TY - JOUR T1 - Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression JF - bioRxiv DO - 10.1101/085316 SP - 085316 AU - Nao Hiranuma AU - Jie Liu AU - Chaozhong Song AU - Jacob Goldsmith AU - Michael O. Dorschner AU - Colin C. Pritchard AU - Kimberly A. Burton AU - Elisabeth M. Mahen AU - Sibel Blau AU - Francis M. Senecal AU - Wayne L. Monsky AU - Stephanie Parker AU - Stephen C. Schmechel AU - Stephen K. Allison AU - Vijayakrishna K. Gadi AU - Sophie R. Salama AU - Amie J. Radenbaugh AU - Mary Goldman AU - Jill M. Johnsen AU - Shelly Heimfeld AU - Vitalina Komashko AU - Marissa LaMadrid-Hermannsfeldt AU - Zhijun Duan AU - Steven C. Benz AU - Patrick Soon-Shiong AU - David Haussler AU - Jingchun Zhu AU - Walter L. Ruzzo AU - William S. Noble AU - C. Anthony Blau Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/11/05/085316.abstract N2 - About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression. ER -