There are several mutations and structural variations common to
breast cancer. Many of these genomic changes are thought to represent driver mutations in
oncogenesis. Less well understood is how and when these changes take place in
breast cancer development. Previous studies have identified gene rearrangements in the microtubule-associated
serine-threonine kinase (MAST) and NOTCH gene families in 5% to 7% of invasive breast
cancers. Some of these translocations can be detected by fluorescence in situ hybridization (FISH) allowing for examination of the correlation between these genomic changes and concurrent morphologic changes in early breast
neoplasia. NOTCH and MAST gene rearrangements were identified by FISH in a large series of
breast cancer cases organized on tissue microarrays (TMA). When translocations were identified by TMA, we performed full cross-section FISH to evaluate concurrent pre-invasive lesions. FISH break-apart assays were designed for NOTCH1 and MAST2 gene rearrangements. Translocations were identified in 16 cases of invasive
carcinoma; 10 with MAST2 translocations (2.0%) and 6 cases with NOTCH1 translocations (1.2%). Whole section FISH analysis of these cases demonstrated that the translocations are present in the majority of concurrent
ductal carcinoma in situ (
DCIS) (6/8). When
DCIS wasn't associated with an invasive component, it was never translocated (0/170, P=.0048). We have confirmed the presence of MAST and NOTCH family gene rearrangements in invasive
breast carcinoma, and show that FISH studies can effectively be used with TMAs to screen normal, pre-invasive, and coexisting invasive disease. Our findings suggest that these translocations occur during the transition to
DCIS and/or invasive
carcinoma.