Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.
School of Public Health, University of Alberta, Edmonton, Alberta, Canada.
Cancer Epidemiol Biomarkers Prev. 2023 Nov 1;32(11):1518-1523. doi: 10.1158/1055-9965.EPI-22-1073.
What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors?
The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ.
Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii).
First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants.
This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. See related In the Spotlight, p. 1477.
女性乳腺癌风险的主要决定因素是什么？罕见突变，如 BRCA1/2 基因中的突变、全基因组关联研究确定的常见等位基因的多基因评分，还是非遗传因素？
基于人群的北欧双胞胎癌症研究，对 21054 对同卵（MZ）和 30939 对异卵（DZ）女性双胞胎中的 3933 例乳腺癌病例进行了分析，为这个问题提供了三个关键线索：（i）平均终生风险约为 8%，双胞胎的亲缘关系不影响风险；（ii）当双胞胎都患病时（即疾病一致性），诊断之间的平均时间间隔也不随亲缘关系而变化；但是，（iii）如果双胞胎之一患有疾病，则 MZ 双胞胎中双胞胎的发病率为每年约 1%，DZ 双胞胎中为每年 0.5%。
假设非遗传风险因素在不考虑亲缘关系的情况下在双胞胎中相似，我们可以从（i）到（iii）得出两个结论。
首先，（i）和（iii）意味着风险的主要决定因素在于种系 DNA，因为条件发病率比 MZ 双胞胎的平均风险（8%的终生风险）高出数倍，但在 DZ 双胞胎中仅为一半。其次，如果种系 DNA 中的风险因素是罕见变体而不是常见变体，那么条件发病率的两倍（iii）与疾病一致性中双胞胎间疾病间隔的均等性（ii）之间的似乎不一致可以得到解决。
本文详细介绍了这些结论的简单演绎推理，并对乳腺癌病因学提出了关键推断。请参阅相关的“聚焦论文”，第 1477 页。
