Identification of Germline Mutations in East‑Asian Young Never‑Smokers with Lung Adenocarcinoma by Whole‑Exome Sequencing

Recently,an increasing number of young never-smokers are diagnosed with lung cancer.The aim of this study is to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers.Peripheral blood was collected from 123 never-smoking east-Asian patients diagnosed with lung adenocarcinoma before the age of 40.Whole-exome sequencing(WES)was conducted on genomic DNA extracted from peripheral blood cells.As a result,3,481 single nucleotide variants were identified.By bioinformatical tools and the published gene list associated with genetic predisposition of cancer,pathogenic variants were detected in ten germline genes:ATR,FANCD2,FANCE,GATA2,HFE,MSH2,PDGFRA,PMS2,SDHB,and WAS.Patients with pathogenic variants were more likely to occur in females(9/10,90.0%)and have stage IV lung adenocarcinoma(4/10,40%).Furthermore,germline muta-tions in 17 genes(ASB18,B3GALT5,CLEC4F,COL6A6,CYP4B1,C6orf132,EXO1,GATA4,HCK,KCP,NPHP4,PIGX,PPIL2,PPP1R3G,RRBP1,SALL4,and TTC28),which occurred in at least two patients,displayed potentially pathogenic effects.Gene ontology analysis further showed that these genes with germline mutations were mainly located in nucleo-plasm and associated with DNA repair-related biological processes.The study provides spectrum of pathogenic variants and functional explanation for genetic predisposition of lung adenocarcinoma in young never-smokers,which sheds a light on prevention and early diagnosis of lung cancer.

Mutually exclusive epigenetic modification on SIX6 with hypermethylation for precancerous stage and metastasis emergence tracing

Dear Editor,Aberrant DNA methylation gets involved in cancer initiation,progression,and recurrence,which in turn makes it an ideal cancer biomarker.Various methylation markers or their panels have been developed in diverse cancer types.However,the model-constructing based marker mining strategy and incompatibility of application have greatly impeded their ways to clinic.Thus,single methylation marker applicable to all/most cancer types and multiple clinical scenarios is desperately needed.The hope came from the unexpected observation that HIST1H4F was universally hypermethylated in all 17 cancer types;thus,we raised the concept of“Universal Cancer Only Marker(UCOM)”and established a paradigm for discovery and clinical application of UCOM.1 Recently,a novel UCOM,hypermethylated PCDHGB7,was identified and found to advance cervical cancer(CC)screening to the precancerous stage.2 During the screening of UCOM,we discerned a bunch of cancer cell-differentially methylated regions.1 Among them,sine oculis(SIX)homeobox family of transcription factors,which were found to function as tumorigenesis regulator by promoting epithelial-to-mesenchymal transition and metastasis recently in addition to their traditional roles in tissue formation and organogenesis,3 sparked our special attention.Herein,we interrogate whether SIX6 methylation could serve as a novel UCOM and its potential applications.