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MAST2 and NOTCH1 translocations in breast carcinoma and associated pre-invasive lesions
Michael R Clay1, Sushama Varma, Robert B West
1Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305-5324, USA.
Abstract:
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.
Insights
Gene rearrangements in NOTCH1 and MAST2 are common in invasive breast cancer. These translocations appear to occur during the transition to ductal carcinoma in situ (DCIS) or invasive disease.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genomic alterations, including driver mutations, are crucial in breast cancer development.
- Gene rearrangements in the microtubule-associated serine-threonine kinase (MAST) and NOTCH gene families are observed in 5-7% of invasive breast cancers.
- The timing and mechanism of these genomic changes during breast cancer progression are not fully understood.
Purpose of the Study:
- To investigate the presence and timing of MAST and NOTCH gene rearrangements in breast cancer development.
- To evaluate the utility of fluorescence in situ hybridization (FISH) on tissue microarrays (TMAs) for detecting these genomic alterations.
- To correlate gene translocations with morphologic changes in pre-invasive and invasive breast lesions.
Main Methods:
- Utilized FISH break-apart assays to detect NOTCH1 and MAST2 gene rearrangements.
- Screened a large series of breast cancer cases using TMAs.
- Performed whole-section FISH analysis on cases with identified translocations to examine concurrent pre-invasive lesions (DCIS).
Main Results:
- Identified MAST2 translocations in 2.0% (10/477) and NOTCH1 translocations in 1.2% (6/477) of invasive breast carcinomas.
- Found that these translocations were present in the majority of concurrent ductal carcinoma in situ (DCIS) lesions (6/8).
- Observed no translocations in DCIS lesions not associated with an invasive component (0/170, P=.0048).
Conclusions:
- Confirmed the presence of MAST and NOTCH family gene rearrangements in invasive breast carcinoma.
- Demonstrated that FISH studies on TMAs are effective for screening genomic changes across normal, pre-invasive, and invasive breast disease.
- Suggests that MAST and NOTCH gene translocations occur during the transition to DCIS and/or invasive carcinoma.
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