Weight History, Smoking, Physical Activity and Breast Cancer Risk among French-Canadian Women Non-Carriers of More Frequent BRCA1/2 Mutations

Several lifestyle factors play a significant role in determining an individual's risk of breast cancer. Many of them could be modified to protect against the malignancy. A nested case-control study was conducted to examine the association between selected lifestyle factors and non-BRCA-related breast cancer risk among French-Canadian women. Some 280 women with breast cancer and who were nongene carriers of mutated BRCA gene were recruited as cases. Another 280 women, without any cancer and nongene carriers of mutated BRCA gene served as controls. A tested lifestyle questionnaire was interviewer administered to incident cases to obtain information on weight history, smoking, physical activity, and other lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in logistic regression models. Comparing cases to controls, breast cancer risk was higher among subjects who reached their maximum body mass index (BMI) at an older age (>50 years) (OR = 2.83; 95% CI: 2.34–2.91). A positive association was noted between breast cancer risk and weight gain of >34 lbs compared to weight gain of ≤15 lbs, since the age of 20 (OR = 1.68; 95% CI: 1.10–2.58). Weight gain of >24 lbs compared to weight gain of ≤9 lbs, since the age of 30 also resulted in the same relationship (OR = 1.96; 95% CI: 1.46–3.06). Similarly, since the age of 40, weight gain of >12 lbs compared to weight gain of ≤1 lb was associated with increased breast cancer risk (OR = 1.91; 95% CI: 1.53–2.66). Women who smoked >9 pack-years of cigarettes had a 59% higher breast cancer risk (P = .05). Subjects who engaged in >24.8 metabolic-equivalent- (MET-) hours per week compared to ≤10.7 MET-hours per week of moderate physical activity had a 52% (P = .01) decreased risk and total physical activity between 16.2 and 33.2 MET-hours per week compared to ≤16.2 MET-hours per week, resulted in a 43% (P = .05) lower risk of breast cancer. In conclusion, weight history did affect breast cancer risk. Moreover, smoking appeared to raise the risk, whereas moderate physical activity had a protective effect

Non-Carriers of More Frequent BRCA1/2 Mutations

Recommended by Paolo Boffetta Several lifestyle factors play a significant role in determining an individual's risk of breast cancer. Many of them could be modified to protect against the malignancy. A nested case-control study was conducted to examine the association between selected lifestyle factors and non-BRCA-related breast cancer risk among French-Canadian women. Some 280 women with breast cancer and who were nongene carriers of mutated BRCA gene were recruited as cases. Another 280 women, without any cancer and nongene carriers of mutated BRCA gene served as controls. A tested lifestyle questionnaire was interviewer administered to incident cases to obtain information on weight history, smoking, physical activity, and other lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in logistic regression models. Comparing cases to controls, breast cancer risk was higher among subjects who reached their maximum body mass index (BMI) at an older age (>50 years) (OR = 2.83; 95% CI: 2.34-2.91). A positive association was noted between breast cancer risk and weight gain of >34 lbs compared to weight gain of ≤15 lbs, since the age of 20 (OR = 1.68; 95% CI: 1.10-2.58). Weight gain of >24 lbs compared to weight gain of ≤9 lbs, since the age of 30 also resulted in the same relationship (OR = 1.96; 95% CI: 1.46-3.06). Similarly, since the age of 40, weight gain of >12 lbs compared to weight gain of ≤1 lb was associated with increased breast cancer risk (OR = 1.91; 95% CI: 1.53-2.66). Women who smoked >9 pack-years of cigarettes had a 59% higher breast cancer risk (P = .05). Subjects who engaged in >24.8 metabolic-equivalent-(MET-) hours per week compared to ≤10.7 MET-hours per week of moderate physical activity had a 52% (P = .01) decreased risk and total physical activity between 16.2 and 33.2 MET-hours per week compared to ≤16.2 MET-hours per week, resulted in a 43% (P = .05) lower risk of breast cancer. In conclusion, weight history did affect breast cancer risk. Moreover, smoking appeared to raise the risk, whereas moderate physical activity had a protective effect

Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women

<p>Abstract</p> <p>Background</p> <p><it>BRCA1 </it>and <it>BRCA2 </it>account for the majority of the known familial breast cancer risk, however, the impact of other cancer susceptibility genes largely remains to be elucidated. Checkpoint Kinase 2 (<it>CHEK2</it>) is an important signal transducer of cellular responses to DNA damage, whose defects have been associated with an increase in breast cancer risk. Previous studies have identified low penetrance <it>CHEK2 </it>alleles such as 1100delC and I157T, as well as variants such as S428F in the Ashkenazi Jewish population and IVS2 + 1G>A in the Polish population. No founder allele has been specifically identified in the French Canadian population.</p> <p>Methods</p> <p>The 14 coding exons of <it>CHEK2 </it>were fully sequenced for variant alleles in a panel of 25 affected French Canadian women and 25 healthy controls. Two variants were identified of which one novel variant was further screened for in an additional panel of 667 breast cancer patients and 6548 healthy controls. Additional genotyping was conducted using allele specific PCR and a restriction digest assay. Significance of amino acid substitutions were deduced by employing comparative analysis techniques.</p> <p>Results</p> <p>Two variants were identified: the previously reported silent substitution 252A>G (E84E) and the novel missense variant, 1217G>A (R406H). No significant difference in allele distribution between French Canadian women with breast cancer and healthy controls was observed (3/692, 0.43% vs. 22/6573, 0.33%, respectively, P = 0.73).</p> <p>Conclusion</p> <p>The novel CHEK2 missense variant identified in this study, R406H, is unlikely to contribute to breast cancer risk in French Canadian women.</p

Effect of Prior Bilateral Oophorectomy on the Presentation of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

Purpose: To compare the presentation of invasive breast cancer in BRCA1 and BRCA2 mutation carriers with and without prior bilateral oophorectomy. Patients and methods: Women with a BRCA1 or BRCA2 mutation with the diagnosis of invasive breast cancer were identified from ten cancer genetics clinics. The medical history, medical treatment records and pathology reports for the breast cancers were reviewed. Information was abstracted from medical charts, including history (and date) of oophorectomy, date of breast cancer diagnosis, stage of disease, and pathologic characteristics of the breast cancer. Women with prior bilateral oophorectomy were matched by age, year of diagnosis, and mutation with one or more women who had two intact ovaries at the time of breast cancer diagnosis. Characteristics of the breast tumours were compared between the two groups

Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Abstract Objective. Hormone replacement therapy (HRT) is commonly prescribed to alleviate the climacteric symptoms of menopause. Recent findings from the Women&apos;s Health Initiative has raised questions about the routine use of HRT due to the increased observed incidence of cardiovascular disease and of breast and ovarian cancers in the treatment arm of the trial. In the general population, the association between HRT use and risk of ovarian cancer has not yet been resolved. This association has not been evaluated in BRCA1 or BRCA2 mutation carriers who face very high lifetime risks of both breast and ovarian cancers. Methods. We conducted a matched case-control study on 162 matched sets of women who carry a deleterious mutation in either the BRCA1 or BRCA2 gene. Women who had been diagnosed with ovarian cancer were matched to control subjects by mutation, year of birth, and age at menopause. Information on HRT use was derived from a questionnaire routinely administered to women who were found to be carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between HRT use and the risk of ovarian cancer, stratified by mutation status and type of HRT. Results. Compared with those who had never used HRT, the odds ratio associated with ever use of HRT was 0.93 (95% CI = 0.56 -1.56). There was no significant relationship with increasing duration of HRT use. There was a suggestion that progestinbased HRT regimens might protect against ovarian cancer (odds ratio = 0.57) but this association was not statistically significant ( P = 0.20). Conclusion. HRT use does not appear to adversely influence the risk of ovarian cancer in BRCA mutation carriers.

Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women

Abstract Background PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. Methods We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. Results We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. Conclusion We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population

Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

BACKGROUND: The 3398delAAAAG mutation in BRCA2 was recently found to recur in breast and/or ovarian cancer families from the French Canadian population of Quebec, a population that has genetic attributes consistent with a founder effect. To characterize the contribution of this mutation in this population, this study established the frequency of this mutation in breast and ovarian cancer cases unselected for family history of cancer, and determined if mutation carriers shared a common ancestry. METHODS: The frequency was estimated by assaying the mutation in series of French Canadian breast cancer cases diagnosed before age 41 (n = 60) or 80 (n = 127) years of age, and ovarian cancer cases (n = 80) unselected for family history of cancer by mutation analysis. Haplotype analysis was performed to determine if mutation carriers shared a common ancestry. Members from 11 families were analyzed using six polymorphic microsatellite markers (cen-D13S260-D13S1699-D13S1698-D13S1697-D13S1701-D13S171-tel) spanning approximately a 3.6 cM interval at the chromosomal region 13q13.1, which contains BRCA2. Allele frequencies were estimated by genotyping 47 unaffected female individuals derived from the same population. Haplotype reconstruction of unaffected individuals was performed using the program PHASE. RESULTS: The recurrent BRCA2 mutation occurred in 1 of 60 (1.7%) women diagnosed with breast cancer before 41 years of age and one of 80 (1.3%) women with ovarian cancer. No mutation carriers were identified in the series of breast cancer cases diagnosed before age 80. Mutation carriers harboured one of two haplotypes, 7-3-9-3 – [3/4]-7, that varied with marker D13S1701 and which occurred at a frequency of 0.001. The genetic analysis of D13S1695, a polymorphic marker located approximately 0.3 cM distal to D13S171, did not favour a genetic recombination event to account for the differences in D13S1701 alleles within the haplotype. Although mutation carriers harbour genotypes that are frequent in the French Canadian population, neither mutation-associated haplotype was plausible in reconstructed haplotypes of 47 individuals of French Canadian descent. CONCLUSION: These results suggest that mutation carriers share a related ancestry; further supporting the concept that recurrent BRCA1 and BRCA2 mutations in the French Canadian population could be attributed to common founders. This finding provides further support for targeted screening of recurrent mutations in this population before large-scale mutation analyses are performed

Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

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