title: Unique Genetic and Survival Characteristics of Invasive Mucinous Adenocarcinoma of the Lung.
abstract: BACKGROUND
  Invasive mucinous adenocarcinoma is a unique histologic subtype of lung cancer, and our knowledge of its genetic and clinical characteristics is rapidly evolving. Here, we present next- generation sequencing analysis of nucleotide variant and fusion events along with clinical follow-up in a series of lung mucinous adenocarcinoma.
  
  
  METHODS
  We collected 72 mucinous adenocarcinomas from the United States and Korea. All had been previously assessed for KRAS and EGFR mutations. For KRAS wild-type cases (n = 30), we performed deep targeted next-generation sequencing for gene fusions and nucleotide variants and correlated survival and other clinical features.
  
  
  RESULTS
  As expected, KRAS mutations were the most common alteration found (63% of cases); however, the distribution of nucleotide position alterations was more similar to that observed in gastrointestinal tumors than other lung tumors. Within the KRAS-negative cases, we found numerous potentially targetable gene fusions and mutations, including CD74-NRG1, VAMP2-NRG1, TRIM4-BRAF, TPM3-NTRK1, and EML4-ALK gene fusions and ERBB2, BRAF, and PIK3CA mutations. Unexpectedly, we found only two cases with TP53 mutation, which is much lower than observed in lung adenocarcinomas in general. The overall mutation burden was low in histologically confirmed mucinous adenocarcinomas from the public The Cancer Genome Atlas exome data set, regardless of smoking history, suggesting a link between TP53 status and mutation burden in mucinous tumors. There was no significant difference for recurrence-free survival between stage-matched mucinous and nonmucinous adenocarcinomas. It was notable that all recurrence sites were in the lungs for completely resected cases.
  
  
  CONCLUSIONS
  Our data suggest that mucinous adenocarcinoma is typified by (1) frequent KRAS mutations and a growing list of gene fusions, but rare TP53 mutations, (2) a low mutation burden overall, and (3) a recurrence-free survival similar to stage-matched nonmucinous tumors, with recurrences limited to the lungs.
authors.affiliation: *Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; †Department of Pathology, Yonsei University College of Medicine, Seoul, Korea; and ‡Department of Thoracic Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Hyo Sup
authors.initials: HS
authors.lastname: Shim
authors.forename: Mari-
authors.initials: M
authors.lastname: Kenudson
authors.forename: Zongli
authors.initials: Z
authors.lastname: Zheng
authors.forename: Matthew
authors.initials: M
authors.lastname: Liebers
authors.forename: Yoon Jin
authors.initials: YJ
authors.lastname: Cha
authors.forename: Quan
authors.initials: Q
authors.lastname: Hoang Ho
authors.forename: Maristela
authors.initials: M
authors.lastname: Onozato
authors.forename: Long
authors.initials: L
authors.lastname: Phi Le
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020890:Neuregulin-1 / Q000235:genetics; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics; D014335:Tropomyosin / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D050988:Vesicle-Associated Membrane Protein 2 / Q000235:genetics
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D000949:Histocompatibility Antigens Class II; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D020917:Receptor, trkA; D014335:Tropomyosin; D016159:Tumor Suppressor Protein p53; D050988:Vesicle-Associated Membrane Protein 2; C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; C094131:NRG1 protein, human; C495901:TP53 protein, human; C498783:TPM3 protein, human; C494807:VAMP2 protein, human; C045084:invariant chain; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human