title: Codon-level co-occurrences of germline variants and somatic mutations in cancer are rare but often lead to incorrect variant annotation and underestimated impact prediction.
abstract: Cancer cells explore a broad mutational landscape, bringing the possibility that tumor-specific somatic mutations could fall in the same codons as germline SNVs and leverage their presence to produce substitutions with a larger impact on protein function. While multiple, temporally consecutive mutations to the same codon have in the past been detected in the germline, this phenomenon has not yet been explored in the context of germline-somatic variant co-occurrences during cancer development. We examined germline context at somatic mutation sites for 1395 patients across four cancer cohorts (breast, skin, colon, and head and neck) and found 392 codon-level co-occurrences between germline and somatic variants, including over a dozen in well-known cancer genes. We found that for the majority of these co-occurrence events, traditional somatic calling led to an inaccurate representation of the protein site and a significantly lower predicted impact on protein fitness. We conclude that these events often lead to imprecise annotation of somatic variants but do not appear to be a frequent source of driver events during cancer development.
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.|Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Koire
authors.affiliation: Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Young Won
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jarey
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Katsonis
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Haijing
authors.initials: H
authors.lastname: Jin
authors.affiliation: Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D003062:Codon / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D058977:Molecular Sequence Annotation / Q000379:methods; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics
chemical_list: D003062:Codon