Abstract PR3: Exome sequencing of head and neck squamous cell carcinoma reveals a higher frequency of mutations in TP53 among African Americans
Authors: Guerrero-Preston Rafael , Agrawal Nishant , Sidransky David , Li Ryan J. , Westra William H. , Koch Wayne M. , Califano Joseph A. , Vogelstein Bert , Velculescu Victor E. , Papadopoulos Nickolas , Kinzler Kenneth W. 
Published: June 2012

This abstract will be presented as a proffered talk on Wednesday, September 21, in Plenary Session 8.

African American (AA) and Puerto Rican (PR) men have a higher oral (OSCC) and head and neck squamous cell carcinoma (HNSCC) burden than White men in the United States (US), but the biological basis for these differences are poorly understood. Overall Five-Year relative survival rates for patients diagnosed with oral cavity cancer increased from 53% in 1975 to 63% in 2005 across all races in the US, an increase that parallels a decline in smoking among males during the same period of time. However, the disparity in overall survival rates between Whites and African American patients has remained, practically unchanged from 1975 (19%) to 2005 (18%). The survival disparity difference in HNSCC among AA may be due, among other factors, to a higher prevalence of genetic alterations.

To gain an initial profile of the disparities in genetic alterations between Whites and Non-Whites HNSCC patients we performed a secondary analysis on a convenience sample from an exome-sequencing project that was undertaken at Johns Hopkins School of Medicine. For this project we sequenced ∼18,000 protein-encoding genes in tumors from 17 HNSCC patients which comprised the Discovery set. DNA was purified from these tumors as well as matched non-neoplastic tissue and used to generate libraries suitable for massively parallel sequencing. After capture of the coding sequences with a SureSelect (Agilent) the DNA was sequenced using an Illumina GAIIx/HiSeq instrument. The average coverage of each base in the targeted regions was 77-fold and 92.6% of targeted bases were represented by at least 10 reads in this platform.

The majority of patients (82%) in the Discovery setwere White and the remainder were African American (18%). All the African American patients were smokers. The majority of the AA patients were males (60%), over 60 yrs old (80%) with an oropharyngeal cancer (40%). Using stringent criteria for analysis of these data we identified 249 somatic mutations. The range of confirmed mutations per tumor was 2 to 78, with a mean and standard deviation of 19 ± 16.5 mutations per tumor.

We selected genes for further analysis if they or closely related genes were altered in at least two of the 17 tumors sequenced. The genes included were PIK3AP1, RIMBP2, SI, NRXN2, NRXN3, EPHA7, RASA1, RXFP3, PIK3CA, HRAS, TP53, CDKN2A, NOTCH1, and FBXW7. We then analyzed the sequences of these genes in additional HNSCC and their corresponding normal tissues. In total, somatic mutations in TP53, NOTCH1, CDKN2A, PIK3CA, FBXW7, and HRAS were identified in 47%, 15%, 9%, 6%, 5% and 4% of patients, respectively. Most of the mutations (84%) were observed in White patients. There was no significant difference in the number of mutations per patient in White (14.6) vs African American (13.7) patients. Breaking down the somatic mutations by race we found that the mutations among African Americans was higher (73%) for TP53, when compared to Whites (55%) or to previously observed frequency of TP53 mutations in HNSCC. The mutations in NOTCH1, CDKN2A, PIK3CA had similar mutation frequency in African Americans and in White patients. African American patients did not have somatic mutations in FBXW7 and HRAS.

This is the first exome sequencing study to report HNSCC mutation disparities in African Americans. Although the number of HNSCC African American patients examined in this project is small, the results of this study provide evidence that HNSCCs, although morphologically similar, are comprised of distinct diseases at the molecular level. These results should be examined in a larger cohort of African American patients. Our preliminary findings that HNSCCs have few directly targetable mutations has implications for controlling this disease in the future. In particular, it suggests that prevention, careful surveillance of patients at risk, and early detection are the optimal approaches for reducing cancer health disparities in this disease.

Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PR3.