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Created page with "<h1 class="article-heading">Initial genome sequencing and analysis of multiple myeloma</h1> <p>Michael A. Chapman,1, 22 <br /> Michael S. Lawrence,1 <br /> Jonathan J. Keats,2, 3..."
<h1 class="article-heading">Initial genome sequencing and analysis of multiple myeloma</h1>
<p>Michael A. Chapman,1, 22 <br />
Michael S. Lawrence,1 <br />
Jonathan J. Keats,2, 3 <br />
Kristian Cibulskis,1 <br />
Carrie Sougnez,1 <br />
Anna C. Schinzel,4 <br />
Christina L. Harview,1 <br />
Jean-Philippe Brunet,1 <br />
Gregory J. Ahmann,2, 3 <br />
Mazhar Adli,1, 5 <br />
Kenneth C. Anderson,3, 4 <br />
Kristin G. Ardlie,1 <br />
Daniel Auclair,3, 6 <br />
Angela Baker,7 <br />
P. Leif Bergsagel,2, 3 <br />
Bradley E. Bernstein,1, 5, 8, 9 <br />
Yotam Drier,1, 10 <br />
Rafael Fonseca,2, 3 <br />
Stacey B. Gabriel,1 <br />
Craig C. Hofmeister,3, 11 <br />
Sundar Jagannath,3, 12 <br />
Andrzej J. Jakubowiak,3, 13 <br />
Amrita Krishnan,3, 14 <br />
Joan Levy,3, 6 <br />
Ted Liefeld,1 <br />
Sagar Lonial,3, 15 Scott Mahan,1 Bunmi Mfuko,3, 6 Stefano Monti,1 Louise M. Perkins,3, 6 Robb Onofrio,1 Trevor J. Pugh,1 S. Vincent Rajkumar,3, 16 Alex H. Ramos,1 David S. Siegel,3, 17 Andrey Sivachenko,1 A. Keith Stewart,2, 3 Suzanne Trudel,3, 18 Ravi Vij,3, 19 Douglas Voet,1 Wendy Winckler,1 Todd Zimmerman,3, 20 John Carpten,7 Jeff Trent,7 William C. Hahn,1, 4, 8 Levi A. Garraway,1, 4 Matthew Meyerson,1, 4, 8 Eric S. Lander,1, 8, 21 Gad Getz1 & Todd R. Golub1, 4, 8, 9 <br />
</p>
<p><span style="font-size: medium">Abstract</span></p>
<p> </p>
<p><span style="font-size: medium">Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.</span></p>
<p><a href="http://www.nature.com/nature/journal/v471/n7339/full/nature09837.html">http://www.nature.com/nature/journal/v471/n7339/full/nature09837.html</a></p>
<p> </p>
<p><span style="font-size: large">References</span></p>
<p><span style="font-size: small">1. Bergsagel, P. L. & Kuehl, W. M. Molecular pathogenesis and a consequent<br />
classification of multiple myeloma. J. Clin. Oncol. 23, 6333–6338 (2005).<br />
2. Keats, J. J. et al. Promiscuousmutations activate the noncanonical NF-kBpathway<br />
in multiple myeloma. Cancer Cell 12, 131–144 (2007).<br />
3. Annunziata, C. M. et al. Frequentengagement of the classicaland alternativeNF-kB<br />
pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12,<br />
115–130 (2007).<br />
4. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene<br />
UTX in human cancer. Nature Genet. 41, 521–523 (2009).<br />
5. Lee, W. et al. Themutation spectrumrevealed by paired genomesequences froma<br />
lung cancer patient. Nature 465, 473–477 (2010).<br />
6. Campbell, P. J. et al. Identification of somatically acquired rearrangements in<br />
cancer using genome-wide massively parallel paired-end sequencing. Nature<br />
Genet. 40, 722–729 (2008).<br />
7. Ley, T. J. et al. DNA sequencing of a cytogenetically normal acute myeloid<br />
leukaemia genome. Nature 456, 66–72 (2008).<br />
8. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single<br />
nucleotide resolution. Nature 461, 809–813 (2009).<br />
9. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and<br />
xenograft. Nature 464, 999–1005 (2010).<br />
10. Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of<br />
tobacco exposure. Nature 463, 184–190 (2010).<br />
11. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a<br />
human cancer genome. Nature 463, 191–196 (2010).<br />
12. Reva, B., Antipin, Y. & Sander, C. Determinants of protein function revealed by<br />
combinatorial entropy optimization. Genome Biol. 8, R232 (2007).<br />
13. Dziembowski, A. et al. A single subunit, Dis3, is essentially responsible for yeast<br />
exosome core activity. Nature Struct. Mol. Biol. 14, 15–22 (2007).<br />
14. Schmid, M. & Jensen, T. H. The exosome: a multipurpose RNA-decay machine.<br />
Trends Biochem. Sci. 33, 501–510 (2008).<br />
15. Schneider, C., Anderson, J. T. & Tollervey, D. The exosome subunit Rrp44 plays a<br />
direct role in RNA substrate recognition. Mol. Cell 27, 324–331 (2007).<br />
16. Barbas, A. et al. Determination of key residues for catalysis and RNA cleavage<br />
specificity: one mutation turns RNase II into a ‘‘SUPER-ENZYME’’. J. Biol. Chem.<br />
284, 20486–20498 (2009).<br />
17. Ibrahim, H., Wilusz, J. & Wilusz, C. J. RNA recognition by 39-to-59 exonucleases: the<br />
substrate perspective. Biochim. Biophys. Acta 1779, 256–265 (2008).<br />
18. Zhan, F. et al. The molecular classification of multiple myeloma. Blood 108,<br />
2020–2028 (2006).<br />
19. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based<br />
approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci.<br />
USA 102, 15545–15550 (2005).<br />
20. Mootha, V. K. et al.PGC-1a-responsive genes involved in oxidative phosphorylation<br />
are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273<br />
(2003).<br />
21. Tanay, A., Regev, A. & Shamir, R. Conservation and evolvability in regulatory<br />
networks: the evolution of ribosomal regulation in yeast. Proc. Natl Acad. Sci. USA<br />
102, 7203–7208 (2005).<br />
22. Carrasco, D. R. et al. The differentiation and stress response factor XBP-1 drives<br />
multiple myeloma pathogenesis. Cancer Cell 11, 349–360 (2007).<br />
23. Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism<br />
with pleomorphic pathology. Neuron 44, 601–607 (2004).<br />
24. Paisa´n-Ruı´z, C. et al. Cloning of the gene containing mutations that cause PARK8-<br />
linked Parkinson’s disease. Neuron 44, 595–600 (2004).<br />
25. Forman, M. S., Lee, V. M. & Trojanowski, J. Q. ‘Unfolding’ pathways in<br />
neurodegenerative disease. Trends Neurosci. 26, 407–410 (2003).<br />
26. Masciarelli, S. et al.CHOP-independent apoptosisandpathway-selective induction<br />
of the UPR in developing plasma cells. Mol. Immunol. 47, 1356–1365 (2010).<br />
27. Cenci, S. & Sitia, R. Managing and exploiting stress in the antibody factory. FEBS<br />
Lett. 581, 3652–3657 (2007).<br />
28. Todd, D. J., Lee, A. H. & Glimcher, L. H. The endoplasmic reticulumstress response<br />
in immunity and autoimmunity. Nature Rev. Immunol. 8, 663–674 (2008).<br />
29. Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer<br />
Cell 5, 417–421 (2004).<br />
30. Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231<br />
(2008).<br />
31. Mandelbaum, J. et al. BLIMP1 is a tumor suppressor gene frequently disrupted in<br />
activatedBcell-likediffuse largeBcell lymphoma. Cancer Cell 18,568–579(2010).<br />
32. Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse largeBcell<br />
lymphoma. J. Exp. Med. 203, 311–317 (2006).<br />
33. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by<br />
extinguishing the mature B cell gene expression program. Immunity 17, 51–62<br />
(2002).<br />
34. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin<br />
secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620<br />
(2003).<br />
35. Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing<br />
protein that can drive the maturation of B lymphocytes into immunoglobulinsecreting<br />
cells. Cell 77, 297–306 (1994).<br />
36. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by<br />
oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).<br />
37. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417,<br />
949–954 (2002).<br />
38. Flaherty, K. et al. Phase I study of PLX4032: Proof of concept for V600E BRAF<br />
mutation as a therapeutic target in human cancer. In 2009 ASCO Meeting (American<br />
Society of Clinical Oncology, 2009).<br />
39. Kim, K. et al. Blockade of the MEK/ERK signalling cascade by AS703026, a novel<br />
selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and<br />
in vivo. Br. J. Haematol. 149, 537–549 (2010).<br />
40. Lessard, J. & Sauvageau, G. Polycomb group genes as epigenetic regulators of<br />
normal and leukemic hemopoiesis. Exp. Hematol. 31, 567–585 (2003).<br />
41. Bernstein, B. E., Meissner, A. & Lander, E. S. Themammalian epigenome. Cell 128,<br />
669–681 (2007).<br />
42. Ruf, W. & Mueller, B. M. Thrombin generation and the pathogenesis of cancer.<br />
Semin. Thromb. Hemost. 32 (suppl. 1), 61–68 (2006).<br />
43. Esumi, N., Fan, D. & Fidler, I. J. Inhibition of murine melanoma experimental<br />
metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor.<br />
Cancer Res. 51, 4549–4556 (1991).<br />
44. Migliazza, A. et al. Frequent somatic hypermutation of the 59 noncoding region of<br />
the BCL6 gene in B-cell lymphoma. Proc. Natl Acad. Sci. USA 92, 12520–12524<br />
(1995).<br />
45. Zani, V. J. et al. Molecular cloning of complex chromosomal translocation<br />
t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphomacell line defines a newgene<br />
(BCL7A) with homology to caldesmon. Blood 87, 3124–3134 (1996).<br />
46. Zhang, W. et al. Unravelling the hidden heterogeneities of diffuse large B-cell<br />
lymphoma based on coupled two-way clustering. BMC Genomics 8, 332 (2007).<br />
47. Carbone, A. et al. Array-based comparative genomic hybridization in early-stage<br />
mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A,SMAC/<br />
DIABLO, and RHOF. Genes Chromosom. Cancer 47, 1067–1075 (2008).</span></p>
<p>Michael A. Chapman,1, 22 <br />
Michael S. Lawrence,1 <br />
Jonathan J. Keats,2, 3 <br />
Kristian Cibulskis,1 <br />
Carrie Sougnez,1 <br />
Anna C. Schinzel,4 <br />
Christina L. Harview,1 <br />
Jean-Philippe Brunet,1 <br />
Gregory J. Ahmann,2, 3 <br />
Mazhar Adli,1, 5 <br />
Kenneth C. Anderson,3, 4 <br />
Kristin G. Ardlie,1 <br />
Daniel Auclair,3, 6 <br />
Angela Baker,7 <br />
P. Leif Bergsagel,2, 3 <br />
Bradley E. Bernstein,1, 5, 8, 9 <br />
Yotam Drier,1, 10 <br />
Rafael Fonseca,2, 3 <br />
Stacey B. Gabriel,1 <br />
Craig C. Hofmeister,3, 11 <br />
Sundar Jagannath,3, 12 <br />
Andrzej J. Jakubowiak,3, 13 <br />
Amrita Krishnan,3, 14 <br />
Joan Levy,3, 6 <br />
Ted Liefeld,1 <br />
Sagar Lonial,3, 15 Scott Mahan,1 Bunmi Mfuko,3, 6 Stefano Monti,1 Louise M. Perkins,3, 6 Robb Onofrio,1 Trevor J. Pugh,1 S. Vincent Rajkumar,3, 16 Alex H. Ramos,1 David S. Siegel,3, 17 Andrey Sivachenko,1 A. Keith Stewart,2, 3 Suzanne Trudel,3, 18 Ravi Vij,3, 19 Douglas Voet,1 Wendy Winckler,1 Todd Zimmerman,3, 20 John Carpten,7 Jeff Trent,7 William C. Hahn,1, 4, 8 Levi A. Garraway,1, 4 Matthew Meyerson,1, 4, 8 Eric S. Lander,1, 8, 21 Gad Getz1 & Todd R. Golub1, 4, 8, 9 <br />
</p>
<p><span style="font-size: medium">Abstract</span></p>
<p> </p>
<p><span style="font-size: medium">Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge.</span></p>
<p><a href="http://www.nature.com/nature/journal/v471/n7339/full/nature09837.html">http://www.nature.com/nature/journal/v471/n7339/full/nature09837.html</a></p>
<p> </p>
<p><span style="font-size: large">References</span></p>
<p><span style="font-size: small">1. Bergsagel, P. L. & Kuehl, W. M. Molecular pathogenesis and a consequent<br />
classification of multiple myeloma. J. Clin. Oncol. 23, 6333–6338 (2005).<br />
2. Keats, J. J. et al. Promiscuousmutations activate the noncanonical NF-kBpathway<br />
in multiple myeloma. Cancer Cell 12, 131–144 (2007).<br />
3. Annunziata, C. M. et al. Frequentengagement of the classicaland alternativeNF-kB<br />
pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12,<br />
115–130 (2007).<br />
4. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene<br />
UTX in human cancer. Nature Genet. 41, 521–523 (2009).<br />
5. Lee, W. et al. Themutation spectrumrevealed by paired genomesequences froma<br />
lung cancer patient. Nature 465, 473–477 (2010).<br />
6. Campbell, P. J. et al. Identification of somatically acquired rearrangements in<br />
cancer using genome-wide massively parallel paired-end sequencing. Nature<br />
Genet. 40, 722–729 (2008).<br />
7. Ley, T. J. et al. DNA sequencing of a cytogenetically normal acute myeloid<br />
leukaemia genome. Nature 456, 66–72 (2008).<br />
8. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single<br />
nucleotide resolution. Nature 461, 809–813 (2009).<br />
9. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and<br />
xenograft. Nature 464, 999–1005 (2010).<br />
10. Pleasance, E. D. et al. A small-cell lung cancer genome with complex signatures of<br />
tobacco exposure. Nature 463, 184–190 (2010).<br />
11. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a<br />
human cancer genome. Nature 463, 191–196 (2010).<br />
12. Reva, B., Antipin, Y. & Sander, C. Determinants of protein function revealed by<br />
combinatorial entropy optimization. Genome Biol. 8, R232 (2007).<br />
13. Dziembowski, A. et al. A single subunit, Dis3, is essentially responsible for yeast<br />
exosome core activity. Nature Struct. Mol. Biol. 14, 15–22 (2007).<br />
14. Schmid, M. & Jensen, T. H. The exosome: a multipurpose RNA-decay machine.<br />
Trends Biochem. Sci. 33, 501–510 (2008).<br />
15. Schneider, C., Anderson, J. T. & Tollervey, D. The exosome subunit Rrp44 plays a<br />
direct role in RNA substrate recognition. Mol. Cell 27, 324–331 (2007).<br />
16. Barbas, A. et al. Determination of key residues for catalysis and RNA cleavage<br />
specificity: one mutation turns RNase II into a ‘‘SUPER-ENZYME’’. J. Biol. Chem.<br />
284, 20486–20498 (2009).<br />
17. Ibrahim, H., Wilusz, J. & Wilusz, C. J. RNA recognition by 39-to-59 exonucleases: the<br />
substrate perspective. Biochim. Biophys. Acta 1779, 256–265 (2008).<br />
18. Zhan, F. et al. The molecular classification of multiple myeloma. Blood 108,<br />
2020–2028 (2006).<br />
19. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based<br />
approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci.<br />
USA 102, 15545–15550 (2005).<br />
20. Mootha, V. K. et al.PGC-1a-responsive genes involved in oxidative phosphorylation<br />
are coordinately downregulated in human diabetes. Nature Genet. 34, 267–273<br />
(2003).<br />
21. Tanay, A., Regev, A. & Shamir, R. Conservation and evolvability in regulatory<br />
networks: the evolution of ribosomal regulation in yeast. Proc. Natl Acad. Sci. USA<br />
102, 7203–7208 (2005).<br />
22. Carrasco, D. R. et al. The differentiation and stress response factor XBP-1 drives<br />
multiple myeloma pathogenesis. Cancer Cell 11, 349–360 (2007).<br />
23. Zimprich, A. et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism<br />
with pleomorphic pathology. Neuron 44, 601–607 (2004).<br />
24. Paisa´n-Ruı´z, C. et al. Cloning of the gene containing mutations that cause PARK8-<br />
linked Parkinson’s disease. Neuron 44, 595–600 (2004).<br />
25. Forman, M. S., Lee, V. M. & Trojanowski, J. Q. ‘Unfolding’ pathways in<br />
neurodegenerative disease. Trends Neurosci. 26, 407–410 (2003).<br />
26. Masciarelli, S. et al.CHOP-independent apoptosisandpathway-selective induction<br />
of the UPR in developing plasma cells. Mol. Immunol. 47, 1356–1365 (2010).<br />
27. Cenci, S. & Sitia, R. Managing and exploiting stress in the antibody factory. FEBS<br />
Lett. 581, 3652–3657 (2007).<br />
28. Todd, D. J., Lee, A. H. & Glimcher, L. H. The endoplasmic reticulumstress response<br />
in immunity and autoimmunity. Nature Rev. Immunol. 8, 663–674 (2008).<br />
29. Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer<br />
Cell 5, 417–421 (2004).<br />
30. Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231<br />
(2008).<br />
31. Mandelbaum, J. et al. BLIMP1 is a tumor suppressor gene frequently disrupted in<br />
activatedBcell-likediffuse largeBcell lymphoma. Cancer Cell 18,568–579(2010).<br />
32. Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse largeBcell<br />
lymphoma. J. Exp. Med. 203, 311–317 (2006).<br />
33. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by<br />
extinguishing the mature B cell gene expression program. Immunity 17, 51–62<br />
(2002).<br />
34. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin<br />
secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620<br />
(2003).<br />
35. Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing<br />
protein that can drive the maturation of B lymphocytes into immunoglobulinsecreting<br />
cells. Cell 77, 297–306 (1994).<br />
36. Wan, P. T. et al. Mechanism of activation of the RAF-ERK signaling pathway by<br />
oncogenic mutations of B-RAF. Cell 116, 855–867 (2004).<br />
37. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417,<br />
949–954 (2002).<br />
38. Flaherty, K. et al. Phase I study of PLX4032: Proof of concept for V600E BRAF<br />
mutation as a therapeutic target in human cancer. In 2009 ASCO Meeting (American<br />
Society of Clinical Oncology, 2009).<br />
39. Kim, K. et al. Blockade of the MEK/ERK signalling cascade by AS703026, a novel<br />
selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and<br />
in vivo. Br. J. Haematol. 149, 537–549 (2010).<br />
40. Lessard, J. & Sauvageau, G. Polycomb group genes as epigenetic regulators of<br />
normal and leukemic hemopoiesis. Exp. Hematol. 31, 567–585 (2003).<br />
41. Bernstein, B. E., Meissner, A. & Lander, E. S. Themammalian epigenome. Cell 128,<br />
669–681 (2007).<br />
42. Ruf, W. & Mueller, B. M. Thrombin generation and the pathogenesis of cancer.<br />
Semin. Thromb. Hemost. 32 (suppl. 1), 61–68 (2006).<br />
43. Esumi, N., Fan, D. & Fidler, I. J. Inhibition of murine melanoma experimental<br />
metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor.<br />
Cancer Res. 51, 4549–4556 (1991).<br />
44. Migliazza, A. et al. Frequent somatic hypermutation of the 59 noncoding region of<br />
the BCL6 gene in B-cell lymphoma. Proc. Natl Acad. Sci. USA 92, 12520–12524<br />
(1995).<br />
45. Zani, V. J. et al. Molecular cloning of complex chromosomal translocation<br />
t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphomacell line defines a newgene<br />
(BCL7A) with homology to caldesmon. Blood 87, 3124–3134 (1996).<br />
46. Zhang, W. et al. Unravelling the hidden heterogeneities of diffuse large B-cell<br />
lymphoma based on coupled two-way clustering. BMC Genomics 8, 332 (2007).<br />
47. Carbone, A. et al. Array-based comparative genomic hybridization in early-stage<br />
mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A,SMAC/<br />
DIABLO, and RHOF. Genes Chromosom. Cancer 47, 1067–1075 (2008).</span></p>
