Analysis Of OMM Genomic Landscape And Identification Of Clinically Relevant Genetic Aberrations

Purpose: Oral mucosal melanomas(OMMs)that arising from the oral and maxillofacial region are one of the deadliest subtypes of melanoma,with 5-year survival rates ranging from only 20% to 25%.Unlike advances in the genomics-driven precision treatment of cutaneous melanomas,the poor current understanding of the molecular basis of OMMs has hindered such progress for these patients.Thus,we sought to characterize the genomic landscape of OMM to identify genomic alterations with prognostic and/or therapeutic implications,and to acceralerat the clinical translation and application of the personalized treatment for OMM patients.Methods:(1)Paried tumor samples were collected from OMM patients.Wholegenome sequencing(WGS)was performed on 65 MM samples,including 63 paired tumor blood samples and 2 matched lymph node metastases.The genomic landscape of OMM was depicted with bioinformatic methods by calling the somatic singlenucleotide variants(SNVs),In/Dels,copy number variants(CNVs),and structural variations(SVs)of the OMM tumors;(2)A total of 80 formalin-fixed paraffinembedded(FFPE)OMM clinical samples were collected and laser capture microdissection and droplet digital PCR(dd PCR)was used to validate the amplification of the oncogenes(CDK4,TERT,AGAP2 and MDM2)detected by WGS;(3)A genetically characterized patient-derived xenograft(PDX)cohort(obtained from the OMM PDX platform that we previously established)was used to conduct a PDX Trial.Guided by the genomic feature of OMM,the FDA-approved CDK4/6 inhibitor palbociclib,was tested in this OMM PDX trial,and potential predictive biomarkers were analyzed to guide the design of further clinical trial.Results:(1)Besides the identification of well-recognized driver mutations of BRAF(3.1%),RAS family(6.2%),NF1(7.8%)and KIT(23.1%)in OMMs,we found that mutations and amplifications in the transmembrane nucleoporin gene POM121(30.8%)defined a patient subgroup with higher tumor proliferation rates;(2)Clusters of breakpoints/structural variants,indicating that frequent complex genomic rearrangement events,were found to be enriched on chromosomes 5 and 12,and noted that an increased frequency of such rearrangement events were associated with poor prognosis;(3)Over 50% of the MM patients harbored recurrent focal amplification of several oncogenes(CDK4,MDM2 and AGAP2)at 12q13-15,and this co-occurred significantly with amplification of TERT at 5p15,which was verified in the validation cohort(n = 80);(4)The PDX cohort recapitulated the genetic feature we observed in OMM,the PDX trial demonstrated robust anti-tumor effects of palbociclib in MMs harboring CDK4 amplification.Conclusion: Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution.The genomic landscape of OMM is dramatically different from that of cutaneous melanoma.The overall genomic landscape of MM indicates the biological significance of large-scale genomic rearrangements,especially the enriched SVs between chromosomes 5 and 12,during the development of OMMs.The PDX trial demonstrated the feasibility of targeted treatment approach(targeting CDK4 amplification)in OMMs,which would accelerate the clinical translation of the personalized treatment for patients with this deadly disease.