Genetic alterations in head and neck squamous cell carcinoma:The next-gen sequencing era

Head and neck squamous cell carcinoma is the sixth most common cancer in the world with approximately650000 new cases diagnosed annually.Next-generation molecular techniques and results from phase 2 of the Cancer Genome Atlas becoming available have drastically improved our current knowledge on the genetics basis of head and neck squamous cell carcinoma.New insights and new perspectives on the mutational landscape implicated in head and neck squamous cell carcinoma provide improved tools for prognostication.More importantly,depend on the patient's tumor subtypes and prognosis,deescalated or more aggressive therapy maybe chosen to achieve greater potency while minimizing the toxicity of therapy.This paper aims to review our current knowledge on the genetic mutations and altered molecular pathways in head and neck squamous cell carcinoma.Some of the most common mutations in head and neck squamous cell carcinoma reported by the cancer genome atlas including TP53,NOTCH1,Rb,CDKN2 A,Ras,PIK3 CA and EGFR are described here.Additionally,the emerging role of epigenetics and the role of human papilloma virus in head and neck squamous cell carcinoma are also discussed in this review.The molecular pathways,clinical applications,actionable molecular targets and potential therapeutic strategies are highlighted and discussed in details.

Somatic genetic aberrations in gallbladder cancer: comparison between Chinese and US patients

Background:Gallbladder cancer(GBC)is often diagnosed at an advanced stage with limited therapeutic options and poor prognosis.The five-year survival rate of this cancer when diagnosed at an advanced stage is below 5%,and the median survival time is less than a year with standard gemcitabine-based chemotherapy.Survival benefit with second-line treatment is unknown.Thus,there is an urgent need for novel treatment strategies and targeted therapy based on next generation sequencing(NGS)may be of value.Methods:Comprehensive genomic profiling(CGP)was performed with NGS panel on paraffin-embedded tumors from a cohort of 108 Chinese and 107 US GBC patients.Clinical data were collected using an IRB approved protocol from a single-center in US and from China.Results:In Chinese and US GBC cohorts,an average of 6.4 vs.3.8 genomic alterations(GAs)were identified per patient.The most frequent alterations were TP53(69.4%),CDKN2A/B(26%),ERBB2(18.5%),PIK3CA(17%)and CCNE1(13%)in Chinese cohort,TP53(57.9%),CDKN2A/B(25%),SMAD4(17%),ARID1A(14%),PIK3CA(14%)and ERBB2(13.1%)in US patients.NFE2L2 mutations were present in 6.5%of Chinese patients and not observed in the US cohort.Interestingly,ERBB2 genetic aberrations were significantly associated with better pathological tumor differentiation and tended to co-occurrence with CDKN2A/B mutations in both the Chinese and US GBC cases.Out of the top 9 dysregulated genetic pathways in cancer,Chinese patients harbored more frequent mutations in ERBB genes(30.6%vs.19.0%,P=0.04).High frequency of PI3K/mTOR pathway variations was observed in both Chinese(37%)and US cohort(33%)(P=0.5).Additionally,both Chinese and US GBC patients exhibited a relatively high tumor mutational burden(TMB)(17.6%and 17.0%,respectively).In the Chinese cohort,a significant association was seen between direct repair gene alterations and TMB≥10 muts/Mb(P=0.004).Conclusions:In our study,over 83%Chinese and 68%US GBC patients had actionable alterations that could potentially guide and influence personalized treatment options.The identification of high TMB,ERBB2,CDKN2A/B,PI3K/mTOR pathway and DNA repair mutations indicated that both Chinese and US GBC patients may benefit from targeted or immune checkpoint inhibitors.