
| Written | 2014-08 | Jean-Loup Huret |
| Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France |
| Identity |
| Atlas_Id | 6651 |
| Phylum | Lung, Heart, Skin, Other::Small cell carcinoma |
| Classification |
| In the group of malignant epithelial tumours of the lungs, small cell carcinomas (small cell lung cancer (SCLC)) are usually opposed to non-small cell carcinomas (non-small cell lung cancer (NSCLC)). Small cell carcinoma is a pulmonary neuroendocrine tumour. Other neuroendocrine tumours of the lungs are large cell neuroendocrine carcinomas, typical carcinoids, and atypical carcinoids. |
| Clinics and Pathology |
| Disease | Lung small cell carcinoma |
| Epidemiology | Small cell carcinomas comprise about 15-20% of lung cancers. Small cell carcinoma is more often associated with tobacco smoking than adenocarcinoma, and less than squamous cell carcinoma. |
| Clinics | Patients are typically men older than 60-70 years. Small cell carcinoma more often presents with symptoms of early metastases. Location of the tumour is usually central, but SCLC may occur in a peripheral location. Bronchoscopic biopsy is often positive (van Meerbeeck et al., 2011). |
| Cytology | Small round or oval cells with a finely granular nucleus and frequent mitoses. |
| Pathology | Immunohistochemistry is often positive for neuroendocrine markers, such as chromogranin, synaptophysin, and CD56; SCLCs are also positive for NKX2-1 (14q13, also called TTF-1, a tissue-specific transcription factor in lung epithelial cells) in most cases. |
| Prognosis | Although SCLC is extremely sensitive to initial chemotherapy and radiotherapy, most patients eventually relapse. SCLC is an aggressive disease with poor prognosis, with a five years survival of 5%. High expression of SOX2 (3q26) and FGFR1 (8p11) are associated with the worst outcome (Yang et al., 2013). |
| Genetics |
| Note | TP53 (17p13) mutations are detected in 70 to 90% of SCLCs. RB1 (13q14) and the retinoblastoma pathway are inactivated in most SCLCs. PTEN (10q23) is mutated in 2 to 10%. MYC (8q24) amplifications and amplification of MYC family members are found in 30% of SCLCs in pre-invasive stages. Loss of heterozygocity (LOH) on chromosome arm 3p is found in more than 80% of SCLCs, including the loss of FHIT (3p14) protein expression. FHIT controls the invasive phenotype of lung cancer cells by regulating the expression of genes associated with epithelial-mesenchymal transition. FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-KB/SLUG pathway (Wu et al., 2014). In wide genomic analyses, an elevated rate of C:G>A:T transversions were found, compared to neutral mutations, consistent with demonstrated effects of tobacco smoke carcinogens on DNA. SOX2, a transcription factor, one of the genes able to reprogram human somatic cells to pluripotent stem cells (Lin et al., 2011) was amplified in 27% of the samples. A recurrent RLF/MYCL translocation was found in 9% of SCLCs, and the RLF/MYCL fusion overexpressed MYCL (1p34). FGFR1 was amplified in 6%. Chromatin-modifying enzymes such as EP300 (22q13) were frequently mutated (Peifer et al., 2012; Rudin et al., 2012). To be noted that SOX2 and FGFR1 are also known to be implicated in a subset of squamous cell carcinoma of the lung (Pietanza and Ladanyi, 2012). In contrast with lung adenocarcinomas, there is no molecularly targeted agents yet for small cell carcinomas of the lung. |
| Cytogenetics |
| Note | Only a few genes have been found implicated in many different translocations: - RLF (1p34), a zinc finger protein, which may be involved in transcriptional regulation. Depletion of Rlf leads to DNA hypermethylation in the mouse. RLF is likely to be involved in epigenetic processes (Daxinger et al., 2013), RLF is translocated with 10 different partners (herein below) in SCLCs; - BCL2L1 (20q11) an inhibitor of cell death, involved in various cancers, translocated with 7 different partners (herein below) in SCLCs; - PVT1 (8q24), a non-protein coding and oncofetal gene, translocated with various partners in: breast cancer, Ewing/PNET spectrum, and hematological malignancies, and with 7 different partners (herein below) in SCLCs; PVT1 is a hotspot for chromosomal breaks during MYC amplification (L'Abbate et al., 2014). - Other genes recurrently found are HM13 (20q11), translocated with 3 different partners, and MYCL, BMP8B (1p34), CAP1 (1p34), CREBBP (16p13), and DNM2 (19p13), implicated twice each. |
| Cytogenetics Morphological | Fusion transcripts were often found in amplified regions in 1p34, 2p24, 8q24, and 9p24, suggesting that amplification and fusion of genes occur simultaneously by chromothripsis (Iwakawa et al., 2013). One hundred translocations have so far been reported in small cell carcinoma of the lung. They are the following: t(1;1)(p36;p36) RERE/SLC2A5 (Iwakawa et al., 2013) t(2;5)(p22;q14) BIRC6/BHMT2 (Rudin et al., 2012) t(3;3)(p21;p21) NEK4/SFMBT1 (Rudin et al., 2012) t(5;5)(q13;q13) NAIP/OCLN (Iwakawa et al., 2013) del(6)(q21q22) CEP85L/SCML4 (Rudin et al., 2012) del(7)(p21p21) ANKMY2/ISPD (Rudin et al., 2012) t(8;8)(q12;q24) PVT1/CHD7 (Campbell et al., 2008; Pleasance et al., 2010) t(9;9)(p24;p24) KANK1/DOCK8 (Rudin et al., 2012) t(10;10)(p12;p12) WAC/GPR158 (Iwakawa et al., 2013) t(11;11)(p15;q23) ATP5L/TEAD1 (Iwakawa et al., 2013) t(12;12)(p13;p13) ENO2/ACRBP (Iwakawa et al., 2013) t(14;14)(q23;q23) MTHFD1/SYNE2 (Rudin et al., 2012) t(15;15)(q21;q21) SPG11/SORD (Iwakawa et al., 2013) t(16;16)(p13;p13) CREBBP/RHBDF1 (Peifer et al., 2012; Iwakawa et al., 2013) t(17;17)(p11;p13) MPRIP/TP53 (Peifer et al., 2012) t(18;18)(p11;q12) TWSG1/PIK3C3 (Iwakawa et al., 2013) t(19;19)(p13;p13) NFIX/GATAD2A (Iwakawa et al., 2013) t(20;20)(q11;q11) BCL2L1/HM13 (Iwakawa et al., 2013) |
| Bibliography |
| Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. |
| Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T, Stebbings LA, Leroy C, Edkins S, Hardy C, Teague JW, Menzies A, Goodhead I, Turner DJ, Clee CM, Quail MA, Cox A, Brown C, Durbin R, Hurles ME, Edwards PA, Bignell GR, Stratton MR, Futreal PA. |
| Nat Genet. 2008 Jun;40(6):722-9. doi: 10.1038/ng.128. Epub 2008 Apr 27. |
| PMID 18438408 |
| An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse. |
| Daxinger L, Harten SK, Oey H, Epp T, Isbel L, Huang E, Whitelaw N, Apedaile A, Sorolla A, Yong J, Bharti V, Sutton J, Ashe A, Pang Z, Wallace N, Gerhardt DJ, Blewitt ME, Jeddeloh JA, Whitelaw E. |
| Genome Biol. 2013;14(9):R96. |
| PMID 24025402 |
| Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer. |
| Iwakawa R, Takenaka M, Kohno T, Shimada Y, Totoki Y, Shibata T, Tsuta K, Nishikawa R, Noguchi M, Sato-Otsubo A, Ogawa S, Yokota J. |
| Genes Chromosomes Cancer. 2013 Sep;52(9):802-16. doi: 10.1002/gcc.22076. Epub 2013 May 28. |
| PMID 23716474 |
| Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer. |
| L'Abbate A, Macchia G, D'Addabbo P, Lonoce A, Tolomeo D, Trombetta D, Kok K, Bartenhagen C, Whelan CW, Palumbo O, Severgnini M, Cifola I, Dugas M, Carella M, De Bellis G, Rocchi M, Carbone L, Storlazzi CT. |
| Nucleic Acids Res. 2014;42(14):9131-45. doi: 10.1093/nar/gku590. Epub 2014 Jul 17. |
| PMID 25034695 |
| SOX2 (SRY (sex determining region Y)-box 2). |
| Lin B, Huang X, Han X, Foltz G. |
| Atlas Genet Cytogenet Oncol Haematol. 2011;15(12):1054-1057. URL : http://AtlasGeneticsOncology.org/Genes/SOX2ID44064ch3q26.html. |
| Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. |
| Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Muller C, Di Cerbo V, Schildhaus HU, Altmuller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Bohm D, Ansen S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grutter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sanger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Buttner R, Wolf J, Nurnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK. |
| Nat Genet. 2012 Oct;44(10):1104-10. doi: 10.1038/ng.2396. Epub 2012 Sep 2. |
| PMID 22941188 |
| Bringing the genomic landscape of small-cell lung cancer into focus. |
| Pietanza MC, Ladanyi M. |
| Nat Genet. 2012 Oct;44(10):1074-5. doi: 10.1038/ng.2415. |
| PMID 23011222 |
| A small-cell lung cancer genome with complex signatures of tobacco exposure. |
| Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordo¤ez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, Costa GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes MD, McKernan KJ, Stratton MR, Futreal PA, Campbell PJ. |
| Nature. 2010 Jan 14;463(7278):184-90. doi: 10.1038/nature08629. Epub 2009 Dec 16. |
| PMID 20016488 |
| Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. |
| Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella-Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna JD, Brock MV, Seshagiri S. |
| Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2. |
| PMID 22941189 |
| FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-kB/Slug-mediated PUMA reduction. |
| Wu DW, Lee MC, Hsu NY, Wu TC, Wu JY, Wang YC, Cheng YW, Chen CY, Lee H. |
| Oncogene. 2014 Jul 7. doi: 10.1038/onc.2014.184. [Epub ahead of print] |
| PMID 24998847 |
| Elevated expression of SOX2 and FGFR1 in correlation with poor prognosis in patients with small cell lung cancer. |
| Yang F, Gao Y, Geng J, Qu D, Han Q, Qi J, Chen G. |
| Int J Clin Exp Pathol. 2013 Nov 15;6(12):2846-54. eCollection 2013. |
| PMID 24294370 |
| Small-cell lung cancer. |
| van Meerbeeck JP, Fennell DA, De Ruysscher DK. |
| Lancet. 2011 Nov 12;378(9804):1741-55. doi: 10.1016/S0140-6736(11)60165-7. Epub 2011 May 10. (REVIEW) |
| PMID 21565397 |
| Citation |
| This paper should be referenced as such : |
| JL Huret |
| Lung: Translocations in Small Cell Carcinoma |
| Atlas Genet Cytogenet Oncol Haematol. 2015;19(3):230-233. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Tumors/TranslocLungSmallCellCarcID6651.html |
| Translocations implicated (Data extracted from papers in the Atlas) |
| t(1;1)(p36;p36) RERE/SLC2A5 | |
| t(1;1)(p36;p34) RLF/FAM132A | |
| t(1;1)(p36;p34) RLF/UBE2J2 | |
| t(1;1)(p35;p35) SERINC2/ZCCHC17 | |
| inv(1)(p34p34) BMP8B/RLF | |
| inv(1)(p34p34) CAP1/BMP8B | |
| inv(1)(p34p34) RLF/PPT1 | |
| t(1;1)(p34;p34) CAP1/MACF1 | |
| t(1;1)(p34;p34) INPP5B/SF3A3 | |
| t(1;1)(p34;p34) RLF/MYCL | |
| inv(1)(p34p34) RLF/MYCL | |
| t(1;1)(p34;p34) RLF/COL9A2 | |
| t(1;1)(p34;p34) RLF/SMAP2 | |
| t(1;1)(p34;p34) SF3A3/GNL2 | |
| t(1;1)(p34;p34) SMAP2/MYCL | |
| t(1;1)(p34;p34) ZMPSTE24/MFSD2A | |
| t(1;1)(q21;q21) TXNIP/NOTCH2NL | |
| t(1;1)(q25;q25) XPR1/TRMT1L | |
| del(1)(q44q44) ZNF695/TFB2M | |
| t(1;12)(p34;q24) TRIT1/EP400 | |
| t(1;19)(p36;q13) UBE4B/TBCB | |
| t(1;20)(p34;q11) BCL2L1/BMP8B | |
| t(1;20)(p34;q11) BCL2L1/DEM1 | |
| t(1;20)(p34;q11) BCL2L1/RIMS3 | |
| t(1;20)(p34;q11) BCL2L1/RLF | |
| t(1;20)(p34;q11) BCL2L1/ZNF643 | |
| t(1;20)(p34;q11) BCL2L1/ZNF684 | |
| t(1;20)(p34;q11) PPT1/BCL2L1 | |
| t(1;20)(p34;q11) RLF/HM13 | |
| t(2;5)(p22;q14) BIRC6/BHMT2 | |
| t(2;6)(q31;p12) RCAN2/RAPGEF4 | |
| t(2;12)(p23;p13) CACNA2D4/WDR43 | |
| t(3;3)(p21;p21) NEK4/SFMBT1 | |
| t(3;3)(p21;q23) RASA2/NICN1 | |
| t(3;3)(q13;q22) STAG1/STXBP5L | |
| del(3)(q23q23) SPSB4/ACPL2 | |
| t(3;3)(q23;q24) SLC25A36/PLSCR1 | |
| t(3;3)(q26;q26) GPR160/NCEH1 | |
| inv(3)(q26q27) DCUN1D1/ATP11B | |
| del(3)(q28q28) LPP/TPRG1 | |
| t(3;11)(p24;p15) NGLY1/CCKBR | |
| t(3;11)(p22;q14) DLEC1/ODZ4 | |
| t(3;11)(p21;p15) SFMBT1/AP2A2 | |
| t(3;12)(q13;p11) NAA50/MRPS35 | |
| t(3;16)(q21;p13) TXNDC11/RUVBL1 | |
| t(3;17)(q11;q21) NPEPPS/EPHA6 | |
| t(5;5)(q13;q13) NAIP/OCLN | |
| t(5;5)(q31;q31) SKP1/CDKL3 | |
| t(5;5)(q31;q31) JADE2/UBE2B | |
| del(6)(q21q22) CEP85L/SCML4 | |
| t(6;8)(p21;p21) HMBOX1/ZFAND3 | |
| t(6;20)(p21;p12) CRLS1/KCNK17 | |
| del(7)(p21p21) ANKMY2/ISPD | |
| t(8;8)(q12;q24) PVT1/CHD7 | |
| t(8;8)(q12;q24) PVT1/CLVS1 | |
| inv(8)(q22q23) OXR1/COX6C | |
| inv(8)(q22q23) YWHAZ/OXR1 | |
| t(8;8)(q23;q23) NUDCD1/SYBU | |
| t(8;8)(q23;q24) CSMD3/MYC | |
| t(8;8)(q23;q24) PTK2/PKHD1L1 | |
| t(8;8)(q24;q24) PVT1/LY6H | |
| t(8;14)(p23;q22) AGPAT5/TXNDC16 | |
| t(8;14)(q24;q11) PVT1/CCNB1IP1 | |
| t(8;14)(q24;q11) PVT1/MYH7 | |
| t(8;14)(q24;q11) PVT1/SLC7A7 | |
| t(8;18)(q24;q12) PVT1/NOL4 | |
| t(9;9)(p24;p24) KANK1/DOCK8 | |
| t(9;9)(p24;p24) RIC1/JAK2 | |
| t(10;10)(p12;p12) WAC/GPR158 | |
| t(10;10)(p11;q21) CCDC7/UBE2D1 | |
| t(10;10)(q21;q21) CCDC6/CTNNA3 | |
| t(11;11)(p15;q23) ATP5L/TEAD1 | |
| t(11;11)(q14;q14) PICALM/CCDC81 | |
| t(11;11)(q14;q14) GAB2/NARS2 | |
| t(12;12)(p13;p13) ENO2/ACRBP | |
| inv(12)(p13p13) ERC1/ANO2 | |
| inv(12)(p13p13) C12orf4/CD9 | |
| del(12)(p13p13) ANO2/FBXL14 | |
| del(12)(q12q13) RPAP3/SCAF11 | |
| t(12;12)(q14;q21) PAWR/GNS | |
| t(12;12)(q23;q23) CHPT1/UTP20 | |
| t(12;12)(q24;q24) CIT/RFC5 | |
| t(12;12)(q24;q24) NCOR2/SCARB1 | |
| t(14;14)(q23;q23) MTHFD1/SYNE2 | |
| t(14;16)(q32;q12) SMEK1/HEATR3 | |
| t(15;15)(q21;q21) SPG11/SORD | |
| t(16;16)(p13;p13) CREBBP/RHBDF1 | |
| t(16;16)(p13;p13) CREBBP/SLX4 | |
| del(16)(p13p13) CREBBP/SLX4 | |
| t(17;17)(p11;p13) MPRIP/TP53 | |
| t(17;17)(q25;q25) LRRC45/GCGR | |
| t(17;17)(q25;q25) FOXK2/HEXDC | |
| t(18;18)(p11;q12) TWSG1/PIK3C3 | |
| t(19;19)(p13;p13) NFIX/GATAD2A | |
| t(19;19)(p13;p13) DNM2/ILF3 | |
| del(19)(p13p13) DNM2/KCNN1 | |
| inv(19)(p13p13) GIPC1/PKN1 | |
| del(19)(q13q13) PPP1R37/KLC3 | |
| t(20;20)(q11;q11) BCL2L1/HM13 | |
| t(20;20)(q11;q11) TPX2/HM13 | |
| inv(20)(q11q13) CEP250/DPM1 | |
| inv(22)(q13q13) TTLL1/TSPO | |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year articles | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:25:20 CEST 2017 |
For comments and suggestions or contributions, please contact us