Yost Shawn, Ruark Elise, Alexandrov Ludmil B, Rahman Nazneen
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
Department of Cellular and Molecular Medicine.
JNCI Cancer Spectr. 2019 Apr 19;3(2):pkz028. doi: 10.1093/jncics/pkz028. eCollection 2019 Jun.
It is often assumed any cancer in a germline or (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals.
We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided.
Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls ( = 1.0x10 and = 1.4x10, respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations ( = 5.1x10 and = 3.7x10) and cancers without BRCA mutations ( = 2.8x10 and = 1.0x10). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS ( = 3.8x10 and = 1.6x10) or benign variants ( = 1.2x10 and = 2.2x10). There was no difference between individuals with BRCA VUS and those with benign variants.
These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.
人们常常认为，种系或（统称为BRCA）突变携带者身上的任何癌症都是由该突变引起的。人们还常常认为，意义未明变异（VUS）个体发生乳腺癌或卵巢癌表明该VUS具有致病性。这些假设对癌症患者和健康个体的治疗具有深远影响。
我们比较了7632名患有28种癌症的个体和1000名人群对照中BRCA突变、等位基因缺失和特征3的频率。由于本研究仅关注频率增加情况，所有统计检验均为单侧检验。
与对照组相比，乳腺癌或卵巢癌患者的种系BRCA致病突变频率增加（分别为1.0×10和1.4×10）。其他癌症类型未见增加。与其他携带BRCA突变的癌症（分别为5.1×10和3.7×10）以及未携带BRCA突变的癌症（分别为2.8×10和1.0×10）相比，携带BRCA突变的乳腺癌和卵巢癌中野生型等位基因缺失和特征3在统计学上显著更高。携带BRCA突变的非乳腺癌和非卵巢癌与未携带BRCA突变的癌症之间无差异。与携带VUS（分别为3.8×10和1.6×10）或良性变异（分别为1.2×10和2.2×10）的个体相比，携带BRCA致病突变的个体中，乳腺癌和卵巢癌的等位基因缺失和特征3在统计学上显著更高。携带BRCA VUS的个体与携带良性变异的个体之间无差异。
这些数据表明，种系BRCA致病突变个体中的非乳腺癌和非卵巢癌通常与该突变无因果关系，且BRCA VUS极不可能具有致病性。这些结果应减少对种系BRCA信息的不当处理。
