KEGG   DISEASE: Non-small cell lung cancer
H00014                      Disease                                
Non-small cell lung cancer
Solid tumor [DS:H02421]
Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector. Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
Human diseases [BR:br08402]
  Cancers of the lung and pleura
   H00014  Non-small cell lung cancer
Human diseases in ICD-11 classification [BR:br08403]
 02 Neoplasms
  Malignant neoplasms, except primary neoplasms of lymphoid, haematopoietic, central nervous system or related tissues
   Malignant neoplasms, stated or presumed to be primary, of specified sites, except of lymphoid, haematopoietic, central nervous system or related tissues
    Malignant neoplasms of middle ear, respiratory or intrathoracic organs
     2C25  Malignant neoplasms of bronchus or lung
      H00014  Non-small cell lung cancer
Tumor markers [br08442.html]
Cancer-associated carbohydrates [br08441.html]
hsa05223  Non-small cell lung cancer
hsa05200  Pathways in cancer
hsa05206  MicroRNAs in cancer
nt06234  cAMP signaling
nt06266  Non-small cell lung cancer
EML4-ALK (translocation) [HSA:238] [KO:K05119]
CD74-ROS1,SLC34A2-ROS1 (translocation) [HSA:6098] [KO:K05088]
KIF5B-RET (inversion) [HSA:5979] [KO:K05126]
RARB (promoter hypermethylation) [HSA:5915] [KO:K08528]
RASSF1 (promoter hypermethylation) [HSA:11186] [KO:K09850]
KRAS [HSA:3845] [KO:K07827]
EGFR [HSA:1956] [KO:K04361]
FHIT [HSA:2272] [KO:K01522]
CDKN2A [HSA:1029] [KO:K06621]
TP53 [HSA:7157] [KO:K04451]
MET [HSA:4233] [KO:K05099]
BRAF [HSA:673] [KO:K04365]
PIK3CA [HSA:5290] [KO:K00922]
IRF1 [HSA:3659] [KO:K09444]
PPP2R1B [HSA:5519] [KO:K03456]
Arsenic and arsenic compounds [CPD:C06269]
Arsenic in drinking-water
Asbestos [CPD:C16442]
Mustard gas (Sulfur mustard)
Nickel compounds
Plutonium-239 and its decay products (may contain plutonium-240 and other isotopes), as aerosols
Radon-222 and its decay products
Silica, crystalline (inhaled in the form of quartz orcristobalite from occupational sources) [CPD:C16459]
Tobacco smoking and tobacco smoke
*Aluminium production
*Benzo[a]pyrene [CPD:C07535]
*Cadmium and cadmium compounds
*Chimney sweeping
*Coal gasification
*Coal-tar pitches [CPD:C16451]
*Coke production
*Furniture and cabinet making
*Haematite mining (underground) with exposure to radon
*Household combustion of coal, indoor emissions from
*Involuntary smoking (exposure to secondhand or environmental tobacco smoke)
*Iron and steel founding
*Mineral oils, untreated and mildly treated
*Painter (occupational exposure as a)
*Paving and roofing with coal-tar pitch
*Shale-oils [CPD:C16458]
*Strong-inorganic-acid mists containing sulfuric acid
*Talc containing asbestiform fibres
*X- and gamma-radiation
*: Although this is a risk factor for lung cancer in general, the strength of association with different histological tumor types is not well understood.
Methotrexate sodium [DR:D02115]
Pemetrexed sodium hydrate [DR:D06503]
Gemcitabine hydrochloride [DR:D01155]
Vinorelbine tartrate [DR:D01935]
Paclitaxel [DR:D00491]
Docetaxel [DR:D07866]
Docetaxel [DR:D02165]
Gefitinib [DR:D01977] (EGFR mutation positive)
Erlotinib hydrochloride [DR:D04023] (EGFR mutation positive)
Afatinib dimaleate [DR:D09733] (EGFR mutation positive)
Osimertinib mesylate [DR:D10766] (EGFR mutation positive)
Dacomitinib [DR:D10514] (EGFR mutation positive)
Dabrafenib mesylate [DR:D10104] (BRAF mutation positive)
Crizotinib [DR:D09731] (ALK or ROS1-positive)
Ceritinib [DR:D10551] (ALK positive)
Alectinib hydrochloride [DR:D10450] (ALK positive)
Brigatinib [DR:D10866] (ALK positive)
Lorlatinib [DR:D11012] (ALK positive)
Trametinib dimethyl sulfoxide [DR:D10176] (BRAF mutation positive)
Entrectinib [DR:D10926] (ROS1-positive)
Capmatinib hydrochloride [DR:D10891] (MET exon 14 skipping positive)
Tepotinib hydrochloride [DR:D11073] (MET exon 14 skipping)
Selpercatinib [DR:D11713] (RET fusion positive)
Pralsetinib [DR:D11712] (RET fusion positive)
Necitumumab [DR:D10018]
Nivolumab [DR:D10316]
Pembrolizumab [DR:D10574] (PD-L1 expressed)
Durvalumab [DR:D10808]
Atezolizumab [DR:D10773]
Cemiplimab [DR:D11108]
Bevacizumab [DR:D06409]
Ramucirumab [DR:D09371]
Amivantamab [DR:D11894] (EGFR exon 20 insertion)
Sotorasib [DR:D12055] (KRAS G12C-mutated)
Mobocertinib succinate [DR:D11969] (EGFR exon 20 insertion mutation)
Other DBs
ICD-11: 2C25.0 2C25.2 2C25.3
ICD-10: C34
MeSH: D002289
Yokota J, Nishioka M, Tani M, Kohno T.
Genetic alterations responsible for metastatic phenotypes of lung cancer cells.
Clin Exp Metastasis 20:189-93 (2003)
Sanchez-Cespedes M.
Dissecting the genetic alterations involved in lung carcinogenesis.
Lung Cancer 40:111-21 (2003)
Mitsuuchi Y, Testa JR.
Cytogenetics and molecular genetics of lung cancer.
Am J Med Genet 115:183-8 (2002)
Panani AD, Roussos C.
Cytogenetic and molecular aspects of lung cancer.
Cancer Lett 239:1-9 (2006)
Meuwissen R, Berns A.
Mouse models for human lung cancer.
Genes Dev 19:643-64 (2005)
Toyooka S, Mitsudomi T, Soh J, Aokage K, Yamane M, Oto T, Kiura K, Miyoshi S
Molecular oncology of lung cancer.
Gen Thorac Cardiovasc Surg 59:527-37 (2011)
Koudelakova V, Kneblova M, Trojanec R, Drabek J, Hajduch M
Non-small cell lung cancer--genetic predictors.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 157:125-36 (2013)
Sundar R, Chenard-Poirier M, Collins DC, Yap TA
Imprecision in the Era of Precision Medicine in Non-Small Cell Lung Cancer.
Front Med (Lausanne) 4:39 (2017)
PMID:17625570 (EML4-ALK translocation)
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Nature 448:561-6 (2007)
PMID:19406209 (CD74-ROS1,SLC34A2-ROS1  translocation)
Brenner JC, Chinnaiyan AM
Translocations in epithelial cancers.
Biochim Biophys Acta 1796:201-15 (2009)
PMID:22327623 (KIF5B-RET  inversion)
Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y
RET, ROS1 and ALK fusions in lung cancer.
Nat Med 18:378-81 (2012)
PMID:18349282 (RARB promoter hypermethylation)
Feng Q, Hawes SE, Stern JE, Wiens L, Lu H, Dong ZM, Jordan CD, Kiviat NB, Vesselle H
DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients.
Cancer Epidemiol Biomarkers Prev 17:645-54 (2008)
PMID:11333291 (RASSF1 promoter hypermethylation)
Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M, Minna JD
Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression.
J Natl Cancer Inst 93:691-9 (2001)
PMID:16533793 (KRAS)
Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP
Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.
Clin Cancer Res 12:1647-53 (2006)
PMID:15118073 (EGFR)
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
N Engl J Med 350:2129-39 (2004)
PMID:8620533 (FHIT)
Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, De Gregorio L, Pastorino U, Pierotti MA, Ohta M, Huebner K, Croce CM
The FHIT gene 3p14.2 is abnormal in lung cancer.
Cell 85:17-26 (1996)
PMID:8060323 (CDKN2A)
Hayashi N, Sugimoto Y, Tsuchiya E, Ogawa M, Nakamura Y
Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas.
Biochem Biophys Res Commun 202:1426-30 (1994)
PMID:2554494 (TP53)
Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD
p53: a frequent target for genetic abnormalities in lung cancer.
Science 246:491-4 (1989)
PMID:28502721 (MET)
Lee GD, Lee SE, Oh DY, Yu DB, Jeong HM, Kim J, Hong S, Jung HS, Oh E, Song JY, Lee MS, Kim M, Jung K, Kim J, Shin YK, Choi YL, Kim HR
MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values.
J Thorac Oncol 12:1233-1246 (2017)
PMID:12460918 (BRAF)
Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL
BRAF and RAS mutations in human lung cancer and melanoma.
Cancer Res 62:6997-7000 (2002)
PMID:15608678 (PIK3CA)
Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH
PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.
Oncogene 24:1477-80 (2005)
PMID:10395927 (IRF1)
Eason DD, Shepherd AT, Blanck G
Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes DNA binding.
Biochim Biophys Acta 1446:140-4 (1999)
PMID:9765152 (PPP2R1B)
Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J, Evans GA
Alterations of the PPP2R1B gene in human lung and colon cancer.
Science 282:284-7 (1998)

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