It is now widely accepted that cancer is a disease mediated by alterations in specific genes. The last decade has witnessed a dramatic increase in our understanding of the genomic characteristics of human cancer. In my laboratory we began these studies through a systematic analysis of gene families in human cancer, identifying PIK3CA as one of the most commonly mutated cancer genes. We extended these approaches with colleagues at JHU and other institutions to perform the first analyses of cancer genomes in breast, colorectal, pancreas, brain and other cancers. These efforts revealed the genomic landscape of human cancers, identifying new therapeutic targets such as mutant IDH genes in brain cancers and dysregulation of chromatin remodeling as a major mechanism of tumorigenesis. These analyses were spurred through novel genomic approaches we developed, including SAGE, Digital Karyotyping, and high throughput sequencing methods.
Despite the progress that has been made, much remains to be discovered in understanding the dynamic changes that occur in cancer genomes during therapy, resistance and progression, and using this information for early detection and intervention. My group currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow non-invasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.
Bertotti A, Papp E, Jones S, Adleff V, Anagnostou V, Lupo B, Sausen M, Phallen J, Hruban CA, Tokheim C, Niknafs N, Nesselbush M, Lytle K, Sassi F, Cottino F, Migliardi G, Zanella ER, Ribero D, Russolillo N, Mellano A, Muratore A, Paraluppi G, Salizzoni M, Marsoni S, Kragh M, Lantto J, Cassingena A, Li QK, Karchin R, Scharpf R, Sartore-Bianchi A, Siena S, Diaz LA Jr, Trusolino L, Velculescu VE. The genomic landscape of response to EGFR blockade in colorectal cancer. Nature. 2015 PMID: 26416732.
Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, Anagnostou V, Parpart-Li S, Murphy D, Kay Li Q, Hruban CA, Scharpf R, White JR, O'Dwyer PJ, Allen PJ, Eshleman JR, Thompson CB, Klimstra DS, Linehan DC, Maitra A, Hruban RH, Diaz LA Jr, Von Hoff DD, Johansen JS, Drebin JA, Velculescu VE. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat Commun. 2015 PMID: 26154128.
Jones S, Anagnostou V, Lytle K, Parpart-Li S, Nesselbush M, Riley DR, Shukla M, Chesnick B, Kadan M, Papp E, Galens KG, Murphy D, Zhang T, Kann L, Sausen M, Angiuoli SV, Diaz LA Jr, Velculescu VE. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci Transl Med. 2015 PMID: 25877891.
Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014 PMID: 24801577.
Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, O'Shaughnessy J, Kinzler KW, Parmigiani G, Vogelstein B, Diaz LA Jr, Velculescu VE. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012 PMID: 23197571.