Entry

H00014                      Disease

Name

Non-small cell lung cancer

Supergrp

Solid tumor [DS:H02421]

Description

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.

Category

Cancer

Brite

Human diseases [BR:br08402]
Cancers
  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]
H00014
Cancer-associated carbohydrates [br08441.html]
H00014

Pathway

hsa05223

Non-small cell lung cancer

Network

nt06266 Non-small cell lung cancer

Gene

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]

Drug

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

Reference

PMID:12741677

Authors

Yokota J, Nishioka M, Tani M, Kohno T.

Title

Genetic alterations responsible for metastatic phenotypes of lung cancer cells.

Journal

Clin Exp Metastasis 20:189-93 (2003)
DOI:10.1023/a:1022978932215

Reference

PMID:12711111

Authors

Sanchez-Cespedes M.

Title

Dissecting the genetic alterations involved in lung carcinogenesis.

Journal

Lung Cancer 40:111-21 (2003)
DOI:10.1016/S0169-5002(03)00033-3

Reference

PMID:12407699

Authors

Mitsuuchi Y, Testa JR.

Title

Cytogenetics and molecular genetics of lung cancer.

Journal

Am J Med Genet 115:183-8 (2002)
DOI:10.1002/ajmg.10692

Reference

PMID:16112428

Authors

Panani AD, Roussos C.

Title

Cytogenetic and molecular aspects of lung cancer.

Journal

Cancer Lett 239:1-9 (2006)
DOI:10.1016/j.canlet.2005.06.030

Reference

PMID:15769940

Authors

Meuwissen R, Berns A.

Title

Mouse models for human lung cancer.

Journal

Genes Dev 19:643-64 (2005)
DOI:10.1101/gad.1284505

Reference

PMID:21850578

Authors

Toyooka S, Mitsudomi T, Soh J, Aokage K, Yamane M, Oto T, Kiura K, Miyoshi S

Title

Molecular oncology of lung cancer.

Journal

Gen Thorac Cardiovasc Surg 59:527-37 (2011)
DOI:10.1007/s11748-010-0743-3

Reference

PMID:23733083

Authors

Koudelakova V, Kneblova M, Trojanec R, Drabek J, Hajduch M

Title

Non-small cell lung cancer--genetic predictors.

Journal

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 157:125-36 (2013)
DOI:10.5507/bp.2013.034

Reference

PMID:28443282

Authors

Sundar R, Chenard-Poirier M, Collins DC, Yap TA

Title

Imprecision in the Era of Precision Medicine in Non-Small Cell Lung Cancer.

Journal

Front Med (Lausanne) 4:39 (2017)
DOI:10.3389/fmed.2017.00039

Reference

PMID:17625570 (EML4-ALK translocation)

Authors

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

Title

Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

Journal

Nature 448:561-6 (2007)
DOI:10.1038/nature05945

Reference

PMID:19406209 (CD74-ROS1,SLC34A2-ROS1 translocation)

Authors

Brenner JC, Chinnaiyan AM

Title

Translocations in epithelial cancers.

Journal

Biochim Biophys Acta 1796:201-15 (2009)
DOI:10.1016/j.bbcan.2009.04.005

Reference

PMID:22327623 (KIF5B-RET inversion)

Authors

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

Title

RET, ROS1 and ALK fusions in lung cancer.

Journal

Nat Med 18:378-81 (2012)
DOI:10.1038/nm.2658

Reference

PMID:18349282 (RARB promoter hypermethylation)

Authors

Feng Q, Hawes SE, Stern JE, Wiens L, Lu H, Dong ZM, Jordan CD, Kiviat NB, Vesselle H

Title

DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients.

Journal

Cancer Epidemiol Biomarkers Prev 17:645-54 (2008)
DOI:10.1158/1055-9965.EPI-07-2518

Reference

PMID:11333291 (RASSF1 promoter hypermethylation)

Authors

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

Title

Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression.

Journal

J Natl Cancer Inst 93:691-9 (2001)
DOI:10.1093/jnci/93.9.691

Reference

PMID:16533793 (KRAS)

Authors

Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD, Gazdar AF, Wong MP

Title

Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features.

Journal

Clin Cancer Res 12:1647-53 (2006)
DOI:10.1158/1078-0432.CCR-05-1981

Reference

PMID:15118073 (EGFR)

Authors

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.

Title

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

Journal

N Engl J Med 350:2129-39 (2004)
DOI:10.1056/NEJMoa040938

Reference

PMID:8620533 (FHIT)

Authors

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

Title

The FHIT gene 3p14.2 is abnormal in lung cancer.

Journal

Cell 85:17-26 (1996)
DOI:10.1016/s0092-8674(00)81078-8

Reference

PMID:8060323 (CDKN2A)

Authors

Hayashi N, Sugimoto Y, Tsuchiya E, Ogawa M, Nakamura Y

Title

Somatic mutations of the MTS (multiple tumor suppressor) 1/CDK4l (cyclin-dependent kinase-4 inhibitor) gene in human primary non-small cell lung carcinomas.

Journal

Biochem Biophys Res Commun 202:1426-30 (1994)
DOI:10.1006/bbrc.1994.2090

Reference

PMID:2554494 (TP53)

Authors

Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF, Minna JD

Title

p53: a frequent target for genetic abnormalities in lung cancer.

Journal

Science 246:491-4 (1989)
DOI:10.1126/science.2554494

Reference

PMID:28502721 (MET)

Authors

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

Title

MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values.

Journal

J Thorac Oncol 12:1233-1246 (2017)
DOI:10.1016/j.jtho.2017.04.031

Reference

PMID:12460918 (BRAF)

Authors

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

Title

BRAF and RAS mutations in human lung cancer and melanoma.

Journal

Cancer Res 62:6997-7000 (2002)

Reference

PMID:15608678 (PIK3CA)

Authors

Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH

Title

PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.

Journal

Oncogene 24:1477-80 (2005)
DOI:10.1038/sj.onc.1208304

Reference

PMID:10395927 (IRF1)

Authors

Eason DD, Shepherd AT, Blanck G

Title

Interferon regulatory factor 1 tryptophan 11 to arginine point mutation abolishes DNA binding.

Journal

Biochim Biophys Acta 1446:140-4 (1999)
DOI:10.1016/s0167-4781(99)00078-0

Reference

PMID:9765152 (PPP2R1B)

Authors

Wang SS, Esplin ED, Li JL, Huang L, Gazdar A, Minna J, Evans GA

Title

Alterations of the PPP2R1B gene in human lung and colon cancer.

Journal

Science 282:284-7 (1998)
DOI:10.1126/science.282.5387.284

DISEASE: Non-small cell lung cancer