title: KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma.
abstract: KRAS mutations define a clinically distinct subgroup of lung adenocarcinoma patients, characterized by smoking history, resistance to EGFR-targeted therapies, and adverse prognosis. Whether KRAS-mutated lung adenocarcinomas also have distinct histopathological features is not well established. We tested 180 resected lung adenocarcinomas for KRAS and EGFR mutations by high-sensitivity mass spectrometry-based genotyping (Sequenom) and PCR-based sizing assays. All tumors were assessed for the proportion of standard histological patterns (lepidic, acinar, papillary, micropapillary, solid, and mucinous), several other histological and clinical parameters, and TTF-1 expression by immunohistochemistry. Among 180 carcinomas, 63 (35%) had KRAS mutations (KRAS+), 35 (19%) had EGFR mutations (EGFR+), and 82 (46%) had neither mutation (KRAS-/EGFR-). Solid growth pattern was significantly over-represented in KRAS+ carcinomas: the mean±s.d. for the amount of solid pattern in KRAS+ carcinomas was 27±34% compared with 3±10% in EGFR+ (P<0.001) and 15±27% in KRAS-/EGFR- (P=0.033) tumors. Furthermore, at least focal (≥20%) solid component was more common in KRAS+ (28/63; 44%) compared with EGFR+ (2/35; 6%; P<0.001) and KRAS-/EGFR- (21/82; 26%; P=0.022) carcinomas. KRAS mutations were also over-represented in mucinous carcinomas and were significantly associated with the presence of tumor-infiltrating leukocytes and heavier smoking history. EGFR mutations were associated with non-mucinous non-solid patterns, particularly lepidic and papillary, lack of necrosis, lack of cytological atypia, hobnail cytology, TTF-1 expression, and never/light smoking history. In conclusion, extended molecular and clinicopathological analysis of lung adenocarcinomas reveals a novel association of KRAS mutations with solid histology and tumor-infiltrating inflammatory cells and expands on several previously recognized morphological and clinical associations of KRAS and EGFR mutations. Solid growth pattern was recently shown to be a strong predictor of aggressive behavior in lung adenocarcinomas, which may underlie the unfavorable prognosis associated with KRAS mutations in these tumors.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rekhtman
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Ang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Andre L
authors.initials: AL
authors.lastname: Moreira
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins