Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

Maria Teresa Landi and colleagues report genomic tumor data for a cohort of patients with lung adenocarcinoma, focusing on implications for tumor initiation and distant metastasis.

Vyšlo v časopise: Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study. PLoS Med 13(12): e32767. doi:10.1371/journal.pmed.1002162
Kategorie: Research Article


Maria Teresa Landi and colleagues report genomic tumor data for a cohort of patients with lung adenocarcinoma, focusing on implications for tumor initiation and distant metastasis.


1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–2917. doi: 10.1002/ijc.25516 21351269

2. Consonni D, Pierobon M, Gail MH, Rubagotti M, Rotunno M, Goldstein A, et al. Lung Cancer Prognosis Before and After Recurrence in a Population-Based Setting. J Natl Cancer Inst. 2015;107(6):djv059. doi: 10.1093/jnci/djv059 25802059

3. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R, et al. Characterizing the cancer genome in lung adenocarcinoma. Nature. 2007;450(7171):893–898. PubMed Central PMCID: PMC2538683. doi: 10.1038/nature06358 17982442

4. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543–550. PubMed Central PMCID: PMC4231481. doi: 10.1038/nature13385 25079552

5. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455(7216):1069–1075. PubMed Central PMCID: PMC2694412. doi: 10.1038/nature07423 18948947

6. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. 2010;466(7308):869–873. doi: 10.1038/nature09208 20668451

7. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150(6):1107–1120. PubMed Central PMCID: PMC3557932. doi: 10.1016/j.cell.2012.08.029 22980975

8. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121–1134. PubMed Central PMCID: PMC3656590. doi: 10.1016/j.cell.2012.08.024 22980976

9. Liu P, Morrison C, Wang L, Xiong D, Vedell P, Cui P, et al. Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing. Carcinogenesis. 2012;33(7):1270–1276. PubMed Central PMCID: PMC3499051. doi: 10.1093/carcin/bgs148 22510280

10. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–566. doi: 10.1038/nature05945 17625570

11. Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375–377. doi: 10.1038/nm.2644 22327624

12. Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436–445. PubMed Central PMCID: PMC3290779. doi: 10.1101/gr.133645.111 22194472

13. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378–381. doi: 10.1038/nm.2658 22327623

14. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Thorac Oncol. 2013;8(7):823–859. PubMed Central PMCID: PMC4159960. doi: 10.1097/JTO.0b013e318290868f 23552377

15. Landi MT, Consonni D, Rotunno M, Bergen AW, Goldstein AM, Lubin JH, et al. Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case-control study of lung cancer. BMC Public Health. 2008;8:203. Epub 2008/06/10. PubMed Central PMCID: PMC2464602. doi: 10.1186/1471-2458-8-203 18538025

16. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–219. PubMed Central PMCID: PMC3833702. doi: 10.1038/nbt.2514 23396013

17. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45(9):970–976. doi: 10.1038/ng.2702 23852170

18. McPherson A, Hormozdiari F, Zayed A, Giuliany R, Ha G, Sun MG, et al. deFuse: an algorithm for gene fusion discovery in tumor RNA-Seq data. PLoS Comput Biol. 2011;7(5):e1001138. PubMed Central PMCID: PMC3098195. doi: 10.1371/journal.pcbi.1001138 21625565

19. Shi J, Marconett CN, Duan J, Hyland PL, Li P, Wang Z, et al. Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue. Nat Commun. 2014;5:3365. PubMed Central PMCID: PMC3982882. doi: 10.1038/ncomms4365 24572595

20. Beroukhim R, Getz G, Nghiemphu L, Barretina J, Hsueh T, Linhart D, et al. Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma. Proc Natl Acad Sci U S A. 2007;104(50):20007–20012. doi: 10.1073/pnas.0710052104 18077431

21. Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41. PubMed Central PMCID: PMC3218867. doi: 10.1186/gb-2011-12-4-r41 21527027

22. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 2013;152(4):714–726. PubMed Central PMCID: PMC3575604. doi: 10.1016/j.cell.2013.01.019 23415222

23. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–218. PubMed Central PMCID: PMC3919509. doi: 10.1038/nature12213 23770567

24. Hua X, Hyland PL, Huang J, Song L, Zhu B, Caporaso NE, et al. MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations. Am J Hum Genet. 2016;98(3):442–455. doi: 10.1016/j.ajhg.2015.12.021 26899600

25. Babur O, Gonen M, Aksoy BA, Schultz N, Ciriello G, Sander C, et al. Systematic identification of cancer driving signaling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 2015 Feb 26;16:45. doi: 10.1186/s13059-015-0612-6

26. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014;505(7484):495–501. doi: 10.1038/nature12912 24390350

27. Salichs E, Ledda A, Mularoni L, Alba MM, de la Luna S. Genome-Wide Analysis of Histidine Repeats Reveals Their Role in the Localization of Human Proteins to the Nuclear Speckles Compartment. PLoS Genet. 2009;5(3):e1000397. WOS:000266320100003. doi: 10.1371/journal.pgen.1000397 19266028

28. Akiyama T, Kawasaki Y. Wnt signalling and the actin cytoskeleton. Oncogene. 2006;25(57):7538–7544. doi: 10.1038/sj.onc.1210063 17143298

29. Sandoval J, Heyn H, Moran S, Serra-Musach J, Pujana MA, Bibikova M, et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics. 2011;6(6):692–702. 21593595

30. McGranahan N, Favero F, de Bruin EC, Birkbak NJ, Szallasi Z, Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution. Sci Transl Med. 2015;7(283):283ra54. PubMed Central PMCID: PMC4636056. doi: 10.1126/scitranslmed.aaa1408 25877892

31. Dhanasekaran SM, Balbin OA, Chen G, Nadal E, Kalyana-Sundaram S, Pan J, et al. Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes. Nat Commun. 2014;5:5893. PubMed Central PMCID: PMC4274748. doi: 10.1038/ncomms6893 25531467

32. Kosaka T, Yatabe Y, Onozato R, Kuwano H, Mitsudomi T. Prognostic Implication of EGFR, KRAS, and TP53 Gene Mutations in a Large Cohort of Japanese Patients with Surgically Treated Lung Adenocarcinoma. J Thorac Oncol. 2009;4(1):22–29. doi: 10.1097/JTO.0b013e3181914111 19096302

33. Hofree M, Shen JP, Carter H, Gross A, Ideker T. Network-based stratification of tumor mutations. Nat Methods. 2013;10(11):1108–1115. PubMed Central PMCID: PMC3866081. doi: 10.1038/nmeth.2651 24037242

34. Budhram-Mahadeo VS, Irshad S, Bowen S, Lee SA, Samady L, Tonini GP, et al. Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells. Oncogene. 2008;27(1):145–154. doi: 10.1038/sj.onc.1210621 17637757

35. Ounzain S, Bowen S, Patel C, Fujita R, Heads RJ, Budhram-Mahadeo VS. Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERalpha and growth factors via MAPK pathway. Breast Cancer Res. 2011;13(1):R5. PubMed Central PMCID: PMC3109571. doi: 10.1186/bcr2809 21241485

36. Budhram-Mahadeo V, Ndisang D, Ward T, Weber BL, Latchman DS. The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells. Oncogene. 1999;18(48):6684–6691. doi: 10.1038/sj.onc.1203072 10597274

37. Samady L, Dennis J, Budhram-Mahadeo V, Latchman DS. Activation of CDK4 gene expression in human breast cancer cells by the Brn-3b POU family transcription factor. Cancer Biol Ther. 2004;3(3):317–323. 14726699

38. Fujita R, Ounzain S, Wang AC, Heads RJ, Budhram-Mahadeo VS. Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment. Cell Stress Chaperones. 2011;16(4):427–439. PubMed Central PMCID: PMC3118820. doi: 10.1007/s12192-011-0256-8 21279488

39. Budhram-Mahadeo VS, Bowen S, Lee S, Perez-Sanchez C, Ensor E, Morris PJ, et al. Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression. Nucleic Acids Res. 2006;34(22):6640–6652. doi: 10.1093/nar/gkl878 17145718

40. Fan LQ, Li Y, Zhao Q, Tan BB, Ma LG, Liu Y, et al. Comparative proteomics in gastric cancer cell line BGC823 after ZNF139 gene inhibited with RNA interference. Hepatogastroenterology. 2014;61(134):1822–1829. 25436386

41. Li Y, Tan BB, Zhao Q, Fan LQ, Liu Y, Wang D. Regulatory mechanism of ZNF139 in multi-drug resistance of gastric cancer cells. Mol Biol Rep. 2014;41(6):3603–3610. doi: 10.1007/s11033-014-3224-4 24515389

42. Li Y, Tan BB, Zhao Q, Fan LQ, Wang D, Liu Y. ZNF139 promotes tumor metastasis by increasing migration and invasion in human gastric cancer cells. Neoplasma. 2014;61(3):291–298. 24824930

43. Li Y, Zhao Q, Fan LQ, Wang LL, Tan BB, Leng YL, et al. Zinc finger protein 139 expression in gastric cancer and its clinical significance. World J Gastroenterol. 2014;20(48):18346–18353. PubMed Central PMCID: PMC4277971. doi: 10.3748/wjg.v20.i48.18346 25561801

44. Muzny DM, Bainbridge MN, Chang K, Dinh HH, Drummond JA, Fowler G, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–337. doi: 10.1038/nature11252 22810696

45. Pfeifer GP. Mutagenesis at methylated CpG sequences. Curr Top Microbiol. 2006;301:259–281.

46. Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, et al. Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J Biol Chem. 1996;271(22):12767–12774. 8662714

47. Hendrich B, Hardeland U, Ng HH, Jiricny J, Bird A. The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites. Nature. 1999;401(6750):301–304. doi: 10.1038/45843 10499592

48. Nilsen H, Haushalter KA, Robins P, Barnes DE, Verdine GL, Lindahl T. Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase. EMBO J. 2001;20(15):4278–4286. doi: 10.1093/emboj/20.15.4278 11483530

49. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. PubMed Central PMCID: PMC3776390. doi: 10.1038/nature12477 23945592

50. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395(6697):89–93. doi: 10.1038/25779 9738504

51. Denissenko MF, Chen JX, Tang MS, Pfeifer GP. Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci U S A. 1997;94(8):3893–3898. 9108075

52. Mazor T, Pankov A, Johnson BE, Hong C, Hamilton EG, Bell RJ, et al. DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors. Cancer Cell. 2015;28(3):307–317. PubMed Central PMCID: PMC4573399. doi: 10.1016/j.ccell.2015.07.012 26373278

53. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science. 2014;346(6206):251–256. doi: 10.1126/science.1253462 25301630

54. Zhang JJ, Fujimoto J, Zhang JH, Wedge DC, Song XZ, Zhang JX, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014;346(6206):256–259. doi: 10.1126/science.1256930 25301631

Interné lekárstvo

Článok vyšiel v časopise

PLOS Medicine

2016 Číslo 12
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.


Nemáte účet?  Registrujte sa