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KIT genetic alterations in breast cancer
Mahsa Vahdatinia1, Fatemeh Derakhshan1, Arnaud Da Cruz Paula2
1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Aims:
Activating somatic mutations or gene amplification of KIT result in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence of KIT genetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours.
Methods:
A retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs with KIT alterations. A histological assessment of KIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lacking KIT genetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type.
Results:
We identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affecting KIT, including activating somatic mutations (n=4) or gene amplification (n=14). All KIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lacking KIT genetic alterations, no distinctive genetic features were identified. In two metastatic KIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, the KIT mutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers.
Conclusions:
KIT genetic alterations are vanishingly rare in BC. KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations in KIT might be late events in the evolution and/or progression of BC.
Insights
Genetic alterations in the KIT gene are extremely rare in breast cancer (BC). These rare KIT-altered BCs are high-grade but lack distinct features, suggesting KIT alterations may be late-stage events.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Activating mutations or amplification of the KIT receptor tyrosine kinase are targetable in various solid tumors.
- The role and frequency of KIT genetic alterations in breast cancer (BC) remain largely unexplored.
Purpose of the Study:
- To investigate the presence of KIT genetic alterations in breast cancer.
- To characterize the histological and genomic features of KIT-altered breast cancers.
Main Methods:
- Retrospective analysis of 5,575 breast cancers using targeted sequencing (MSK-IMPACT).
- Identification of cases with KIT alterations.
- Histological assessment and genomic comparison of KIT-altered versus non-altered BCs.
Main Results:
- KIT genetic alterations were identified in 0.32% (18/5,575) of breast cancers, including mutations and amplifications.
- All identified KIT-altered breast cancers were high histological grade but lacked distinctive histological features.
- In metastatic cases, KIT mutations appeared to be late evolutionary events.
Conclusions:
- KIT genetic alterations are exceptionally rare in breast cancer.
- KIT-altered breast cancers are high-grade but histologically indistinguishable from other high-grade tumors.
- KIT alterations may represent late-stage events in breast cancer evolution or progression.
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