UPMC Hillman Cancer Center

Precision Genomic Medicine

DNA strainNext generation sequencing technology has enabled genome-wide examination of genetic alterations within cancer cells that promote survival, growth, and metastasis. Identifying and understanding the role of genomic alterations in HNC can guide the development and use of precision therapies that will improve patient outcomes and decrease toxcities.

Selected Publications

  • Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway, and were examined in HPV-positive oropharyngeal carcinoma samples. Genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma. (Chiosea et. al., BMC Cancer. 2013 Dec 17;13:602.)
  • Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Analysis of whole-exome sequencing data from 151 HNSCC tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA-wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection. (Lui et. al., Cancer Discov. 2013 Jul;3(7):761-9.)
  • Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms. (Stransky et. al., Science. 2011 Aug 26;333(6046):1157-60.)


Chiosea, Simion, MD, FASCP
Nikiforov, Yuri, MD, PhD
Duvvuri, Umamaheswar, MD, PhD, FACS
Saunders, William, PhD
Biological Sciences
Ferris, Robert L., MD, PhD, FACS
Seethala, Raja, MD, FASCP
Gooding, William, MS
Yip, Linwah, MD