Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Genet Med. 2022 Mar;24(3):576-585. doi: 10.1016/j.gim.2021.11.009. Epub 2021 Nov 18.
We aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk.
A total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life.
Cumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio.
PRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification.
我们旨在研究多基因风险评分（PRS）、罕见致病性种系变异（PVs）和家族史联合影响乳腺癌和前列腺癌风险的程度。
英国生物库中的 200643 人被分为以下几类：（1）中高危癌症基因中 PV 的杂合子或非杂合子，（2）PRS 分层，（3）有无癌症家族史。多变量逻辑回归和 Cox 比例风险模型用于计算组间比值和终生累积发病率。
PRS 分层的非杂合子在 70 岁之前的累积发病率在乳腺癌和前列腺癌中分别为 9%至 32%和 9%至 35%。在中危基因中，PV 杂合子的发病率从 20%到 48%不等，高危基因的发病率从 51%到 74%不等，而在前列腺癌风险基因中，发病率从 30%到 59%不等。家族史总是与癌症比值比的增加有关。
PRS 单独提供了有意义的风险梯度，可与中危基因中的 PV 进行风险分层，而在考虑高危基因时则作为风险修饰因子。同时考虑 PV、PRS 和家族史可进一步改善癌症风险分层。
