CORRESPONDENCE

Preliminary Sibpair Linkage Analysis of Percent Mammographic Density

Celine M. Vachon, Richard A. King, Larry D. Atwood, Christopher C. Kuni, Thomas A. Sellers

Affiliations of authors: C. M. Vachon, T. A. Sellers, Mayo Foundation, Department of Health Sciences Research, Rochester, MN; R. A. King (Institute of Human Genetics and Department of Medicine), L. D. Atwood (Division of Epidemiology, School of Public Health and Institute of Human Genetics), University of Minnesota, Minneapolis; C. C. Kuni, Department of Radiology, University of Colorado, Denver.

Correspondence to: Thomas A. Sellers, Ph.D., M.P.H., Mayo Foundation, Harwick 6, 200 First St., S.W., Rochester, MN 55905 (e-mail: Sellers.Thomas{at}mayo.edu).

Interindividual variability in mammographic breast density has been shown to be a major independent risk factor for breast cancer (1). There is evidence for a genetic influence on breast density (2,3). In the Journal (4), we recently reported a segregation analysis of breast density performed on 1370 women from 258 families in the Minnesota Breast Cancer Family Cohort (5). After adjustment for eight epidemiologic risk factors, percent breast density was consistent with mendelian models of inheritance (4). To provide additional evidence for a major gene influence on breast density, we report results from a preliminary sibpair linkage analysis on a sample of women from the same large breast cancer family cohort.

The sibpairs used in the linkage analysis were selected from a convenience sample of women from the family study who participated in the venipuncture, mammogram, and telephone interview components of the Breast Cancer Family Cohort (5). Women with prior breast cancer were not eligible for this analysis to reduce potential genetic heterogeneity. Written informed consent was obtained from the subjects in this study.

The fraction of the mammogram occupied by fibroglandular elements was estimated visually by a radiologist experienced in mammography (C. C. Kuni). Density estimation was made in 5% increments from a video display of the left mediolateral oblique view; the right mediolateral oblique view was used if the left was unavailable.

Because there are no obvious candidate genes for breast density, we performed a genome screen using a set of highly polymorphic short-tandem repeat polymorphism markers spaced approximately 30 cM apart. Evidence for linkage was determined with both two-point [SIBPAL in SAGE (6)] and multipoint [MAPMAKER/SIBS (7)] linkage analyses on both the unadjusted breast density trait and the trait adjusted for the influence of nongenetic covariates. The SIBPAL test for linkage is a test of negative slope (i.e., Ho: ß1 >= 0 versus Ha: ß1 < 0), so one-sided P values are presented for these tests.

A total of 68 individuals in 71 sibpairs and 10 mother-daughter pairs in 22 families were eligible for the linkage analysis. Mean percent breast density was 36.2% (95% confidence interval [CI] = 31.5-40.9); the mean age was 58 years (95% CI = 55.4-60.4), and 16.4% of the women were premenopausal.

We initially analyzed 147 markers across the genome; six additional markers in suggestive regions were subsequently typed. The two-point sibpair analyses on the unadjusted and adjusted breast density trait revealed three regions of suggestive linkage, including F13A1 on chromosome 6 (P value from one-sided t test of regression coefficient; P = .002), D17S1290 on chromosome 17 (P = .01), and D20S480 on chromosome 20 (P<=.007) (see Table 1).Go Of the six additional markers analyzed in the regions on chromosomes 6, 17, and 20, only one marker on chromosome 17 (D17S1299) was statistically significant at P = .01 (see Table 1)Go.


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Table 1. Chromosomal regions of suggestive linkage in sibpair linkage analysis of mammographic percent breast density

 
The multipoint analyses confirmed the suggestion of linkage to the regions on chromosome 6 (logarithm of odds [LOD] score = 1.58) and chromosome 20 (LOD score = 1.52) for the unadjusted percent breast density trait. When adjusted for covariates, only the region on chromosome 6 remained suggestive (LOD score = 1.67).

These preliminary results provide suggestive evidence for a genetic component to percent breast density. Given that increased measures of breast density are common in the population, a gene for breast density could account for a large percentage of breast cancers in the population.

Supported in part by Public Health Service grants R01CA55747 (National Cancer Institute [NCI]), T32CA09607 (to C. M. Vachon) (NCI), and M01RR00400 (National Center for Research Resources), National Institutes of Health, Department of Health and Human Services.

REFERENCES

1 Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev1998; 7:1133-44.[Abstract]

2 Wolfe J. Albert S, Belle S, Salane M. Familial influences of breast parenchymal patterns. Cancer 1980;46:2433-7.[Medline]

3 Kaprio J, Alanko A, Kivisaari L, Standertskjold-Nordenstam CG. Mammographic patterns in twins pairs discordant for breast cancer. Br J Radiol 1987;60:459-62.[Abstract]

4 Pankow JS, Vachon CM, Kuni CC, King RA, Arnett DK, Grabrick DM, et al. Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 1997;89:549-56.[Abstract/Free Full Text]

5 Sellers TA, Anderson VE, Potter JD, Bartow SA, Chen PL, Everson L, et al. Epidemiologic and genetic follow-up study of 544 Minnesota breast cancer families: design and methods. Genet Epidemiol 1995;12:417-29.[Medline]

6 Statistical Analysis for Genetic Epidemiology [computer program]. Cleveland: Rammelkamp Center for Education and Research, Case Western Reserve University; 1994.

7 Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet1996; 58:1347-63.[Medline]


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