RT Journal Article SR Electronic T1 Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression JF bioRxiv FD Cold Spring Harbor Laboratory SP 085316 DO 10.1101/085316 A1 Nao Hiranuma A1 Jie Liu A1 Chaozhong Song A1 Jacob Goldsmith A1 Michael O. Dorschner A1 Colin C. Pritchard A1 Kimberly A. Burton A1 Elisabeth M. Mahen A1 Sibel Blau A1 Francis M. Senecal A1 Wayne L. Monsky A1 Stephanie Parker A1 Stephen C. Schmechel A1 Stephen K. Allison A1 Vijayakrishna K. Gadi A1 Sophie R. Salama A1 Amie J. Radenbaugh A1 Mary Goldman A1 Jill M. Johnsen A1 Shelly Heimfeld A1 Vitalina Komashko A1 Marissa LaMadrid-Hermannsfeldt A1 Zhijun Duan A1 Steven C. Benz A1 Patrick Soon-Shiong A1 David Haussler A1 Jingchun Zhu A1 Walter L. Ruzzo A1 William S. Noble A1 C. Anthony Blau YR 2016 UL http://biorxiv.org/content/early/2016/11/05/085316.abstract AB 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.