Campa Daniele, Barrdahl Myrto, Gaudet Mia M, Black Amanda, Chanock Stephen J, Diver W Ryan, Gapstur Susan M, Haiman Christopher, Hankinson Susan, Hazra Aditi, Henderson Brian, Hoover Robert N, Hunter David J, Joshi Amit D, Kraft Peter, Le Marchand Loic, Lindström Sara, Willett Walter, Travis Ruth C, Amiano Pilar, Siddiq Afshan, Trichopoulos Dimitrios, Sund Malin, Tjønneland Anne, Weiderpass Elisabete, Peeters Petra H, Panico Salvatore, Dossus Laure, Ziegler Regina G, Canzian Federico, Kaaks Rudolf
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
Epidemiology Research Program, American Cancer Society, 250 Williams Street NW, Atlanta, GA, 30303, USA.
Breast Cancer Res. 2015 Jun 13;17(1):82. doi: 10.1186/s13058-015-0596-x.
Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.
To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.
We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10(-4)) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10(-3)). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.
Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.
原位乳腺癌（BCIS）诊断作为浸润性乳腺癌的前驱病变，在实施筛查计划的国家中约占所有乳腺癌（BC）的20%。乳腺癌家族史被认为是原位乳腺癌最强的风险因素之一。
为评估乳腺癌易感基因座与原位乳腺癌风险的关联，我们在国立癌症研究所的乳腺癌和前列腺癌队列联盟（BPC3）中的1317例原位乳腺癌病例、10645例浸润性乳腺癌病例和14006例健康对照中，对39个与浸润性乳腺癌风险相关的单核苷酸多态性（SNP）进行了基因分型。使用针对年龄和研究进行调整的无条件逻辑回归模型，我们通过两个不同的比较组估计SNP与原位乳腺癌的关联：健康对照和浸润性乳腺癌受试者，以研究原位乳腺癌和浸润性乳腺癌是否具有共同的遗传特征。
我们发现五个SNP（CDKN2BAS-rs1011970、FGFR2-rs3750817、FGFR2-rs2981582、TNRC9-rs3803662、5p12-rs10941679）与原位乳腺癌风险显著相关（经多重比较调整后的P值<0.0016）。比较浸润性乳腺癌和原位乳腺癌，差异最大的是CDKN2BAS-rs1011970，它与原位乳腺癌呈正相关（比值比=1.24，95%可信区间：1.11-1.38，P=1.27×10⁻⁴），与浸润性乳腺癌无关联（比值比=1.03，95%可信区间：0.99-1.07，P=0.06），病例对照比较的P值为0.006。对导管原位癌（DCIS）关联的亚组分析发现了类似的关联，尽管不太显著（比值比=1.25，95%可信区间：1.09-1.42，P=1.07×10⁻³）。额外的风险分析显示，28个等位基因在0.05水平与浸润性疾病有显著关联，且比值比估计值与其他研究报告的一致。
我们的研究进一步证明，几个已知的乳腺癌易感基因座是原位乳腺癌和浸润性乳腺癌的风险因素，但位于CDKN2BAS基因中的可能具有功能的SNP rs1011970可能是个例外，它可能是一个特定的原位乳腺癌易感基因座。
