Holstege Henne, Joosse Simon A, van Oostrom Conny Th M, Nederlof Petra M, de Vries Annemieke, Jonkers Jos
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Cancer Res. 2009 Apr 15;69(8):3625-33. doi: 10.1158/0008-5472.CAN-08-3426. Epub 2009 Mar 31.
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, frameshift, 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.
大约一半的遗传性乳腺癌由于BRCA1或BRCA2功能丧失，其DNA修复机制存在缺陷。先前的研究发现BRCA突变与TP53突变之间存在很强的相关性。然而，TP53突变状态通常通过累积的p53蛋白的免疫组织化学染色间接评估。我们对21例BRCA1相关乳腺癌和37例散发性乳腺肿瘤的TP53外显子2至9进行了测序。令人惊讶的是，所有BRCA1相关乳腺肿瘤都含有TP53突变，而这些肿瘤中只有一半p53累积染色呈阳性。p53阳性染色与BRCA1相关和散发性乳腺肿瘤中TP53热点突变的存在相关。然而，虽然大多数p53累积染色呈阴性的散发性乳腺肿瘤具有野生型TP53，但大多数p53累积染色呈阴性的BRCA1相关乳腺肿瘤具有蛋白质截短的TP53突变（无义、移码和剪接突变）。因此，BRCA1相关肿瘤中对p53缺失的强烈选择是通过蛋白质截短的TP53突变增加而非热点突变实现的。因此，TP53突变的免疫组织化学检测可能会导致大约一半的BRCA1相关肿瘤被误诊。大多数（如果不是全部）BRCA1相关乳腺癌中存在有害的TP53突变表明p53功能丧失对于BRCA1相关肿瘤发生至关重要。因此，BRCA1相关肿瘤不仅可以用针对BRCA1缺陷的药物（如聚（ADP-核糖）聚合酶抑制剂）治疗，还可以用选择性针对p53缺陷细胞的药物治疗。这为针对BRCA1缺陷型乳腺癌和具有同源重组缺陷的BRCA1样肿瘤的联合治疗带来了有趣的可能性。
