TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions

Abstract
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Abstract

TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.

Data availability

The following previously published data sets were used

1. Cancer Genome Atlas Network
(2013) Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/index.do?Action=Submit&genetic_profile_ids=laml_tcga_pub_mutations&case_set_id=laml_tcga_pub_all&cancer_study_id=laml_tcga_pub&gene_list=TP53&tab_index=tab_visualize&#mutation_details&show_samples=false&
1. Ciriello G
2. Gatza ML
3. Beck AH
4. Wilkerson MD
5. Rhie SK
6. Pastore A
7. Zhang H
8. McLellan M
9. Yau C
10. Kandoth C
11. Bowlby R
12. Shen H
13. Hayat S
14. Fieldhouse R
15. Lester SC
16. Tse GM
17. Factor RE
18. Collins LC
19. Allison KH
20. Chen YY
21. Jensen K
22. Johnson NB
23. Oesterreich S
24. Mills GB
25. Cherniack AD
26. Robertson G
27. Benz C
28. Sander C
29. Laird PW
30. Hoadley KA
31. King TA; TCGA Research Network
32. Perou CM.
(2015) Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=brca_tcga_pub2015#summary
1. Cancer Genome Atlas Network
(2012) Comprehensive molecular characterization of human colon and rectal cancer.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=coadread_tcga_pub#summary
1. Dulak AM
2. Stojanov P
3. Peng S
4. Lawrence MS
5. Fox C
6. Stewart C
7. Bandla S
8. Imamura Y
9. Schumacher SE
10. Shefler E
11. McKenna A
12. Carter SL
13. Cibulskis K
14. Sivachenko A
15. Saksena G
16. Voet D
17. Ramos AH
18. Auclair D
19. Thompson K
20. Sougnez C
21. Onofrio RC
22. Guiducci C
23. Beroukhim R
24. Zhou Z
25. Lin L
26. Lin J
27. Reddy R
28. Chang A
29. Landrenau R
30. Pennathur A
31. Ogino S
32. Luketich JD
33. Golub TR
34. Gabriel SB
35. Lander ES
36. Beer DG
37. Godfrey TE
38. Getz G
39. Bass AJ.
(2013) Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=esca_broad#summary
1. Lin DC
2. Hao JJ
3. Nagata Y
4. Xu L
5. Shang L
6. Meng X
7. Sato Y
8. Okuno Y
9. Varela AM
10. Ding LW
11. Garg M
12. Liu LZ
13. Yang H
14. Yin 8
15. Shi ZZ
16. Jiang YY
17. Gu WY
18. Gong T
19. Zhang Y
20. Xu X
21. Kalid O
22. Shacham S
23. Ogawa S
24. Wang MR
25. Koeffler HP.
(2014) Genomic and molecular characterization of esophageal squamous cell carcinoma.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=escc_ucla_2014#summary
1. Brennan CW
2. Verhaak RG
3. McKenna A
4. Campos B
5. Noushmehr H
6. Salama SR
7. Zheng S
8. Chakravarty D
9. Sanborn JZ
10. Berman SH
11. Beroukhim R
12. Bernard B
13. Wu CJ
14. Genovese G
15. Shmulevich I
16. Barnholtz-Sloan J
17. Zou L
18. Vegesna R
19. Shukla SA
20. Ciriello G
21. Yung WK
22. Zhang W
23. Sougnez C
24. Mikkelsen T
25. Aldape K
26. Bigner DD
27. Van Meir EG
28. Prados M
29. Sloan A
30. Black KL
31. Eschbacher J
32. Finocchiaro G
33. Friedman W
34. Andrews DW
35. Guha A
36. Iacocca M
37. O'Neill BP
38. Foltz G
39. Myers J
40. Weisenberger DJ
41. Penny R
42. Kucherlapati R
43. Perou CM
44. Hayes DN
45. Gibbs R
46. Marra M
47. Mills GB
48. Lander E
49. Spellman P
50. Wilson R
51. Sander C
52. Weinstein J
53. Meyerson M
54. Gabriel S
55. Laird PW
56. Haussler D
57. Getz G
58. Chin L; TCGA Research Network.
(2013) The somatic genomic landscape of glioblastoma.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=gbm_tcga_pub2013#summary
1. Cancer Genome Atlas Network
(2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=hnsc_tcga_pub#summary
1. Cancer Genome Atlas Network
(2014) Comprehensive molecular profiling of lung adenocarcinoma
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=luad_tcga_pub#summary
1. Cancer Genome Atlas Network
(2012) Comprehensive genomic characterization of squamous cell lung cancers.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=lusc_tcga_pub#summary
(2014) Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=mm_broad#summary
1. Beltran H
2. Prandi D
3. Mosquera JM
4. Benelli M
5. Puca L
6. Cyrta J
7. Marotz C
8. Giannopoulou E
9. Chakravarthi BV
10. Varambally S
11. Tomlins SA
12. Nanus DM
13. Tagawa ST
14. Van Allen EM
15. Elemento O1
16. 6
17. Sboner A
18. Garraway LA
19. Rubin MA
20. Demichelis F.
(2016) Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=nepc_wcm_2016#summary
1. Cancer Genome Atlas Network
(2011) Integrated genomic analyses of ovarian carcinoma.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=ov_tcga_pub#summary
1. Cancer Genome Atlas Network
(2015) The Molecular Taxonomy of Primary Prostate Cancer.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=prad_tcga_pub#summary
1. George J
2. Lim JS
3. Jang SJ
4. Cun Y
5. Ozretić L
6. Kong G
7. Leenders F
8. Lu X
9. Fernández-Cuesta L
10. Bosco G
11. Müller C
12. Dahmen I
13. Jahchan NS
14. Park KS
15. Yang D
16. Karnezis AN
17. Vaka D
18. Torres A
19. Wang MS
20. Korbel JO
21. Menon R
22. Chun SM
23. Kim D
24. Wilkerson M
25. Hayes N
26. Engelmann D
27. Pützer B
28. Bos M
29. Michels S
30. Vlasic I
31. Seidel D
32. Pinther B
33. Schaub P
34. Becker C
35. Altmüller J
36. Yokota J
37. Kohno T
38. Iwakawa R
39. Tsuta K
40. Noguchi M
41. Muley T
42. Hoffmann H
43. Schnabel PA
44. Petersen I
45. Chen Y
46. Soltermann A
47. Tischler V
48. Choi CM
49. Kim YH
50. Massion PP
51. Zou Y
52. Jovanovic D
53. Kontic M
54. Wright GM
55. Russell PA
56. Solomon B
57. Koch I
58. Lindner M
59. Muscarella LA
60. la Torre A
61. Field JK
62. Jakopovic M
63. Knezevic J
64. Castaños-Vélez E
65. Roz L
66. Pastorino U
67. Brustugun OT
68. Lund-Iversen M
69. Thunnissen E
70. Köhler J
71. Schuler M
72. Botling J
73. Sandelin M
74. Sanchez-Cespedes M
75. Salvesen HB
76. Achter V
77. Lang U
78. Bogus M
79. Schneider PM
80. Zander T
81. Ansén S
82. Hallek M
83. Wolf J
84. Vingron M
85. Yatabe Y
86. Travis WD
87. Nürnberg P
88. Reinhardt C
89. Perner S
90. Heukamp L
91. Büttner R
92. Haas SA
93. Brambilla E
94. Peifer M
95. Sage J
96. Thomas RK
(2015) Comprehensive genomic profiles of small cell lung cancer.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=sclc_ucologne_2015#summary
1. Cancer Genome Atlas Network
(2014) Comprehensive molecular characterization of gastric adenocarcinoma.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=stad_tcga_pub#summary
1. Cancer Genome Atlas Research Network
2. Kandoth C
3. Schultz N
4. Cherniack AD
5. Akbani R
6. Liu Y
7. Shen H
8. Robertson AG
9. Pashtan I
10. Shen R
11. Benz CC
12. Yau C
13. Laird PW
14. Ding L
15. Zhang W
16. Mills GB
17. Kucherlapati R
18. Mardis ER
19. Levine DA.
(2013) Integrated genomic characterization of endometrial carcinoma.
Publicly available at the cBioPortal (http://www.cbioportal.org) .

http://www.cbioportal.org/study?id=ucec_tcga_pub#summary

Article and author information

Author details

Nitin H Shirole

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

Competing interests
The authors declare that no competing interests exist.
Debjani Pal

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Edward R Kastenhuber

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

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The authors declare that no competing interests exist.
Serif Senturk

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Joseph Boroda

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Paola Pisterzi

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Madison Miller

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Gustavo Munoz

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

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The authors declare that no competing interests exist.
Marko Anderluh

Department of Medicinal Chemistry, University of Ljubljana, Ljubljana, Slovenia

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The authors declare that no competing interests exist.
Marc Ladanyi

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

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The authors declare that no competing interests exist.
Scott W Lowe

Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

Competing interests
The authors declare that no competing interests exist.
Raffaella Sordella

Cold Spring Harbor Laboratory, Cold Spring Harbor, United States

For correspondence
sordella@cshl.edu

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9745-1227

Funding

National Cancer Institute (NCI P01 CA129243-06)

Raffaella Sordella
Marc Ladanyi
Scott W Lowe

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed in accordance with National Research Council's Guide for the Care and Use of Laboratory Animals. Protocols were approved by the Cold Spring Harbor Laboratory Animal Care and Use Committee (933922-1 Development of mouse models to study human lung cancer - integrated protocols).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.