JCO:易感基因突变携带者患乳腺癌的风险有多大?新方法给出答案

2021-06-23 MedSci原创 MedSci原创

PRS有利于对易感基因中的PV携带者进行个性化的乳腺癌风险评估。

去年年底,世界卫生组织(WHO)下属国际癌症研究机构(IARC)发布数据显示,乳腺癌已超越肺癌,成为全球最常见的癌症。世界上每20名女性中就有1名在一生的某个时刻被诊断为乳腺癌。同时,乳腺癌以高达15%的死亡率位列女性癌症死亡率之首。

大家都知道,女性罹患乳腺癌的风险受到其遗传的影响。首先,BRCA1BRCA2BRCA1/2)中的高危致病或可能致病的变体(PVs)自20世纪90年代中期以来一直被认为会影响家族风险,并建议有明显家族史的女性进行常规检测。

虽然这些PVs较为罕见,但总的来说,到目前为止,超过10000个单独的BRCA1/2 PVs的特征占到了乳腺癌家族风险的20%BRCA1/2功能和DNA损伤反应途径的进一步了解导致了第二类乳腺癌易感基因的发现,这些基因又占了5%的家族风险。

第三类乳腺癌易感基因是常见的风险变异,主要是单核苷酸变异(SNVs),在大型全基因组关联研究中都提示与乳腺癌风险有关,估计可以解释18%的额外家族风险。虽然单个SNVs的几率(ORs)往往不大,在临床上没有用处,但SNVs的组合可以汇总成多基因风险评分(PRSs),从而对未受影响的妇女进行乳腺癌风险分层。

为了评估乳腺癌易感基因的致病变体(PV)和多基因风险评分(PRS)与普通人群中乳腺癌发生的关系,近期发表在《临床肿瘤学》JCO杂志上的研究给出了答案。

研究人员开展了一项基于人群的研究,对BRCA1BRCA2ATMCHEK2PALB2BARD1BRIP1CDH1NF1中的PV进行了评估。最终共有26798名非西班牙裔的乳腺癌病例和26127名对照。

使用乳腺癌全基因组关联研究的效应估计,创建了基于105个常见变体的PRS;评估了整体乳腺癌PRS和雌激素受体特异性PRS的性能。基于PVsPRS的乳腺癌的几率是用逻辑回归法估计的。

根据PRS的第10和第90个百分位数,在一般人群非携带者中,有或没有一级亲属肿瘤病史的妇女,罹患乳腺癌的终生风险分别为9.1%-23.9%6.7%-18.2%考虑到PRS,95%以上的BRCA1、BRCA2和PALB2携带者一生中患乳腺癌的风险大于20%,而没有一级亲属患乳腺癌的ATM和CHEK2携带者的风险分别为52.5%和69.7%,有一级亲属患乳腺癌的携带者的风险则为78.8%和89.9%。

平均而言,15名妇女中约有2人患乳腺癌。美国国家癌症研究所(NCI)曾指出,在具有BRCA1BRCA2有害变体的妇女中,这一数字可能达到15人中的11人。正如上述所讨论的,遗传性乳腺癌的情况比BRCA更多。

将PRS纳入BC风险估计可能有助于识别>30%的CHEK2和近一半的ATM携带者,低于20%的终生风险阈值,这表明增加PRS可能防止过度筛查,并实现更个性化的风险管理方法。

综上,PRS有利于对易感基因中的PV携带者进行个性化的乳腺癌风险评估。

 

参考文献:

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score. DOI: 10.1200/JCO.20.01992

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    2021-07-08 qblt
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    2021-08-04 lidong40
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    2021-06-23 东海中路小法师

    好好学习

    0

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