Genetic determinants in head and neck squamous cell carcinoma and their influence on global personalized medicine

Abstract

While sequencing studies have provided an improved understanding of the genetic landscape of head and neck squamous cell carcinomas (HNSCC), there remains a significant lack of genetic data derived from non-Caucasian cohorts. Additionally, there is wide variation in HNSCC incidence and mortality worldwide both between and within various geographic regions. These epidemiologic differences are in part accounted for by varying exposure to environmental risk factors such as tobacco, alcohol, high risk human papilloma viruses and betel quid. However, inherent genetic factors may also play an important role in this variability. As limited sequencing data is available for many populations, the involvement of unique genetic factors in HNSCC pathogenesis from epidemiologically diverse groups is unknown. Here, we review current knowledge about the epidemiologic, environmental, and genetic variation in HNSCC cohorts globally and discuss future studies necessary to further our understanding of these differences. Long-term, a more complete understanding of the genetic drivers found in diverse HNSCC cohorts may help the development of personalized medicine protocols for patients with rare or complex genetic events.

Keywords: epidemiology; head and neck squamous cell carcinoma; human papillomavirus; personalized medicine; sequencing.

Figure 1. Age-standardized head and neck cancer incidence rates by sex and subsite for various global cohorts Incidence rates per 100,000 for males and females in various global cohorts with cancers of the oral cavity, oropharynx, or other head and neck sites

Raw incidences, references, and more detailed descriptions of each study can be found in Table S1. * indicates that incidence for oropharyngeal cancer was not reported. † indicates that incidence for cancer of other sites was not reported.

Figure 2. Adjusted cervical HPV infection prevalence among women with normal cytology and oropharyngeal cancer incidence among men by geographic region [66, 69]

HPV prevalence includes infection with both low and high risk viral strains and was adjusted based on patient age, year of study, sample type, HPV screening method, and viral strain(s). Oropharyngeal cancer incidence given for a representative country within each region: Slovakia (Eastern Europe), Brazil (South America), Thailand (Southeastern Asia), Japan (Eastern Asia), Denmark (Northern Europe), Netherlands (Western Europe), Spain (Southern Europe), India (Southern Asia), and United States (North America).

Figure 3. Prevalence of key genetic aberrations in 24 black and 208 white HPV-negative patients (TCGA HNSCC cohort), 37 HPV-negative Indian patients (ICGC HNSCC cohort), 16 Indian HPV-negative patients (Krishnan cohort), and 60 patients from Singapore of unidentified HPV status (Vettore cohort) [, –18]

PIK3CA and NOTCH1 mutations only are reported for the Krishnan cohort. NOTCH1 mutation prevalence only is reported for the Vettore cohort. * indicates significant differences between white and black TCGA cohorts. † indicates significant differences between white TCGA and Indian ICGC cohorts. ‡ indicates significant differences between white TCGA and Vettore cohorts. # indicates significant differences between white TCGA and Krishnan cohorts.

Figure 4. Total mutation load in black and white patients in the TCGA HNSCC cohort

Mutation rates were determined based on data from 24 black and 208 white HPV-negative HNSCC patients assessed as part of TCGA.

Figure 5. Copy number alterations in black and white patients in the TCGA HNSCC cohort

Aberration rates were determined based on data from 24 black and 208 white HPV-negative HNSCC patients assessed as part of TCGA.

Figure 6. Global variation in frequency of PIK3CA aberration in oral cancer

Frequency of PIK3CA amplification (A) and mutation (B) in oral cancer cohorts from countries worldwide. Based on data from Murugan et al. [94] and review of more recent literature, as detailed in Table S2.