Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies.
BACKGROUND
The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer.


METHODS
We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)).


RESULTS
In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (P trend <or= 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes.


CONCLUSIONS
Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer.
Kelemen
Linda E
LE
Department of Population Health Research, Alberta Cancer Board, 1331 29th Street NW, Calgary, AB T2N 4N2, Canada.
Couch
Fergus J
FJ
Ahmed
Shahana
S
Dunning
Alison M
AM
Pharoah
Paul D P
PD
Easton
Douglas F
DF
Fredericksen
Zachary S
ZS
Vierkant
Robert A
RA
Pankratz
V Shane
VS
Goode
Ellen L
EL
Scott
Christopher G
CG
Rider
David N
DN
Wang
Xianshu
X
Cerhan
James R
JR
Vachon
Celine M
CM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics*; D016022:Case-Control Studies; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D058575:Decorin; D004739:England; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics*; D000071234:Lumican; D008875:Middle Aged; D016017:Odds Ratio; D011509:Proteoglycans / Q000235:genetics*; D017154:Stromal Cells / Q000473:pathology*; D055815:Young Adult
D011508:Chondroitin Sulfate Proteoglycans; C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; C000604306:LUM protein, human; D000071234:Lumican; D011509:Proteoglycans; D007632:Keratan Sulfate