title: CHFR aberrant methylation involves a subset of human lung adenocarcinoma associated with poor clinical outcomes.
abstract: Excluding epidermal growth factor receptor (EGFR) mutation, v-Ki-ras2/Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion, the genetic alterations involved in lung adenocarcinogenesis, especially those linked to poor clinical outcomes, are still unknown. In this study, we analyzed abnormal checkpoint gene with forkhead-associated domain and ring finger (CHFR) methylation along with the above 3 mutations in 165 lung adenocarcinomas, evaluated the spectrum of each molecular abnormality, and correlated the results with clinical and pathologic variables. Reverse transcription-polymerase chain reaction assay, reverse transcription-polymerase chain reaction followed by direct DNA sequencing, and methylation-specific polymerase chain reaction were performed to detect these 3 mutations and CHFR hypermethylation. The EML4-ALK transcript or CHFR hypermethylation was found in 11 (6.7%) or 16 (10%) adenocarcinomas, respectively, whereas EGFR or KRAS mutation was detected in 48 (29%) or 13 (8%) cases, respectively. EGFR mutations occurred in patients who were negative for both CHFR hypermethylation and KRAS mutation. Among the 4 genetic or epigenetic abnormalities, only CHFR hypermethylation was significantly correlated with poor prognosis and lymphatic vessel invasion (P = .024). Histopathologically, the molecular abnormality that correlated with alveolar-destructive growth was the CHFR hypermethylation rather than the EGFR mutation (P = .03). Our results demonstrate that CHFR hypermethylation maybe one of the molecular abnormalities involved in a subset of lung adenocarcinomas with poor prognoses that might be induced by destructive growth and lymphatic vessel invasion of carcinoma cells. Thus, CHFR abnormality might be pursued as a novel therapeutic target against lung adenocarcinoma without an already-known mutation.
authors: Department of Pathology, Division of Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University 812-8582, Fukuoka, Japan. takaomi@pathol1.med.kyushu-u.ac.jp
authors: Takaomi
authors: T
authors: Koga
authors: Masafumi
authors: M
authors: Takeshita
authors: Kayo
authors: K
authors: Ijichi
authors: Tokujiro
authors: T
authors: Yano
authors: Yoshihiko
authors: Y
authors: Maehara
authors: Katsuo
authors: K
authors: Sueishi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases