Abstract
<div>Abstract<p>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 <i>TP53</i> mutation. However, <i>TP53</i> mutation status is often indirectly assessed by immunohistochemical staining of accumulated p53 protein. We sequenced <i>TP53</i> exons 2 to 9 in 21 BRCA1-related breast cancers and 37 sporadic breast tumors. Strikingly, all BRCA1-related breast tumors contained <i>TP53</i> mutations, whereas only half of these tumors stained positive for p53 accumulation. Positive p53 staining correlates with the presence of <i>TP53</i> 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 <i>TP53</i>, the majority of BRCA1-associated breast tumors that stained negative for p53 accumulation had protein-truncating <i>TP53</i> 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 <i>TP53</i> mutations rather than hotspot mutations. Hence, immunohistochemical detection of <i>TP53</i> mutation could lead to misdiagnosis in approximately half of all BRCA1-related tumors. The presence of deleterious <i>TP53</i> 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]</p></div>
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