High Incidence of Protein-Truncating TP53 Mutations in BRCA1-Related Breast Cancer
High Incidence of Protein-Truncating TP53 Mutations in BRCA1-Related Breast Cancer
复制标题
DOI：
10.1158/0008-5472.can-08-3426
复制
发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Jonkers, Jos
中科院分区：
文献类型：
--
作者：
Holstege, Henne;Joosse, Simon A.;Jonkers, Jos
大约一半的遗传性乳腺癌由于BRCA 1或BRCA 2功能的丧失而在其DNA修复机制中受损。先前的研究发现BRCA突变和TP 53突变之间存在很强的相关性。然而，TP 53突变状态往往是间接评估积累的p53蛋白的免疫组化染色。我们对21例BRCA 1相关乳腺癌和37例散发性乳腺肿瘤的TP 53外显子2至9进行了测序。引人注目的是，所有BRCA 1相关的乳腺肿瘤都含有TP 53突变，而这些肿瘤中只有一半的p53积累染色阳性。阳性p53染色与BRCA 1相关和散发性乳腺肿瘤中TP 53热点突变的存在相关。然而，尽管大多数p53积聚染色阴性的散发性乳腺肿瘤具有野生型TP 53，但大多数p53积聚染色阴性的BRCA 1相关乳腺肿瘤具有蛋白截短TP 53突变（无义、移码和剪接突变）。因此，BRCA 1相关肿瘤中p53缺失的强选择性是通过增加蛋白截短性TP 53突变而不是热点突变来实现的。因此，TP 53突变的免疫组化检测可能导致大约一半的BRCA 1相关肿瘤的误诊。在大多数（如果不是全部）BRCA 1相关乳腺癌中存在有害的TP 53突变表明，p53功能丧失对BRCA 1相关肿瘤发生至关重要。因此，BRCA 1相关肿瘤不仅可以用针对BRCA 1缺陷的药物进行治疗[例如，聚（ADP-核糖）聚合酶抑制剂]，但也与选择性靶向p53缺陷细胞的药物。这为针对BRCA 1缺陷型乳腺癌和具有同源重组缺陷的BRCA 1样肿瘤的联合疗法提出了有趣的可能性。[Cancer Res 2009;69（8）：3625-33]
Approximately half of all hereditary breast cancers are compromised in their DNA repair mechanisms due to loss of BRCA1 or BRCA2 function. Previous research has found a strong correlation between BRCA mutation and TP53 mutation. However, TP53 mutation status is often indirectly assessed by immunohistochemical staining of accumulated p53 protein. We sequenced TP53 exons 2 to 9 in 21 BRCA1-related breast cancers and 37 sporadic breast tumors. Strikingly, all BRCA1-related breast tumors contained TP53 mutations, whereas only half of these tumors stained positive for p53 accumulation. Positive p53 staining correlates with the presence of TP53 hotspot mutations in both BRCA1-related and sporadic breast tumors. However, whereas the majority of sporadic breast tumors that stained negative for p53 accumulation had wild-type TP53, the majority of BRCA1-associated breast tumors that stained negative for p53 accumulation had protein-truncating TP53 mutations (nonsense, frameshiflt, and splice mutations). Therefore, the strong selection for p53 loss in BRCA1-related tumors is achieved by an increase of protein-truncating TP53 mutations rather than hotspot mutations. Hence, immunohistochemical detection of TP53 mutation could lead to misdiagnosis in approximately half of all BRCA1-related tumors. The presence of deleterious TP53 (mutations in most, if not all, BRCA1-related breast cancers suggests that p53 loss of function is essential for BRCA1-associated tumorigenesis. BRCA1-related tumors may therefore be treated not only with drugs that target BRCA1 deficiency [e.g., poly(ADP-ribose) polymerase inhibitors] but also with drugs that selectively target p53-deficient cells. This raises interesting possibilities for combination therapies against BRCA1-deficient breast cancers and BRCA1-like tumors with homologous recombination deficiency. [Cancer Res 2009;69(8):3625-33]