@article {Hiranuma085316, author = {Nao Hiranuma and Jie Liu and Chaozhong Song and Jacob Goldsmith and Michael O. Dorschner and Colin C. Pritchard and Kimberly A. Burton and Elisabeth M. Mahen and Sibel Blau and Francis M. Senecal and Wayne L. Monsky and Stephanie Parker and Stephen C. Schmechel and Stephen K. Allison and Vijayakrishna K. Gadi and Sophie R. Salama and Amie J. Radenbaugh and Mary Goldman and Jill M. Johnsen and Shelly Heimfeld and Vitalina Komashko and Marissa LaMadrid-Hermannsfeldt and Zhijun Duan and Steven C. Benz and Patrick Soon-Shiong and David Haussler and Jingchun Zhu and Walter L. Ruzzo and William S. Noble and C. Anthony Blau}, title = {Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression}, elocation-id = {085316}, year = {2016}, doi = {10.1101/085316}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2016/11/05/085316}, eprint = {https://www.biorxiv.org/content/early/2016/11/05/085316.full.pdf}, journal = {bioRxiv} }