Published OnlineFirst June 10, 2014; DOI: 10.1158/1078-0432.CCR-14-0899
Clinical
Cancer
Research
CCR Translations
See related article by Molina-Vila et al., p. 4647
TP53 Mutations and Lung Cancer: Not All Mutations Are
Created Equal
Ramaswamy Govindan1,2 and Jason Weber1,2
Mutations in TP53 are common in non–small cell lung cancer. Apart from the loss of tumor-suppressor
functions, TP53 mutations may result in gain of function favoring cellular proliferation, inhibition of
apoptosis, and genomic instability. Some TP53 mutations are more likely to affect the course of the disease
than others. Clin Cancer Res; 20(17); 4419–21. Ó2014 AACR.
In this issue of Clinical Cancer Research, Molina-Vila and
colleagues address the prognostic significance of TP53
mutations in patients with advanced non–small cell lung
cancer (NSCLC), keeping the functional impact of specific
TP53 mutations in mind (1). The complex genomic landscape of lung cancer induced by tobacco smoke is characterized by numerous single-nucleotide variations, gene
amplifications, deletions, and structural variants as outlined recently by The Cancer Genome Atlas Project (TCGA;
ref. 2). Among several novel variants reported, one gene
stands out in lung cancer and other cancers—TP53 (3).
Since the initial discovery of this "master regulator" and
"guardian of the genome," more than 50,000 articles have
been published on TP53 to date; much has been learned,
yet there is more to be understood. That wild-type TP53 is
a bona fide tumor suppressor and mutant TP53 acquires
novel functions facilitating survival of cancer cells against
all odds is not in doubt. However, the clinical implications
of TP53 mutations in lung cancer are not so clear. Does
the presence of TP53 mutations portend a poor prognosis?
Do all mutations in TP53 produce the same effect functionally and clinically? Can targeting mutated TP53 become
the Holy Grail of cancer therapy?
p53 (encoded by the gene TP53) is a stress response
protein that mediates the transcription of genes in response
to genotoxic stress, oncogenic signaling, DNA damage, and
cellular injury. Like most transcription factors, p53 has a
transactivation domain (TA), DNA binding domain (DBD),
and tetramerization and regulatory domain (TD). Expression of p53 protein is largely controlled through its degradation by the mouse double minute 2 (MDM2) E3 ligase
and a related protein, MDM4. In addition, posttranslational
modification of p53 by various kinases/phosphatases and
1
Department of Medicine and 2Alvin J Siteman Cancer Center, Washington
University School of Medicine, St. Louis, Missouri.
Corresponding Author: Ramaswamy Govindan, Washington University
School of Medicine, 4990 Childrens Place, St. Louis, MO 63110. Phone:
314-362-5737; Fax: 314-362-7086; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-14-0899
Ó2014 American Association for Cancer Research.
acetylases/deacetylases regulates its activity. The majority of
the mutations in TP53 are either missense or nonsense
mutations. Mutations in TP53 can result in one of three
possible outcomes—mutations that interfere with its
tumor-suppressor properties (loss of function), mutations
that confer the protein with a dominant-negative phenotype, where it binds and inactivates coexpressed functional
wild-type TP53, and conformational mutations that contribute to the emergence of new functions [gain of function
(GOF)]. GOF mutations contribute to genomic instability,
inhibition of apoptosis, cell migration, and drug resistance.
GOF mutations usually engage in molecular interactions
that either result in the binding and inactivation of TP53related proteins such as TP63 and TP73, or interactions with
other transcriptional factors, resulting in the novel regulation of expression of several genes (3).
Almost all small-cell lung cancers and more than half of
NSCLCs harbor alterations in TP53. Although TP53 mutations are predominantly G-to-T transversions and deletions in tobacco smokers, such alterations are infrequent
in never-smokers. Studies that investigated the role of
TP53 mutations as a prognostic marker in NSCLC have
reported conflicting results (4–10). These conflicting findings may be due to the molecular heterogeneity and
differing functional effects specific to various TP53 genotypes, methodologic issues related to the assessment of
mutation status, and design issues related to small sample
size and nonhomogeneous groups of patients. Finally, the
context in which these mutations occur, the initiating
events and other secondary molecular alterations, may
matter as well.
Instead of treating all TP53 mutations in the same way to
assess their clinical impact, it may be sensible to categorize
them in different groups based on the functional effects they
induce, i.e., loss of tumor-suppressor effect versus GOF.
Mutations involving TP53 can be classified from a structural
viewpoint as "contact mutations" that affect residues directly involved in sequence-specific DNA contacts but do not
alter the conformation of the p53 molecule (prototype
hotspot mutation, R273H) and "conformational mutations" resulting in partial or complete loss of normal conformation of wild-type p53 (prototype hotspot mutation,
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Published OnlineFirst June 10, 2014; DOI: 10.1158/1078-0432.CCR-14-0899
Govindan and Weber
5
158
273
4
245
248
3
2
Figure 1. TP53 mutation profile from
cBIO portal (13, 14) is shown here.
The data include tissue samples
from 178 patients with squamous
cell carcinoma and 576 patients
with adenocarcinoma of the lung.
1
0
1
105
TA
5
154
179
L2
29
95
163—195
215
DBD
250
281
337
L3
236—251
TD
289
318
359
Frameshift InDels
Inframe InDels
Missense
Nonsense
Splice site
© 2014 American Association for Cancer Research
R175H; ref. 11). Conformational changes can interfere with
the recognition of DNA binding elements that are normally
recognized by wild-type TP53 and uncover hitherto hidden
interfaces in these DNA binding domains. Another practical
way to categorize TP53 mutations is as disruptive or nondisruptive based on the location of the mutation and the
predicted amino acid alterations (12). Mutations resulting
in the substitution of amino acids belonging to a different
polarity and charge in the L2 and L3 regions of the DNA
binding domains, or stop codon, are classified as disruptive.
4420
Clin Cancer Res; 20(17) September 1, 2014
All other mutations are categorized as nondisruptive.
Importantly, these mutations have already been characterized for their cellular effects using human cell systems and
mouse models. Many nondisruptive variants are GOF mutations that mediate oncogenesis through mechanisms
already described.
Molina-Vila and colleagues examined retrospectively
the impact of TP53 mutations in 318 patients with stage
IIIB–IV NSCLC, including 125 patients with EGFR mutations (1). In the group of patients with EGFR wild-type
Clinical Cancer Research
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Published OnlineFirst June 10, 2014; DOI: 10.1158/1078-0432.CCR-14-0899
TP53 Mutations and Lung Cancer
NSCLC, the median overall survival was significantly
lower in those with nondisruptive TP53 mutation than
those whose tumor cells had either wild-type TP53 or
with a disruptive TP53 mutation (8.5 months vs. 15.6
months respectively, P ¼ 0.003). This difference was seen
even in the EGFR-mutant group (17.8 months vs. 28.4
months, P ¼ 0.04), underscoring the significant effect of
nondisruptive TP53 mutations independent of EGFR status. These findings were confirmed in a small independent cohort of patients with EGFR-mutant NSCLC. However, these findings are directly in conflict with the results
from Poeta and colleagues (12), who reported worse
outcomes in early-stage head and neck cancers harboring
disruptive TP53 mutants. It is possible that specific TP53
mutants may exert unique and seemingly conflicting
effects based on the tissue of origin and concomitant
genomic alterations. Clearly, more studies need to be
done to validate or refute these observations.
Fortunately, ongoing studies by TCGA and other largescale genomic studies will provide a large body of information on TP53 mutation status from several thousand
patients with NSCLC (Fig. 1). Integration of transcriptomic
and proteomic studies will enable us to tease out the
downstream effects of the various classes of TP53 mutations
in the coming years. Parsing these data carefully using wellcurated clinical specimens and follow-up functional studies
will shed more light on the in vivo effects of various mutations involving TP53.
Disappointingly, therapeutic strategies directed toward
TP53 alterations have largely failed. Many such strategies
focused on the reactivation of TP53 in cancer cells, with the
hope of restoring its tumor-suppressor properties. Characterizing the downstream pathways activated by TP53 GOF
variants is a critical first step before developing therapies
aimed at functionally reestablishing the master regulator
that goes awry in so many cancers.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: R. Govindan
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R. Govindan
Writing, review, and/or revision of the manuscript: R. Govindan,
J. Weber
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R. Govindan
Acknowledgments
The authors thank Siddhartha Devarakonda for his help in preparing this
article.
Received April 30, 2014; accepted May 16, 2014; published online August
14, 2014.
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Clin Cancer Res; 20(17) September 1, 2014
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4421
Published OnlineFirst June 10, 2014; DOI: 10.1158/1078-0432.CCR-14-0899
TP53 Mutations and Lung Cancer: Not All Mutations Are Created
Equal
Ramaswamy Govindan and Jason Weber
Clin Cancer Res 2014;20:4419-4421. Published OnlineFirst June 10, 2014.
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