Mutations at BRCAJ: The Medullary Breast Carcinoma Revisited1

BRCAI-associated breast cancers (BRCAJ-BCs) frequently harbor a high histoprognostic grade, p53 alterations, and estrogen receptor nega thrity. Although these parameters predict a poor outlook, the overall survival in BRCAJ-BCs is equivalent to or even better than that in sporadic cases. These features are reminiscent of what is observed for breast carcinoma of the medullary type, a high-grade tumor with a particular favorable course. To explore a possible relationship between this phenotype and BRCAJ mutations, we first compared 32 BRCAJ-BCs and 200 consecutive cases of breast cancer without familial history for the prevalence of typical medublary breast carcinoma (TMC) using the crite na given by Ridolfi ci aL ER.Ridolfi ci aL, Cancer (Phila.), 40: 1365-1385, 1977]. Second, we searched for BRCA1 mutations in a set of 18 cases of TMC, using denaturing gradient gel electrophoresis and Cleavase frag ment length polymorphism scanning. Six of 32 (19%) BRCAI-BCs were of the TMC type, compared to 0 of 200 controls (P < 0.0001). Among the 18 TMCs, 2 BRCA1 nonsense mutations were found. This corresponds to almost 7 tImes the contribution of BRCA1 mutations in the general population. Two additional missense mutations were identified. Together, these results suggest that, although TMC and BRCAJ-BCs are not strictly coincidental, an important connec tion between the two populations does exist.