title: Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients.
abstract: Intratumor heterogeneity can confound the results of mutation analyses in oncodriver genes using traditional methods thereby challenging the application of targeted cancer therapy strategies for patients Ultradeep sequencing can detect low frequency and expanded clonal mutations in primary tumors to better inform treatment decisions. KRAS coding exons in 61 treatment-naive colorectal cancer (CRC) tumors and KRAS, EGFR, ALK, and MET in lung tumors from three Chinese non-small cell lung cancer (NSCLC) patients were sequenced using ultradeep sequencing methods. Forty-one percent of CRC patients (25/61) harbored mutations in the KRAS active domain, eight of which (13%) were not detected by Sanger sequencing. Three (of eight) had frequencies less than 10% and one patient harbored more than one mutation. Low frequency KRAS active (G12R) and EGFR kinase domain mutations (G719A) were identified in one NSCLC patient. A second NSCLC patient showed an EML4-ALK fusion with ALK, EGFR, and MET mutations. A third NSCLC patient harbored multiple low frequency mutations in KRAS, EGFR, and MET as well as ALK gene copy number increases. Within the same patient, multiple low frequency mutations occurred within a gene. A complex pattern of intrinsic low frequency driver mutations in well-known tumor oncogenes may exist prior to treatment, resulting in resistance to targeted therapies. Ultradeep sequencing can characterize intratumor heterogeneity and identify such mutations to ultimately affect treatment decisions.
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Jiang
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Huang
authors.forename: Chris
authors.initials: C
authors.lastname: Morehouse
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Susana
authors.initials: S
authors.lastname: Korolevich
authors.forename: Dan
authors.initials: D
authors.lastname: Sui
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Ge
authors.forename: Kim
authors.initials: K
authors.lastname: Lehmann
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Christine
authors.initials: C
authors.lastname: Kiefer
authors.forename: Meggan
authors.initials: M
authors.lastname: Czapiga
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D045325:HCT116 Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Ultradeep sequencing; colorectal cancer; low frequency mutations; non-small cell lung cancer; oncogene