"Mitelman Database of Chromosome
Aberrations and Gene Fusions in Cancer (2014). Mitelman F, Johansson B and Mertens F (Eds.),
http://cgap.nci.nih.gov/Chromosomes/Mitelman"
NF-kappa-B is a ubiquitous transcription factor involved in several biological processes. It is held in the cytoplasm in an inactive state by specific inhibitors. Upon degradation of the inhibitor, NF-kappa-B moves to the nucleus and activates transcription of specific genes. NF-kappa-B is composed of NFKB1 or NFKB2 bound to either REL, RELA, or RELB. The most abundant form of NF-kappa-B is NFKB1 complexed with the product of this gene, RELA. Four transcript variants encoding different isoforms have been found for this gene。
Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95–RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95–RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells—the cell of origin of ependymoma—to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95–RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
Anthony B Miller, professor emeritus 1,Claus Wall, data manager 1,Cornelia J Baines, professor emerita 1,Ping Sun, statistician 2,Teresa To, senior scientist 3,Steven A Narod, professor 1,2
1Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada
2Women’s College Research Institute, Women’s College Hospital, Toronto, Ontario M5G 1N8, Canada
3Child Health Evaluative Services, The Hospital for Sick Children, Toronto, Ontario, Canada
Objective
To compare breast cancer incidence and mortality up to 25 years in
women aged 40-59 who did or did not undergo mammography screening.
Design
Follow-up of randomised screening trial by centre coordinators, the
study’s central office, and linkage to cancer registries and vital
statistics databases.
Setting 15 screening centres in six Canadian provinces,1980-85 (Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia).
Participants 89 835 women, aged 40-59, randomly assigned to mammography (five annual mammography screens) or control (no mammography).
Interventions
Women aged 40-49 in the mammography arm and all women aged 50-59 in
both arms received annual physical breast examinations. Women aged 40-49
in the control arm received a single examination followed by usual care
in the community.
Main outcome measure Deaths from breast cancer.
Results
During the five year screening period, 666 invasive breast cancers were
diagnosed in the mammography arm (n=44 925 participants) and 524 in the
controls (n=44 910), and of these, 180 women in the mammography arm and
171 women in the control arm died of breast cancer during the 25 year
follow-up period. The overall hazard ratio for death from breast cancer
diagnosed during the screening period associated with mammography was
1.05 (95% confidence interval 0.85 to 1.30). The findings for women aged
40-49 and 50-59 were almost identical. During the entire study period,
3250 women in the mammography arm and 3133 in the control arm had a
diagnosis of breast cancer, and 500 and 505, respectively, died of
breast cancer. Thus the cumulative mortality from breast cancer was
similar between women in the mammography arm and in the control arm
(hazard ratio 0.99, 95% confidence interval 0.88 to 1.12). After 15
years of follow-up a residual excess of 106 cancers was observed in the
mammography arm, attributable to over-diagnosis.
Conclusion
Annual mammography in women aged 40-59 does not reduce mortality from
breast cancer beyond that of physical examination or usual care when
adjuvant therapy for breast cancer is freely available. Overall, 22%
(106/484) of screen detected invasive breast cancers were
over-diagnosed, representing one over-diagnosed breast cancer for every
424 women who received mammography screening in the trial.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
