the disease (Antoniou et al., 2008a). "
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    ABSTRACT: Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in BRCA1 and BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from BRCA1 and BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.
    Molecular oncology 06/2010; 4(3):174-91. DOI:10.1016/j.molonc.2010.04.011 · 5.33 Impact Factor
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