Purpose: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear.

Experimental Design: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Tyr1915Met). We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls.

Results: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study.

Conclusions: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2339–42)

Rare mutations [minor allele frequency (MAF), <1%] in BRCA1 and BRCA2 cause 5% to 10% of all breast and ovarian cancer and 20% to 30% of hereditary breast and ovarian cancer cases (1). During screenings of breast and ovarian cancer cases with a strong familial history of breast and/or ovarian cancer, missense polymorphisms (MAF, ≥1%) are often discovered. These polymorphisms pose a problem in genetic counseling, as an impact on risk of breast and/or ovarian cancer has not been excluded convincingly.

We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine nonconservative amino acid substituting and thus possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Tyr1915Met). Several of the chosen polymorphisms were furthermore located in regions of BRCA1 and BRCA2 known to be interaction sites for key partner proteins (2, 3), and many of the amino acids concerned are conserved in human, mouse, and rat. We evaluated risk of breast and/or ovarian cancer associated with these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years, and in a case-control study of 1,201 breast cancer cases and 4,120 controls.

For a full description of methods, refer to Dombernowsky et al. (4) and Weischer et al. (5).

Participants

First, we resequenced BRCA1 and BRCA2 in 194 Danish women referred for genetic counseling due to a familial history of breast and/or ovarian cancer.

Second, we did a prospective population-based study of 5,743 White women from the Danish general population participating in the Copenhagen City Heart Study (4-6). Diagnoses of invasive cancer (WHO International Classification of Diseases 7th edition) for the whole cohort from 1947 through August 11th 2007 were obtained from the Danish Patient Registry and the Danish Cancer Registry. Follow-up was 100% complete.

Third, we did a case-control study that included 1,201 White women with invasive breast cancer consecutively recruited at Herlev Hospital, Copenhagen University Hospital, between January 2002 and August 2004 (5, 7).Controls were 4,120 White women from the general population (The Copenhagen City Heart Study) within the same age range as the patients, who had no history of breast cancer before 11th of August 2007.

Genotyping

Genotyping of prospective and case-control study participants was done using TaqMan assays (Applied Biosystems).

Statistical Analyses

In the prospective study, we used log-rank test and Cox regression with delayed entry and age as the underlying time variable. In the case-control study, one breast cancer case was matched with up to four controls within 1-y age strata and conditional logistic regression was done. To increase power, homozygotes were pooled with heterozygotes in analyses of polymorphisms with a MAF of <5%.

We achieved call rates between 99.9% and 100% for all genotypes in both studies. Characteristics of prospective and case-control study participants at study entry were as previously described (4, 5).

In the general population, minor allele frequencies were BRCA1 Gln356Arg 6.4%, BRCA1 Pro871Leu 34.3%, BRCA1 Glu1038Gly 32.7%, BRCA1 Ser1613Gly 32.8%, BRCA1 Met1652Ile 1.2%, BRCA2 Asn289His 3.0%, BRCA2 Asn372His 28.2%, BRCA2 Asp1420Tyr 1.3%, and BRCA2 Tyr1915Met 3.3%. All missense polymorphisms were in Hardy-Weinberg equilibrium (χ2 test: P = 0.61, P = 0.52, P = 0.96, P = 0.84, P = 0.21, P = 0.38, P = 0.47, P = 0.91, and P = 0.96, respectively). BRCA1 Pro871Leu, Glu1038Gly, and Ser1613Gly were in strong linkage disequilibrium (D' = 0.99-1.00; r2 = 0.91-0.99; data not shown).

In the prospective study, 419 women were diagnosed with breast and/or ovarian cancer during 39 years of follow-up. Of these, 342 had breast cancer, 71 had ovarian cancer, and 6 had both breast and ovarian cancer. We found no association between heterozygosity or homozygosity for any of the nine BRCA1 and BRCA2 polymorphisms and risk of breast and/or ovarian cancer in the prospective study (Table 1). Table 1 also shows the hazard ratios we had 80% power to exclude. Furthermore, heterozygosity or homozygosity of any combination of two of the nine polymorphisms did not associate with increased risk of breast and/or ovarian cancer (data not shown). After Bonferroni correction, there were no significant interactions between either of the nine polymorphisms and either of the eight covariates (see Table 1 legend) on risk of breast and/or ovarian cancer [with 14 genotypes tested, the new level of significance was P = 0.05/(8 × 14) = 0.00045].

Table 1.

Incidence and risk of breast and/or ovarian cancer in the prospective study according to genotype

Participants (n)Breast and/or ovarian cancers (n)Incidence (95% CI; per 10,000 person-year)Log-rank PHazard ratio (95% CI)80% power hazard ratio*
Age adjustmentMultifactorial adjustment
BRCA1 
    Gln356Arg 
        Gln-Gln 4,976 356 21 (19-23)  1.0 1.0  
        Gln-Arg 686 60 25 (20-33) 0.06 1.3 (1.0-1.7) 1.1 (0.9-1.5) 1.4 
        Arg-Arg 21 3 39 (13-121) 0.07 2.7 (0.9-8.5) 2.2 (0.7-6.9) 3.3 
    Pro871Leu 
        Pro-Pro 2,443 183 22 (19-25)  1.0 1.0  
        Pro-Leu 2,582 189 21 (19-25) 0.91 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Leu-Leu 657 47 21 (16-28) 0.92 1.0 (0.7-1.4) 1.0 (0.7-1.4) 1.5 
    Glu1038Gly 
        Glu-Glu 2,578 194 22 (19-25)  1.0 1.0  
        Glu-Gly 2,498 183 21 (19-25) 0.89 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Gly-Gly 607 42 20 (15-28) 0.75 0.9 (0.7-1.3) 0.9 (0.7-1.3) 1.5 
    Ser1613Gly 
        Ser-Ser 2,571 193 22 (19-25)  1.0 1.0  
        Ser-Gly 2,498 182 21 (18-25) 0.84 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Gly-Gly 614 44 21 (16-28) 0.89 1.0 (0.7-1.4) 1.0 (0.7-1.3) 1.5 
    Met1652Ile 
        Met-Met 5,547 407 21 (19-24)  1.0 1.0  
    Met-Ile +     Ile-Ile† 137 12 26 (15-46) 0.45 1.3 (0.7-2.2) 1.3 (0.7-2.4) 1.9 
BRCA2        
    Asn289His 
        Asn-Asn  5,351 390 21 (19-24)  1.0 1.0  
    Asn-His +     His-His† 333 29 25 (18-36) 0.64 1.1 (0.7-1.6) 1.1 (0.8-1.6) 1.6 
    Asn372His 
        Asn-Asn 2,921 207 21 (18-24)  1.0 1.0  
        Asn-His 2,322 179 23 (19-26) 0.78 1.0 (0.8-1.3) 1.0 (0.9-1.3) 1.3 
        His-His 440 33 22 (15-30) 0.75 1.1 (0.7-1.5) 0.9 (0.6-1.4) 1.6 
    Asp1420Tyr 
        Asp-Asp  5,542 410 22 (20-24)  1.0 1.0  
        Asp-Tyr + Tyr-Tyr† 142 9 19 (10-36) 0.81 0.9 (0.5-1.8) 0.8 (0.4-1.7) 1.9 
    Tyr1915Met 
        Tyr-Tyr 5,317 396 22 (20-24)  1.0 1.0  
    Tyr-Met + Met-Met† 367 23 19 (12-28) 0.69 0.9 (0.6-1.4) 0.9 (0.6-1.4) 1.6 
Participants (n)Breast and/or ovarian cancers (n)Incidence (95% CI; per 10,000 person-year)Log-rank PHazard ratio (95% CI)80% power hazard ratio*
Age adjustmentMultifactorial adjustment
BRCA1 
    Gln356Arg 
        Gln-Gln 4,976 356 21 (19-23)  1.0 1.0  
        Gln-Arg 686 60 25 (20-33) 0.06 1.3 (1.0-1.7) 1.1 (0.9-1.5) 1.4 
        Arg-Arg 21 3 39 (13-121) 0.07 2.7 (0.9-8.5) 2.2 (0.7-6.9) 3.3 
    Pro871Leu 
        Pro-Pro 2,443 183 22 (19-25)  1.0 1.0  
        Pro-Leu 2,582 189 21 (19-25) 0.91 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Leu-Leu 657 47 21 (16-28) 0.92 1.0 (0.7-1.4) 1.0 (0.7-1.4) 1.5 
    Glu1038Gly 
        Glu-Glu 2,578 194 22 (19-25)  1.0 1.0  
        Glu-Gly 2,498 183 21 (19-25) 0.89 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Gly-Gly 607 42 20 (15-28) 0.75 0.9 (0.7-1.3) 0.9 (0.7-1.3) 1.5 
    Ser1613Gly 
        Ser-Ser 2,571 193 22 (19-25)  1.0 1.0  
        Ser-Gly 2,498 182 21 (18-25) 0.84 1.0 (0.8-1.2) 1.0 (0.8-1.2) 1.3 
        Gly-Gly 614 44 21 (16-28) 0.89 1.0 (0.7-1.4) 1.0 (0.7-1.3) 1.5 
    Met1652Ile 
        Met-Met 5,547 407 21 (19-24)  1.0 1.0  
    Met-Ile +     Ile-Ile† 137 12 26 (15-46) 0.45 1.3 (0.7-2.2) 1.3 (0.7-2.4) 1.9 
BRCA2        
    Asn289His 
        Asn-Asn  5,351 390 21 (19-24)  1.0 1.0  
    Asn-His +     His-His† 333 29 25 (18-36) 0.64 1.1 (0.7-1.6) 1.1 (0.8-1.6) 1.6 
    Asn372His 
        Asn-Asn 2,921 207 21 (18-24)  1.0 1.0  
        Asn-His 2,322 179 23 (19-26) 0.78 1.0 (0.8-1.3) 1.0 (0.9-1.3) 1.3 
        His-His 440 33 22 (15-30) 0.75 1.1 (0.7-1.5) 0.9 (0.6-1.4) 1.6 
    Asp1420Tyr 
        Asp-Asp  5,542 410 22 (20-24)  1.0 1.0  
        Asp-Tyr + Tyr-Tyr† 142 9 19 (10-36) 0.81 0.9 (0.5-1.8) 0.8 (0.4-1.7) 1.9 
    Tyr1915Met 
        Tyr-Tyr 5,317 396 22 (20-24)  1.0 1.0  
    Tyr-Met + Met-Met† 367 23 19 (12-28) 0.69 0.9 (0.6-1.4) 0.9 (0.6-1.4) 1.6 

NOTE: Multifactorial adjustment included age (<50 y vs ≥50 y), body mass index (BMI ≤25 kg/m2 vs 25 kg/m2 < BMI ≤30 kg/m2 vs BMI >30 kg/m2), weekly alcohol intake (0 grams/wk vs 1-168 grams/wk vs >168 grams/wk), parity (number of children), nulliparity (yes/no), use of oral contraceptive drugs at the time of examination (yes/no), menopausal status (premenopausal/postmenopausal), and use of hormonal replacement therapy at the time of examination (yes/no).

Abbreviation: CI, confidence interval.

*We had 80% power at two-sided P value of <0.05 to exclude the hazard ratios given.

†Homozygotes were pooled with heterozygotes in analyses of polymorphisms with a MAF of <5%.

View Large

Likewise, we found no association between heterozygosity or homozygosity of any of the nine missense polymorphisms and risk of breast cancer in the case-control study (Table 2). Table 2 furthermore shows the odds ratios we had 80% power to exclude. After Bonferroni correction, there were no significant interactions between either of the nine polymorphisms and either of the eight covariates (see Table 2 legend) on risk of breast cancer (new level of significance P = 0.00045).

Table 2.

Risk of breast cancer in the case-control study according to genotype

Cases (n)Controls (n)Odds ratio (95% CI)80% power odds ratio*
Age adjustmentMultifactorial adjustment
BRCA1 
    Gln356Arg 
        Gln-Gln 1,048 3,589 1.0 1.0  
        Gln-Arg 147 513 1.0 (0.8-1.2) 1.0 (0.8-1.3) 1.3 
        Arg-Arg 5 17 0.9 (0.3-2.4) 0.8 (0.3-2.5) 3.2 
    Pro871Leu 
        Pro-Pro 550 1,756 1.0 1.0  
        Pro-Leu 496 1,896 0.8 (0.7-1.0) 0.9 (0.7-1.0) 1.2 
        Leu-Leu 155 467 1.1 (0.9-1.3) 1.0 (0.8-1.3) 1.4 
    Glu1038Gly 
        Glu-Glu 563 1,854 1.0 1.0  
        Glu-Gly 491 1,835 0.9 (0.8-1.0) 0.9 (0.8-1.1) 1.2 
        Gly-Gly 145 431 1.1 (0.9-1.4) 1.1 (0.8-1.4) 1.4 
    Ser1613Gly 
        Ser-Ser 557 1,850 1.0 1.0  
        Ser-Gly 508 1,834 0.9 (0.8-1.1) 1.0 (0.8-1.1) 1.2 
        Gly-Gly 133 435 1.0 (0.8-1.3) 1.0 (0.7-1.2) 1.4 
    Met1652Ile 
        Met-Met 1,162 4,030 1.0 1.0  
        Met-Ile + Ile-Ile† 38 90 1.5 (1.0-2.2) 1.5 (0.9-2.3) 1.8 
BRCA2 
    Asn289His 
        Asn-Asn  1,123 3,878 1.0 1.0  
        Asn-His + His-His† 75 242 1.1 (0.8-1.4) 1.1 (0.8-1.5) 1.5 
    Asn372His 
        Asn-Asn 604 2,129 1.0 1.0  
        Asn-His 503 1,677 1.1 (0.9-1.2) 1.0 (0.9-1.2) 1.2 
        His-His 93 313 1.0 (0.8-1.3) 1.0 (0.8-1.3) 1.4 
    Asp1420Tyr 
        Asp-Asp  1,178 4,014 1.0 1.0  
        Asp-Tyr + Tyr-Tyr† 22 106 0.7 (0.4-1.1) 0.7 (0.4-1.2) 1.7 
    Tyr1915Met 
        Tyr-Tyr 1,143 3,844 1.0 1.0  
        Tyr-Met + Met-Met† 57 276 0.7 (0.5-0.9) 0.7 (0.5-1.0) 1.4 
Cases (n)Controls (n)Odds ratio (95% CI)80% power odds ratio*
Age adjustmentMultifactorial adjustment
BRCA1 
    Gln356Arg 
        Gln-Gln 1,048 3,589 1.0 1.0  
        Gln-Arg 147 513 1.0 (0.8-1.2) 1.0 (0.8-1.3) 1.3 
        Arg-Arg 5 17 0.9 (0.3-2.4) 0.8 (0.3-2.5) 3.2 
    Pro871Leu 
        Pro-Pro 550 1,756 1.0 1.0  
        Pro-Leu 496 1,896 0.8 (0.7-1.0) 0.9 (0.7-1.0) 1.2 
        Leu-Leu 155 467 1.1 (0.9-1.3) 1.0 (0.8-1.3) 1.4 
    Glu1038Gly 
        Glu-Glu 563 1,854 1.0 1.0  
        Glu-Gly 491 1,835 0.9 (0.8-1.0) 0.9 (0.8-1.1) 1.2 
        Gly-Gly 145 431 1.1 (0.9-1.4) 1.1 (0.8-1.4) 1.4 
    Ser1613Gly 
        Ser-Ser 557 1,850 1.0 1.0  
        Ser-Gly 508 1,834 0.9 (0.8-1.1) 1.0 (0.8-1.1) 1.2 
        Gly-Gly 133 435 1.0 (0.8-1.3) 1.0 (0.7-1.2) 1.4 
    Met1652Ile 
        Met-Met 1,162 4,030 1.0 1.0  
        Met-Ile + Ile-Ile† 38 90 1.5 (1.0-2.2) 1.5 (0.9-2.3) 1.8 
BRCA2 
    Asn289His 
        Asn-Asn  1,123 3,878 1.0 1.0  
        Asn-His + His-His† 75 242 1.1 (0.8-1.4) 1.1 (0.8-1.5) 1.5 
    Asn372His 
        Asn-Asn 604 2,129 1.0 1.0  
        Asn-His 503 1,677 1.1 (0.9-1.2) 1.0 (0.9-1.2) 1.2 
        His-His 93 313 1.0 (0.8-1.3) 1.0 (0.8-1.3) 1.4 
    Asp1420Tyr 
        Asp-Asp  1,178 4,014 1.0 1.0  
        Asp-Tyr + Tyr-Tyr† 22 106 0.7 (0.4-1.1) 0.7 (0.4-1.2) 1.7 
    Tyr1915Met 
        Tyr-Tyr 1,143 3,844 1.0 1.0  
        Tyr-Met + Met-Met† 57 276 0.7 (0.5-0.9) 0.7 (0.5-1.0) 1.4 

NOTE: Multifactorial adjustment included age (<50 y vs ≥50 y), BMI (≤25 kg/m2 vs 25 kg/m2 <BMI ≤30 kg/m2 vs BMI >30 kg/m2), weekly alcohol intake (0 grams/wk vs 1-168 grams/wk vs >168 g/wk), parity (number of children), nulliparity (yes/no), use of oral contraceptive drugs at the time of examination (yes/no), menopausal status (premenopausal/postmenopausal), and use of hormonal replacement therapy at the time of examination (yes/no).

*We had 80% power at two-sided P value of <0.05 to exclude the odds ratios given.

†Homozygotes were pooled with heterozygotes in analyses of polymorphisms with a MAF of <5%.

View Large

Resequencing of BRCA1 and BRCA2 is offered as part of genetic counseling to women with a strong familial history of breast and/or ovarian cancer. On average, such screenings identify a causative mutation in 20% to 30% of patients (1). However, we identified amino acid substituting polymorphisms in 86% of the 194 women who underwent BRCA1 and BRCA2 resequencing at Herlev Hospital. Clinical geneticists generally regard these common polymorphisms as unimportant, although the literature to support this has been scarce and contradictive (8-24). Importantly, none of the examined nine BRCA1 and BRCA2 missense polymorphisms alone or in combination were associated with increased risk of breast and/or ovarian cancer in the general population, or in the breast cancer case-control study.

Previously, some of these missense polymorphisms have been examined in a number of smaller studies. Some of these found associations to breast and/or ovarian cancer (8, 13, 15, 16, 18, 21-23), whereas others did not (9-12, 14, 15, 17, 19, 20, 24). To the best of our knowledge, this is the first large population-based study of these nine missense polymorphisms. As we were not able to detect any associations despite sufficient power, we accordingly conclude that heterozygosity or homozygosity of any of the examined nine BRCA1 and BRCA2 polymorphisms, alone or in combination, cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms.

No potential conflicts of interest were disclosed.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1
Gerdes
 
AM
,
Cruger
 
DG
,
Thomassen
 
M
,
Kruse
 
TA
. 
Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families
.
Clin Genet
 
2006
;
69
:
171
–
8
.
Google Scholar
Crossref
Search ADS
PubMed
 
2
Deng
 
CX
,
Brodie
 
SG
. 
Roles of BRCA1 and its interacting proteins
.
Bioessays
 
2000
;
22
:
728
–
37
.
Google Scholar
Crossref
Search ADS
PubMed
 
3
Wong
 
AK
,
Pero
 
R
,
Ormonde
 
PA
,
Tavtigian
 
SV
,
Bartel
 
PL
. 
RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2
.
J Biol Chem
 
1997
;
272
:
31941
–
4
.
Google Scholar
Crossref
Search ADS
PubMed
 
4
Dombernowsky
 
SL
,
Weischer
 
M
,
Allin
 
KH
,
Bojesen
 
SE
,
Tybjaerg-Hansen
 
A
,
Nordestgaard
 
BG
. 
Risk of cancer by ATM missense mutations in the general population
.
J Clin Oncol
 
2008
;
26
:
3057
–
62
.
Google Scholar
Crossref
Search ADS
PubMed
 
5
Weischer
 
M
,
Bojesen
 
SE
,
Tybjaerg-Hansen
 
A
,
Axelsson
 
CK
,
Nordestgaard
 
BG
. 
Increased risk of breast cancer associated with CHEK2*1100delC
.
J Clin Oncol
 
2007
;
25
:
57
–
63
.
Google Scholar
PubMed
 
6
Bojesen
 
SE
,
Tybjaerg-Hansen
 
A
,
Nordestgaard
 
BG
. 
Integrin β3 Leu33Pro homozygosity and risk of cancer
.
J Natl Cancer Inst
 
2003
;
95
:
1150
–
7
.
Google Scholar
Crossref
Search ADS
PubMed
 
7
Bojesen
 
SE
,
Tybjaerg-Hansen
 
A
,
Axelsson
 
CK
,
Nordestgaard
 
BG
. 
No association of breast cancer risk with integrin β3 (ITGB3) Leu33Pro genotype
.
Br J Cancer
 
2005
;
93
:
167
–
71
.
Google Scholar
Crossref
Search ADS
PubMed
 
8
Auranen
 
A
,
Spurdle
 
AB
,
Chen
 
X
, et al. 
BRCA2 Arg372His polymorphism and epithelial ovarian cancer risk
.
Int J Cancer
 
2003
;
103
:
427
–
30
.
Google Scholar
Crossref
Search ADS
PubMed
 
9
Auranen
 
A
,
Song
 
H
,
Waterfall
 
C
, et al. 
Polymorphisms in DNA repair genes and epithelial ovarian cancer risk
.
Int J Cancer
 
2005
;
117
:
611
–
8
.
Google Scholar
Crossref
Search ADS
PubMed
 
10
Breast Cancer Association Consortium
. 
Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium
.
J Natl Cancer Inst
 
2006
;
98
:
1382
–
96
.
Crossref
Search ADS
PubMed
 
11
Cox
 
DG
,
Hankinson
 
SE
,
Hunter
 
DJ
. 
No association between BRCA2 N372H and breast cancer risk
.
Cancer Epidemiol Biomarkers Prev
 
2005
;
14
:
1353
–
4
.
Google Scholar
Crossref
Search ADS
PubMed
 
12
Dunning
 
AM
,
Chiano
 
M
,
Smith
 
NR
, et al. 
Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population
.
Hum Mol Genet
 
1997
;
6
:
285
–
9
.
Google Scholar
Crossref
Search ADS
PubMed
 
13
Durocher
 
F
,
Shattuck-Eidens
 
D
,
McClure
 
M
, et al. 
Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations
.
Hum Mol Genet
 
1996
;
5
:
835
–
42
.
Google Scholar
Crossref
Search ADS
PubMed
 
14
Freedman
 
ML
,
Penney
 
KL
,
Stram
 
DO
, et al. 
Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort
.
Hum Mol Genet
 
2004
;
13
:
2431
–
41
.
Google Scholar
Crossref
Search ADS
PubMed
 
15
Garcia-Closas
 
M
,
Egan
 
KM
,
Newcomb
 
PA
, et al. 
Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses
.
Hum Genet
 
2006
;
119
:
376
–
88
.
Google Scholar
Crossref
Search ADS
PubMed
 
16
Healey
 
CS
,
Dunning
 
AM
,
Teare
 
MD
, et al. 
A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability
.
Nat Genet
 
2000
;
26
:
362
–
4
.
Google Scholar
Crossref
Search ADS
PubMed
 
17
Hughes
 
DJ
,
Ginolhac
 
SM
,
Coupier
 
I
, et al. 
Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers
.
Cancer Epidemiol Biomarkers Prev
 
2005
;
14
:
265
–
7
.
Google Scholar
PubMed
 
18
Janezic
 
SA
,
Ziogas
 
A
,
Krumroy
 
LM
, et al. 
Germline BRCA1 alterations in a population-based series of ovarian cancer cases
.
Hum Mol Genet
 
1999
;
8
:
889
–
97
.
Google Scholar
Crossref
Search ADS
PubMed
 
19
Menzel
 
HJ
,
Sarmanova
 
J
,
Soucek
 
P
, et al. 
Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations
.
Br J Cancer
 
2004
;
90
:
1989
–
94
.
Google Scholar
Crossref
Search ADS
PubMed
 
20
Ramus
 
SJ
,
Vierkant
 
RA
,
Johnatty
 
SE
, et al. 
Consortium analysis of 7 candidate SNPs for ovarian cancer
.
Int J Cancer
 
2008
;
123
:
380
–
8
.
Google Scholar
Crossref
Search ADS
PubMed
 
21
Seymour
 
IJ
,
Casadei
 
S
,
Zampiga
 
V
, et al. 
Disease family history and modification of breast cancer risk in common BRCA2 variants
.
Oncol Rep
 
2008
;
19
:
783
–
6
.
Google Scholar
PubMed
 
22
Soucek
 
P
,
Borovanova
 
T
,
Pohlreich
 
P
,
Kleibl
 
Z
,
Novotny
 
J
. 
Role of single nucleotide polymorphisms and haplotypes in BRCA1 in breast cancer: Czech case-control study
.
Breast Cancer Res Treat
 
2007
;
103
:
219
–
24
.
Google Scholar
Crossref
Search ADS
PubMed
 
23
Spurdle
 
AB
,
Hopper
 
JL
,
Chen
 
X
, et al. 
The BRCA2 372 HH genotype is associated with risk of breast cancer in Australian women under age 60 years
.
Cancer Epidemiol Biomarkers Prev
 
2002
;
11
:
413
–
6
.
Google Scholar
PubMed
 
24
Wenham
 
RM
,
Schildkraut
 
JM
,
McLean
 
K
, et al. 
Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer
.
Clin Cancer Res
 
2003
;
9
:
4396
–
403
.
Google Scholar
PubMed
 
©2009 American Association for Cancer Research.
2009