膀胱癌とchromothripsis：72件の文献紹介を含めて

最近「ゲノム遺伝学的解析」が次々と進んでいるのが泌尿器領域である。

natureのオンラインであるが1月に報告されたのが↓

Nature (2014)

Received17 June 2013

Accepted19 December 2013

Published online29 January 2014 

Comprehensive molecular characterization of urothelial bladder carcinoma

• The Cancer Genome Atlas Research Network

• Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

もう一つ
今週号のPNASに掲載されているのが下記文献の3番目のものであるが、この論文は浸潤性膀胱癌のdeepシークエンスを行ったところ、多くの症例で例の「chromothripsis」を認めるというものであった。このカタストロフィックなゲノム改変イベントの最初の報告が下記文献集の71-72番、2011年お正月のCellであるから、もう3年たつのだねえ。感無量。

• Abstract

• Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N-methyl D-aspertate as a potential new therapeutic target in bladder cancer.

今回の膀胱癌の 「chromothripsis」には少々驚いているが、この3年で「chromothripsis」についてどれだけの論文が出たのかまとめてみた。玉石混交であり、また総説・解説論文もまた多いが、いろんな癌腫で認められはじめているようだ。

1.RB1 gene inactivation by chromothripsis in human retinoblastoma.

McEvoy J, Nagahawatte P, Finkelstein D, Richards-Yutz J, Valentine M, Ma J, Mullighan C, Song G, Chen X, Wilson M, Brennan R, Pounds S, Becksfort J, Huether R, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Mardis ER, Wilson RK, Easton J, Zhang J, Downing JR, Ganguly A, Dyer MA.

Oncotarget. 2014 Jan 11.

2.Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens.

Cai H, Kumar N, Bagheri HC, von Mering C, Robinson MD, Baudis M.

BMC Genomics. 2014 Jan 29;15(1):82.

3.Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer.

Morrison CD, Liu P, Woloszynska-Read A, Zhang J, Luo W, Qin M, Bshara W, Conroy JM, Sabatini L, Vedell P, Xiong D, Liu S, Wang J, Shen H, Li Y, Omilian AR, Hill A, Head K, Guru K, Kunnev D, Leach R, Eng KH, Darlak C, Hoeflich C, Veeranki S, Glenn S, You M, Pruitt SC, Johnson CS, Trump DL.

Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):E672-81.

4.Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma.

Fernandez-Banet J, Lee NP, Chan KT, Gao H, Liu X, Sung WK, Tan W, Fan ST, Poon RT, Li S, Ching K, Rejto P, Mao M, Kan Z.

Genomics. 2014 Jan 21. pii: S0888-7543(14)00004-4.

5.Chromothripsis: how does such a catastrophic event impact human reproduction?

Pellestor F.

Hum Reprod. 2014 Jan 21.

6.Loeys-Dietz syndrome type 4, caused by chromothripsis, involving the TGFB2 gene.

Fontana P, Genesio R, Casertano A, Cappuccio G, Mormile A, Nitsch L, Iolascon A, Andria G, Melis D.

Gene. 2014 Jan 15. pii: S0378-1119(14)00038-9.

7.Prevalence and clinical implications of chromothripsis in cancer genomes.

Kloosterman WP, Koster J, Molenaar JJ.

Curr Opin Oncol. 2014 Jan;26(1):64-72.

8.The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia.

Jacoby MA, De Jesus Pizarro RE, Shao J, Koboldt DC, Fulton RS, Zhou G, Wilson RK, Walter MJ.

Leukemia. 2013 Dec 5. 

9.Genome chaos: Survival strategy during crisis.

Liu G, Stevens JB, Horne SD, Abdallah BY, Ye KJ, Bremer SW, Ye CJ, Chen DJ, Heng HH.

Cell Cycle. 2013 Dec 3;13(4).

10.Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements.

Zhang CZ, Leibowitz ML, Pellman D.

Genes Dev. 2013 Dec 1;27(23):2513-30.

11.Chromothripsis in uterine leiomyomas.

Markowski DN, Bullerdiek J.

N Engl J Med. 2013 Nov 28;369(22):2160.

12.Chromothripsis in uterine leiomyomas.

Mehine M, Kaasinen E, Aaltonen LA.

N Engl J Med. 2013 Nov 28;369(22):2160-1.

13.Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer.

Pihan GA.

Front Oncol. 2013 Nov 12;3:277.

14.Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability.

Akagi K, Li J, Broutian TR, Padilla-Nash H, Xiao W, Jiang B, Rocco JW, Teknos TN, Kumar B, Wangsa D, He D, Ried T, Symer DE, Gillison ML.

Genome Res. 2014 Feb;24(2):185-99.

15.Clinical applications of next-generation sequencing in colorectal cancers.

Kim TM, Lee SH, Chung YJ.

World J Gastroenterol. 2013 Oct 28;19(40):6784-93.

16.A familial Cri-du-Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis.

Gu H, Jiang JH, Li JY, Zhang YN, Dong XS, Huang YY, Son XM, Lu X, Chen Z.

PLoS One. 2013 Oct 15;8(10):e76985.

17.Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis.

Boeva V, Jouannet S, Daveau R, Combaret V, Pierre-Eugène C, Cazes A, Louis-Brennetot C, Schleiermacher G, Ferrand S, Pierron G, Lermine A, Rio Frio T, Raynal V, Vassal G, Barillot E, Delattre O, Janoueix-Lerosey I.

PLoS One. 2013 Aug 26;8(8):e72182.

18.Pure 16q21q22.1 deletion in a complex rearrangement possibly caused by a chromothripsis event.

Genesio R, Ronga V, Castelluccio P, Fioretti G, Mormile A, Leone G, Conti A, Cavaliere ML, Nitsch L.

Mol Cytogenet. 2013 Aug 1;6(1):29.

19.Chromothripsis under the microscope: a cytogenetic perspective of two cases of AML with catastrophic chromosome rearrangement.

Mackinnon RN, Campbell LJ.

Cancer Genet. 2013 Jun;206(6):238-51.

20.The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2.

Nazaryan L, Stefanou EG, Hansen C, Kosyakova N, Bak M, Sharkey FH, Mantziou T, Papanastasiou AD, Velissariou V, Liehr T, Syrrou M, Tommerup N.

Eur J Hum Genet. 2013 Jul 17.

21.DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice.

Schipler A, Iliakis G.

Nucleic Acids Res. 2013 Sep;41(16):7589-605.

22.Chromothripsis: breakage-fusion-bridge over and over again.

Sorzano CO, Pascual-Montano A, Sánchez de Diego A, Martínez-A C, van Wely KH.

Cell Cycle. 2013 Jul 1;12(13):2016-23.

23.In Brief: Chromothripsis and cancer.

Wyatt AW, Collins CC.

J Pathol. 2013 Sep;231(1):1-3.

24.Characterization of uterine leiomyomas by whole-genome sequencing.

Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E, Heinonen HR, Bützow R, Kilpivaara O, Kuosmanen A, Ristolainen H, Gentile M, Sjöberg J, Vahteristo P, Aaltonen LA.

N Engl J Med. 2013 Jul 4;369(1):43-53.

25.Mechanisms for Structural Variation in the Human Genome.

Currall BB, Chiang C, Talkowski ME, Morton CC.

Curr Genet Med Rep. 2013 Jun 1;1(2):81-90.

26.Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage owing to dysregulated Aurora-A.

Hammond D, Zeng K, Espert A, Bastos RN, Baron RD, Gruneberg U, Barr FA.

J Cell Sci. 2013 Aug 1;126(Pt 15):3429-40.

27.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.

28.Mitotic errors, aneuploidy and micronuclei in Hodgkin lymphoma pathogenesis.

Krem MM, Horwitz MS.

Commun Integr Biol. 2013 May 1;6(3):e23544.

29.Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing.

Morin RD, Mungall K, Pleasance E, Mungall AJ, Goya R, Huff RD, Scott DW, Ding J, Roth A, Chiu R, Corbett RD, Chan FC, Mendez-Lago M, Trinh DL, Bolger-Munro M, Taylor G, Hadj Khodabakhshi A, Ben-Neriah S, Pon J, Meissner B, Woolcock B, Farnoud N, Rogic S, Lim EL, Johnson NA, Shah S, Jones S, Steidl C, Holt R, Birol I, Moore R, Connors JM, Gascoyne RD, Marra MA.

Blood. 2013 Aug 15;122(7):1256-65.

30.Chromothripsis in Hodgkin lymphoma.

Nagel S, Meyer C, Quentmeier H, Kaufmann M, Drexler HG, MacLeod RA.

Genes Chromosomes Cancer. 2013 Aug;52(8):741-7.

31.Gene fusions by chromothripsis of chromosome 5q in the VCaP prostate cancer cell line.

Teles Alves I, Hiltemann S, Hartjes T, van der Spek P, Stubbs A, Trapman J, Jenster G.

Hum Genet. 2013 Jun;132(6):709-13.

32.Sporadic and reversible chromothripsis in chronic lymphocytic leukemia revealed by longitudinal genomic analysis.

Bassaganyas L, Beà S, Escaramís G, Tornador C, Salaverria I, Zapata L, Drechsel O, Ferreira PG, Rodriguez-Santiago B, Tubio JM, Navarro A, Martín-García D, López C, Martínez-Trillos A, López-Guillermo A, Gut M, Ossowski S, López-Otín C, Campo E, Estivill X.

Leukemia. 2013 Dec;27(12):2376-9.

33.Translocations in normal B cells and cancers: insights from new technical approaches.

Chiarle R.

Adv Immunol. 2013;117:39-71.

34.The genomic and transcriptomic landscape of a HeLa cell line.

Landry JJ, Pyl PT, Rausch T, Zichner T, Tekkedil MM, Stütz AM, Jauch A, Aiyar RS, Pau G, Delhomme N, Gagneur J, Korbel JO, Huber W, Steinmetz LM.

G3 (Bethesda). 2013 Aug 7;3(8):1213-24.

35.The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing.

Wyatt AW, Mo F, Wang Y, Collins CC.

Asian J Androl. 2013 May;15(3):301-8.

36.Criteria for inference of chromothripsis in cancer genomes.

Korbel JO, Campbell PJ.

Cell. 2013 Mar 14;152(6):1226-36.

37.Chromothripsis in congenital disorders and cancer: similarities and differences.

Kloosterman WP, Cuppen E.

Curr Opin Cell Biol. 2013 Jun;25(3):341-8.

38.Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms.

Malhotra A, Lindberg M, Faust GG, Leibowitz ML, Clark RA, Layer RM, Quinlan AR, Hall IM.

Genome Res. 2013 May;23(5):762-76.

39.Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.

Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, Ligon KL, Palescandolo E, Van Hummelen P, Ducar MD, Raza A, Sunkavalli A, Macconaill LE, Stemmer-Rachamimov AO, Louis DN, Hahn WC, Dunn IF, Beroukhim R.

Nat Genet. 2013 Mar;45(3):285-9.

40.DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability.

Donley N, Thayer MJ.

Semin Cancer Biol. 2013 Apr;23(2):80-9.

41.Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma.

Hirsch D, Kemmerling R, Davis S, Camps J, Meltzer PS, Ried T, Gaiser T.

Cancer Res. 2013 Mar 1;73(5):1454-60.

42.Understanding genomic alterations in cancer genomes using an integrative network approach.

Wang E.

Cancer Lett. 2013 Nov 1;340(2):261-9.

43.Chromothripsis: chromosomes in crisis.

Jones MJ, Jallepalli PV.

Dev Cell. 2012 Nov 13;23(5):908-17

44.Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements.

Holland AJ, Cleveland DW.

Nat Med. 2012 Nov;18(11):1630-8.

45.Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes.

Kim TM, Xi R, Luquette LJ, Park RW, Johnson MD, Park PJ.

Genome Res. 2013 Feb;23(2):217-27.

46.Chromothripsis Challenges the Germline.

Poot M.

Mol Syndromol. 2012 Sep;3(3):99-101.

47.De novo CNV formation in mouse embryonic stem cells occurs in the absence of Xrcc4-dependent nonhomologous end joining.

Arlt MF, Rajendran S, Birkeland SR, Wilson TE, Glover TW.

PLoS Genet. 2012 Sep;8(9):e1002981.

48.Cancer genomics and pathology: all together now.

Shibata T.

Pathol Int. 2012 Oct;62(10):647-59.

49.Chromothripsis and cancer: causes and consequences of chromosome shattering.

Forment JV, Kaidi A, Jackson SP.

Nat Rev Cancer. 2012 Oct;12(10):663-70.

50.Poly-gene fusion transcripts and chromothripsis in prostate cancer.

Wu C, Wyatt AW, McPherson A, Lin D, McConeghy BJ, Mo F, Shukin R, Lapuk AV, Jones SJ, Zhao Y, Marra MA, Gleave ME, Volik SV, Wang Y, Sahinalp SC, Collins CC.

Genes Chromosomes Cancer. 2012 Dec;51(12):1144-53.

51.Structural mutations in cancer: mechanistic and functional insights.

Inaki K, Liu ET.

Trends Genet. 2012 Nov;28(11):550-9.

52.Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognár L, Klekner A, Van Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA, Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U, Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel JO, Pfister SM, Marra MA, Taylor MD.

Nature. 2012 Aug 2;488(7409):49-56.

53.Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms.

Kloosterman WP, Tavakoli-Yaraki M, van Roosmalen MJ, van Binsbergen E, Renkens I, Duran K, Ballarati L, Vergult S, Giardino D, Hansson K, Ruivenkamp CA, Jager M, van Haeringen A, Ippel EF, Haaf T, Passarge E, Hochstenbach R, Menten B, Larizza L, Guryev V, Poot M, Cuppen E.

Cell Rep. 2012 Jun 28;1(6):648-55.

54.Shattered and stitched chromosomes-chromothripsis and chromoanasynthesis-manifestations of a new chromosome crisis?

Righolt C, Mai S.

Genes Chromosomes Cancer. 2012 Nov;51(11):975-81.

55.From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer.

Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, Mo F, Zoubeidi A, Anderson S, Bell RH, Haegert A, Shukin R, Wang Y, Fazli L, Hurtado-Coll A, Jones EC, Hach F, Hormozdiari F, Hajirasouliha I, Boutros PC, Bristow RG, Zhao Y, Marra MA, Fanjul A, Maher CA, Chinnaiyan AM, Rubin MA, Beltran H, Sahinalp SC, Gleave ME, Volik SV, Collins CC.

J Pathol. 2012 Jul;227(3):286-97.

56.Mechanisms for recurrent and complex human genomic rearrangements.

Liu P, Carvalho CM, Hastings PJ, Lupski JR.

Curr Opin Genet Dev. 2012 Jun;22(3):211-20.

57.Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration.

Chiang C, Jacobsen JC, Ernst C, Hanscom C, Heilbut A, Blumenthal I, Mills RE, Kirby A, Lindgren AM, Rudiger SR, McLaughlan CJ, Bawden CS, Reid SJ, Faull RL, Snell RG, Hall IM, Shen Y, Ohsumi TK, Borowsky ML, Daly MJ, Lee C, Morton CC, MacDonald ME, Gusella JF, Talkowski ME.

Nat Genet. 2012 Mar 4;44(4):390-7, S1.

58.Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, Versteeg R.

Nature. 2012 Feb 22;483(7391):589-93.

59.Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.

Rausch T, Jones DT, Zapatka M, Stütz AM, Zichner T, Weischenfeldt J, Jäger N, Remke M, Shih D, Northcott PA, Pfaff E, Tica J, Wang Q, Massimi L, Witt H, Bender S, Pleier S, Cin H, Hawkins C, Beck C, von Deimling A, Hans V, Brors B, Eils R, Scheurlen W, Blake J, Benes V, Kulozik AE, Witt O, Martin D, Zhang C, Porat R, Merino DM, Wasserman J, Jabado N, Fontebasso A, Bullinger L, Rücker FG, Döhner K, Döhner H, Koster J, Molenaar JJ, Versteeg R, Kool M, Tabori U, Malkin D, Korshunov A, Taylor MD, Lichter P, Pfister SM, Korbel JO.

Cell. 2012 Jan 20;148(1-2):59-71.

60.Chromothripsis and human disease: piecing together the shattering process.

Maher CA, Wilson RK.

Cell. 2012 Jan 20;148(1-2):29-32.

61.DNA breaks and chromosome pulverization from errors in mitosis.

Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D.

Nature. 2012 Jan 18;482(7383):53-8.

62.[Micronucleus test: cytome assay and health biomarker].

García Sagredo JM.

An R Acad Nac Med (Madr). 2012;129(2):627-40; discussion 641. Spanish.

63.Chromothripsis in a Case of TP53-Deficient Chronic Lymphocytic Leukemia.

Pei J, Jhanwar SC, Testa JR.

Leuk Res Rep. 2012 Jan 1;1(1):4-6.

64.Transient hypermutability, chromothripsis and replication-based mechanisms in the generation of concurrent clustered mutations.

Chen JM, Férec C, Cooper DN.

Mutat Res. 2012 Jan-Mar;750(1):52-9.

65.Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer.

Kloosterman WP, Hoogstraat M, Paling O, Tavakoli-Yaraki M, Renkens I, Vermaat JS, van Roosmalen MJ, van Lieshout S, Nijman IJ, Roessingh W, van 't Slot R, van de Belt J, Guryev V, Koudijs M, Voest E, Cuppen E.

Genome Biol. 2011 Oct 19;12(10):R103.

66.Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.

Liu P, Erez A, Nagamani SC, Dhar SU, Kołodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, Bacino CA, Campos-Acevedo LD, Delgado MR, Freedenberg D, Garnica A, Grebe TA, Hernández-Almaguer D, Immken L, Lalani SR, McLean SD, Northrup H, Scaglia F, Strathearn L, Trapane P, Kang SH, Patel A, Cheung SW, Hastings PJ, Stankiewicz P, Lupski JR, Bi W.

Cell. 2011 Sep 16;146(6):889-903.

67.The consequences of structural genomic alterations in humans: genomic disorders, genomic instability and cancer.

Colnaghi R, Carpenter G, Volker M, O'Driscoll M.

Semin Cell Dev Biol. 2011 Oct;22(8):875-85.

68.Diverse system stresses: common mechanisms of chromosome fragmentation.

Stevens JB, Abdallah BY, Liu G, Ye CJ, Horne SD, Wang G, Savasan S, Shekhar M, Krawetz SA, Hüttemann M, Tainsky MA, Wu GS, Xie Y, Zhang K, Heng HH.

Cell Death Dis. 2011 Jun 30;2:e178.

69.Chromothripsis identifies a rare and aggressive entity among newly diagnosed multiple myeloma patients.

Magrangeas F, Avet-Loiseau H, Munshi NC, Minvielle S.

Blood. 2011 Jul 21;118(3):675-8.

70.Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline.

Kloosterman WP, Guryev V, van Roosmalen M, Duran KJ, de Bruijn E, Bakker SC, Letteboer T, van Nesselrooij B, Hochstenbach R, Poot M, Cuppen E.

Hum Mol Genet. 2011 May 15;20(10):1916-24.

71.Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ.

Cell. 2011 Jan 7;144(1):27-40.

72.Cancer genomes evolve by pulverizing single chromosomes.

Meyerson M, Pellman D.

Cell. 2011 Jan 7;144(1):9-10.