Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm.
Ann Oncol. 2015 Mar;26(3):517-22. doi: 10.1093/annonc/mdu565. Epub 2014 Dec 8.
Polygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences.
A 77 single-nucleotide polymorphism polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term.
PRS weighted by breast cancer overall estimates was found to be differentially associated with 1865 screen-detected and 782 interval cancers in the LIBRO-1 study {age-adjusted odds ratio (OR)perSD [95% confidence interval (CI)] 0.91 [0.83-0.99], P = 0.023}. The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates [ORperSD = 0.90 (0.82-0.98), P = 0.011]. This result was corroborated by two independent studies [combined ORperSD = 0.87 (0.76-1.00), P = 0.058] with no evidence of heterogeneity. When enriched for 'true' interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced [ORperSD = 0.74 (0.62-0.89), P = 0.001], with a significant interaction effect between PRS and mammographic density (Pinteraction = 0.017).
To our knowledge, this is the first report looking into the genetic differences between screen-detected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.
从多个常见乳腺癌易感性等位基因计算出的多基因风险谱已被证明可识别处于不同乳腺癌风险水平的女性。我们评估这种遗传风险分层是否也可用于区分通常与临床病理和生存差异相关的筛查检出癌和间期癌。
构建了用于乳腺癌整体和雌激素受体（ER）状态的 77 个单核苷酸多态性多基因风险评分（PRS）。在仅病例设计中，以连续（每标准差增加）变量的形式检查 PRS。通过拟合附加的交互项来评估 PRS 对乳腺密度的修饰作用。
发现整体乳腺癌风险加权的 PRS 与 LIBRO-1 研究中的 1865 例筛查检出癌和 782 例间期癌存在差异相关{年龄调整后的比值比（OR）每标准差[95%置信区间（CI）]为 0.91 [0.83-0.99]，P=0.023}。对于 ER 阳性乳腺癌风险加权的 PRS，这种相关性更为显著[ORperSD=0.90（0.82-0.98），P=0.011]。这一结果在两项独立研究中得到证实[合并 ORperSD=0.87（0.76-1.00），P=0.058]，且无异质性证据。当在非致密乳腺中富集“真正”的间期癌时，筛查检出癌和间期癌与 PRS 的关联差异变得更加明显[ORperSD=0.74（0.62-0.89），P=0.001]，PRS 和乳腺密度之间存在显著的交互作用（Pinteraction=0.017）。
据我们所知，这是首次研究筛查检出癌和间期癌之间的遗传差异。它证实了这两种类型的乳腺癌可能具有独特的潜在生物学特性。
