The Genomic Landscape of MYC -, MYCL -, and MYCN -Amplified Solid Tumors

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PURPOSE: MYC, MYCN and MYCL amplifications are recurrent oncogenic events across solid tumors. Currently, no standardized selection biomarker is available to identify patients with MYC-dependent tumors. EXPERIMENTAL DESIGN: We analyzed copy number alterations of MYC family genes and their features in over 68,000 tumor-normal paired samples from pediatric and adult patients sequenced with MSK-IMPACT and annotated with FACETS. The relationship between amplification features and MYC mRNA expression levels were evaluated in over 10,000 samples from the TCGA. RESULTS: Across MSKCC samples, MYC amplifications were most common, found in 2,949 samples compared to 310 in MYCL and 217 in MYCN. While MYCN and MYCL amplifications were predominantly focal (<10Mb, 79% and 93% respectively), MYC amplifications were frequently broader (>10Mb, 62%). While most tumor types showed similar features between broad and focal amplifications of MYC, in select cancer types we identified differing co-occurrence and mutual-exclusivity patterns with other disease specific drivers. Furthermore, while MYC amplified TCGA samples showed higher mRNA expression than wild-type ones, the focality of MYC amplification was seen to have limited influence on expression levels. CONCLUSIONS: Our results suggest that MYC-dependency likely depends on many factors including, but not limited to, total copy number of the detected amplification, lineage specific factors, concomitant presence or absence of additional oncogenic alterations, and in some cases amplification focality.

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