The Inherited p53 Mutation in the Brazilian Population
Maria Isabel Achatz1 and Gerard P. Zambetti2
1Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, SP, Brasil
2 Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 Correspondence: gerard.zambetti@stjude.org
A common criticism of studying rare diseases is the often-limited relevance of the findings to human health. Here, we review ~15 years of research into an unusual germline TP53 mutation (p.R337H) that began with its detection in children with adrenocortical carcinoma (ACC), a remarkably rare childhood cancer that is associated with poor prognosis. We have come to learn that the p.R337H mutation exists at a very high frequency in Southern and Southeastern Brazil, occurring in one of 375 individuals within a total population of ~100 million. Moreover, it has been determined that carriers of this founder mutation display variable tumor susceptibility, ranging from isolated cases of pediatric ACC to Li-Fraumeni or Li-Fraumeni-like (LFL) syndromes, thus representing a significant medical issue for this country. Studying the biochemical and molecular consequences of this mutation on p53 tumor-suppressor activity, as well as the putative additional genetic alterations that cooperate with this mutation, is advancing our understanding of how p53 functions in tumor suppres- sion in general. These studies, which originated with a rare childhood tumor, are providing important information for guiding genetic counselors and physicians in treating their patients and are already providing clinical benefit.
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P ediatric adrenocortical carcinoma (ACC) is a very rare cancer that is usually associated with germline TP53 mutations, often occurring within the context of Li-Fraumeni syndrome (LFS) (Ribeiro et al. 2012). The incidence of childhood ACC in Southern Brazil is extraordi- narily high and without precedent. In 2001, a study of pediatric ACC patients from this region and unselected for familial history of cancer were found to harbor the same germline mis- sense mutation in TP53 (p.R337H) in 35 of the 36 cases (Ribeiro et al. 2001). In contrast to the vast majority of constitutional TP53 mutations
associated with LFS, the p.R337H mutation does not fall within the DNA-binding domain (DBD) of the p53 protein, but in a structural motif (an &-helix) that mediates the formation of p53 dimers (Fig. 1) (DiGiammarino et al. 2002). Based on these early data, the penetrance of ACC in p.R337H carriers was estimated to be 1:10 (Figueiredo et al. 2006), which is in sharp contrast to the normal incidence of one in three million in the general population. More detailed studies of Brazilian ACC patients showed that 23 of 30 families that harbored the germline p.R337H mutation were not associated with
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cancer (low risk), but that the remaining seven families could be classified as Li-Fraumeni-like (LFL; occasional breast, brain, gastric tumors) (intermediate risk) (Ribeiro et al. 2001; Figuei- redo et al. 2006).
Although germline TP53 mutations at co- don 337 had been previously reported in the International Agency for Research on Cancer (IARC) database (Petitjean et al. 2007), nearly all were the missense mutation resulting in the arginine to cysteine substitution (R337C). The only exception was a 10-year-old girl with brain cancer from the Institut Gustave Roussy in Paris, France, who was the first identified carrier of the p.R337H mutation (Chompret et al. 2000).
In the early 2000s, the development of on- cogenetics practice in major cancer centers in Southeastern Brazil led to the frequent identifi- cation of families who fulfilled the criteria for LFS (Li et al. 1988) or LFL (Birch et al. 1994; Olivier et al. 2003). A subset of families with a less restricted family history of cancer, as defined by the Chompret criteria (Chompret et al. 2001), is also referred for TP53 mutation analy- sis and genetic counseling. Based on these clin- ical criteria, genetic testing identified seven of 45
probands as carriers of TP53 DBD mutations, typical of those most frequently associated with LFS/LFL (henceforth called “classic” or hotspot mutations) (Achatz et al. 2007). However, six of the 45 probands presented with p.R337H and subsequent analyses of family members indicat- ed that the mutation segregated with cancer risk. Interestingly, the proband carriers were adults who developed multiple cancers (Achatz et al. 2007). The spectrum of cancers occurring in p.R337H carriers resembled those of carriers of classic mutations, including the LFS-associ- ated quartet of early soft tissue sarcomas, early onset breast cancer, cancers of the central ner- vous system, and childhood ACCs (Achatz et al. 2007). Since these initial studies, more than 180 individuals who are positive for the p.R337H mutation have been detected and followed up at oncogenetics cancer clinics throughout Southern Brazil. Careful assessment of the fami- lial cancer patterns points to significant differ- ences between Brazilian carriers of the p.R337H and classic TP53 mutations. First, the pene- trance of cancer appears to be somewhat lower when only 15%-20% of the p.R337H carriers develop cancer by 30 years of age, compared
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with ~50% in carriers of classic mutations. Sec- ond, ACC represents a greater proportion of all cancers in p.R337H carriers (~8% to 10%) than in carriers of classic mutations (~4%) (Klei- hues et al. 1997). Third, whereas breast cancer was the most common malignancy diagnosed in carriers of the p.R337H and classic mutations, these cancers tended to occur at a slightly later median age in p.R337H (40 years) than in classic (32 years) carriers. Fourth, p.R337H carriers presented with a higher occurrence of papillary thyroid cancer in young adults, renal cancers, and lung adenocarcinomas than classic carriers. These results indicate that, although the familial presentation of cancer risk associated with p.R337H can clearly belong to the LFS spec- trum, it shows specific traits that suggest it rep- resents a variant of LFS.
Each of these earlier studies had inherent biases as a result of the context in which pro- bands were selected, with, on the one hand, pa- tients who had pediatric ACC with no striking a priori evidence of familial history, and on the other hand, mostly adult patients selected for familial history of cancer matching LFS/LFL criteria. Overall, these studies suggested that p.R337H might represent a deleterious variant highly prevalent in the Brazilian population, which could be associated with a highly hetero- geneous level of risk of cancer. Indeed, an esti- mate of the prevalence of p.R337H in a popula- tion-based group of healthy women unselected for cancer history and participating in a breast cancer prevention study in the area of Porto Alegre, Rio Grande do Sul, found two carriers in a total of 750 subjects (0.3%) (Palmero et al. 2008). To better estimate the impact of the mu- tation in the population of Southern Brazil, a simple PCR-based assay to detect the 337H mu- tation was developed and applied by Figueiredo and colleagues to screen 175,000 newborns in the State of Parana in Southern Brazil (Custódio et al. 2013). Key findings include (1) one in 375 individuals in Southern Brazil are carriers with- in a total population of ~100 million (~250- 300,000 carriers); (2) the penetrance of child- hood ACC is one in 30 to 40 rather than the initial estimate of one in 10 because of the elim- ination of the selection criteria, but still extraor-
dinarily high; (3) families with carriers that are at low, intermediate, and high risk of cancer were identified; (4) three homozygous carriers were identified, each developed pediatric cancer (two ACC, and one choroid plexus carcinoma); and (5) screening combined with surveillance detected early stage tumors and improved out- come, thus providing clinical benefit (Custódio et al. 2013). A similar study was conducted in the region of Campinas, São Paulo, involving 35,000 newborns. A total of 0.21% of the pop- ulation were found to be carriers of the p.R337H mutant (Caminha et al. 2015).
The extremely heterogeneous patterns of in- dividual and familial cancer risk has led to the hypothesis that p.R337H may be an underlying factor in many cancers belonging to the LFS spectrum, but also contributing to tumor sus- ceptibility in an apparently sporadic manner in the Brazilian population. Indeed, in a cohort of 815 women affected with breast cancer, unse- lected for familial history and recruited at three distinct hospital locations in Southern Brazil, the p.R337H mutation was detected in the germ- line of 12.1% of all patients who developed the disease before age 45 (Giacomazzi et al. 2015). Indeed, the high prevalence of p.R337H in the population of Southern Brazil and the heteroge- neous patterns of risk suggest that this mutation may cause several thousand cancer cases every year in this population, only a fraction of which occur in a familial setting matching LFS/LFL definitions. The notion that individual risk is very heterogeneous is supported by the analysis of several large pedigrees showing that, within the same extended family group, some subclus- ters presented with a familial disease-matching strict LFS definition, whereas other subclusters of distant relatives had only few cancers, among which included pediatric ACC.
GENETICS
Initial studies on the genetic diversity of TP53 alleles in p.R337H carriers were inconclusive and discounted the possibility of a common founder (Ribeiro et al. 2001). Subsequently, Pinto et al. (2004) established a founder effect for the p.R337H mutation using two intragenic
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hypervariable microsatellite markers. In 2010, Garritano and colleagues confirmed and ex- tended these findings using a detailed set of 29 SNPs (single-nucleotide polymorphisms) local- ized throughout the 20-kb TP53 locus. They demonstrated that a group of 12 apparently un- related carriers of the p.R337H mutation all shared the identical relatively rare haplotype of TP53 and that the allele was of European Cau- casian ancestry. Furthermore, the first reported case of p.R337H in the child with adrenocortical cancer tested in France (see above), was a young girl of Portuguese origin who also carried the same TP53 haplotype (Chompret et al. 2000; Garritano et al. 2010). To date, all Brazilian p.R337H carriers who have been tested share the same founder allele. Significantly, this hap- lotype has also been found in a few carriers detected outside Brazil, including a patient treated in Portugal (a documented “reverse” Brazilian migrant) (Pinto et al. 2009) and two patients in the United States (both of docu- mented Brazilian origin) (data not shown). Re- cently, a patient with a germline p.R337H mu- tation was identified in Germany (Herrmann et al. 2012). This patient, a male, who developed an ACC at age 71 and whose family history of cancer includes a father with prostate cancer (at 62 years of age) and a daughter with breast tumor at age 37, carried the mutation on a dif- ferent haplotype than the Brazilian p.R337H carriers. It is, therefore, likely that this German patient represents a distinct, independent oc- currence of the same mutation. It is important to note that the p.R337H mutation occurs at a CpG motif in the TP53 gene, a dinucleotide motif that is prone to spontaneous deamination and highly mutable. Therefore, the independent occurrence of the same mutation at this motif is not unexpected, making even more spectacular the unique founder haplotype detected in all Brazilian carriers.
The remarkable genetic homogeneity of TP53 haplotypes in p.R337H carriers raises the question of whether the wide heterogeneity in cancer risk is caused by genetic and/or lifestyle/ environmental factors. Marcel et al. (2009) and Sagne et al. (2014) analyzed whether TP53 SNPs may be associated with differences in age at first
cancer onset in p.R337H carriers. The inves- tigators have assumed that, because all carriers have the same mutant allele, SNPs on the other wild-type allele may affect p53 function and, therefore, cancer penetrance. They found that a common polymorphism consisting of a repeat of 16 bp in TP53 intron 3 (rs17878362) was as- sociated with a significant difference in age at first cancer onset. The mutant p.R337H allele carries one copy of the 16 bp motif. Carriers of the p.R337H mutation and a wild-type TP53 allele containing a single copy of the 16 bp motif developed early (childhood) can- cer, including ACC. In contrast, carriers with a wild-type allele containing two copies of the 16-bp motif developed only adult cancers, with no cases of ACC. The functional impact of this polymorphism on p53 activity is not fully un- derstood. The polymorphism falls within a re- gion that forms G-quadruplex structures in p53 pre-mRNA (Sagne et al. 2014). G-quadruplexes are secondary motifs involved in the regulation of mRNA stability, processing, and splicing, and there is experimental evidence that this poly- morphism modulates p53 splicing. It is there- fore tempting to speculate that the polymor- phism may have an impact on the level of expression of wild-type p53 in the p.R337H carriers, resulting in different degrees of hap- loinsufficiency, depending on the nature of the wild-type haplotype.
DEMOGRAPHY AND HISTORY
To date, p.R337H carriers have been repeatedly detected throughout a region of Brazil ex- tending from the State of Minas Gerais (South- ern region of Brazil) to the State of Rio Grande do Sul (South region of Brazil), two regions that are separated by more than 2000 kilometers (~1500 miles). A recent study has identified the presence of the mutation in Paraguay, in popu- lations residing along the Brazilian border (Le- gal et al. 2015). The region from Rio Grande do Sul to Minas Gerais in Brazil was settled by mi- grants of Portuguese origin during the late 17th and early 18th centuries. In particular, Southern Brazil was explored and settled by Portuguese immigrants in the first four decades of the
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1700s, opening and progressing along transit routes that became known as the “Tropeiro roads.” Tropeiros were traveling merchants trad- ing cattle and consumer goods between South- ern Brazil and the metropolitan area of São Paulo. Introduction of a mutant allele of Portuguese origin may have occurred in the initial stages of the colonization of Southern Brazil at the time when the population was low and propagated by extensive dissemination along the main trade roads, enabling it to reach the significant prev- alence in the current population (Garritano et al. 2010). However, it remains difficult to ex- plain how a mutation associated with increased cancer risk, which is supposedly detrimental, has maintained itself over time at such a high frequency in a large population. The answer to this apparent paradox may lie in the heteroge- neous pattern of risk associated with p.R337H, which may actually have prevented the repro- duction of only a small subset of the carriers.
The historical premise for the p.R337H founder mutation is supported by the observa- tion that the vast majority of carriers report themselves as being descendants of early Portu- guese settlers, a circumstance documented by the genealogical records of a few large families. This demographic profile is not representative of the diversity of the current population of
Southern Brazil, which has been impacted by successive waves of different European immi- grant groups (Germans and Italians, in partic- ular) during the second half of the 18th and the first half of the 19th century. However, this hy- pothesis has not been formally demonstrated. Of note, data are very scarce on the prevalence of p.R337H in central and Northern Brazil, Uru- guay, or Argentina.
BIOCHEMISTRY
The p.R337H mutation is a consequence of a single nucleotide substitution at codon 337 (CGC→CAC), resulting in the substitution of histidine for arginine. The mutation occurs at a CpG site and possibly arose because of sponta- neous deamination. The p.R337H mutation impacts a salt bridge within the dimerization domain (Fig. 2), and structural studies revealed a pH-dependent nature of this mutation on p53 stability (DiGiammarino et al. 2002). The mu- tant protein is also susceptible to amyloid fiber formation, at least in vitro (Lee et al. 2003). Functional studies show that the p.R337H mu- tant retains significant activity (e.g., transactiva- tion of promoter-reporters and endogenous target genes, cell-cycle arrest, apoptosis, and colony reduction) at a level comparable to
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wild-type p53 when ectopically expressed in a variety of tissue culture cells (Ribeiro et al. 2001). In contrast, DNA-binding mutants that are commonly associated with LFS are com- pletely inactive in these assays. Similar findings demonstrating significant transactivation func- tion by the p.R337H mutant have been observed in yeast reporter studies (Kawaguchi et al. 2005). However, the adrenocortical tumors undergo chromosome 17 LOH ([loss of heterozygosity] deletion of the wild-type p53 allele) and express high levels of the missense protein in the nucleus (Ribeiro et al. 2001). Intuitively, the endogenous p.R337H mutant must be functionally inactive in these tumors when physiologically expressed.
The findings that the p.R337H mutant re- tains substantial function compared with the DNA-binding mutants, at least in the in vitro assays, is consistent with many carriers remain- ing tumor-free. The unique pH-dependent na- ture of this mutation may be influenced by the physiology of the adrenal cortex during devel- opment. During embryogenesis, the adrenal cortex plays an important role in maintaining the function and integrity of the placenta and rapidly expands to become adult size. Shortly after birth, the cortex reorganizes and regresses because of the activation of apoptosis, and loses ~50% of its weight (Bland et al. 2003). We speculate that an adrenocortical cell that was destined to stop dividing during embryogenesis or to die shortly after birth continues to prolif- erate and survive, resulting in tumors 2 to 3 years later, consistent with the peak age of chil- dren who develop ACC. The incomplete pene- trance of p.R337H in promoting ACC may be related to the mutant not forming stable dimers/tetramers with wild-type p53 (DiGiam- marino et al. 2002) and therefore not function- ing as a dominant negative. The multihit nature of adrenocortical tumors requiring additional genetic alterations for tumorigenesis (e.g., chromosome 11p15 and 17 LOH and amplifi- cation of chromosome 9q34) (Pinto et al. 2015) may also limit penetrance.
Whether the p.R337H mutation alters the extensive posttranslational modifications that normally take place during the activation of en- dogenous p53 in response to cell stress (e.g.,
phosphorylation of S15, S20, and acetylation of key lysines within the DBD and carboxyl ter- minus) remains to be determined. Similarly, changes in associated proteins, such as MDM2, p300/CBP, and transcription associated factors (TAFs), must also be addressed to better under- stand how p.R337H function may be affected in a physiologic manner in human tumors.
CLINICAL CONSIDERATIONS
An important lesson learned from the adrenal tumor studies is that not all germline TP53 mutations are equivalent in inactivating tu- mor-suppressor function (Ribeiro et al. 2012). Some are catastrophic and completely disrupt DNA binding, such as p.R175H. This particular mutant creates a Zn finger that inappropriately binds zinc, causing improper folding and a complete loss of DNA-binding and tumor-sup- pressor activity. Individuals who inherit this particular p53 “conformation” mutation are at a remarkably high risk of developing cancer (di- verse tumor spectrum, multiple tumors, and early onset). In contrast, the p.R175L mutant retains partial activity in cell-based assays and individuals who inherit this mutation are at an apparent lower risk of cancer (West et al. 2006). These examples illustrate how different amino acid substitutions at a single site can have very different effects on p53 structure and function and, consequently, on clinical outcome (Zam- betti 2007). The significantly shorter time to tu- mor onset in the homozygous p.R172H (equiv- alent to human p.R175H) knockin mutant p53 mice compared with the p.R172P mutant mice convincingly bears this concept out in a geneti- cally defined animal model (Liu et al. 2000).
In the case of the p.R337H mutation in Southern Brazil, there is a spectrum of tumor susceptibility in families associated with this germline mutation (Fig. 3). In these cases, the individuals all carry the same founder muta- tion, but some are at high risk of breast, brain, and gastric cancers, for example, whereas others are at low risk of cancer and survive to older ages tumor-free (e.g., one individual >100 years). We speculate that the high-risk families have secondary genetic alterations that cooperate
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M.I. Achatz and G.P. Zambetti
with the p.R337H mutation. Identification of these cooperating mutations will be important for genetic counseling purposes and for devel- oping long-term clinical follow-up plans for carriers of germline p.R337H.
Whole-genome sequencing of a cohort of Brazilian pediatric ACCs associated with the germline p.R337H mutation revealed LOH of the entire chromosome 17 in every case, always selecting against the wild-type allele. More de- tailed analyses show that chromosome 17 LOH occurs early during tumorigenesis, consistent with it being a driver event (Pinto et al. 2015). As a consequence of losing wild-type p53 func- tion, the tumors were expected to display chro- mosomal instability. However, a spectrum of genetic alterations was observed, ranging from very quiet genomes to tumors encountering massive chromosomal alterations, including large deletions, amplifications, and rearrange- ments. Those tumors with the highest degree of genomic instability were associated with so- matic mutations in ATRX, which encodes a heli- case that functions in chromatin remodeling and telomere maintenance. Perhaps not too sur- prisingly, these tumors correlated with the worst prognosis. The identification of mutations that cooperate with p.R337H during tumorigenesis, such as ATRX, will be important for advancing our understanding of adrenocortical tumor bi- ology, which hopefully will lead to new and im- proved treatments for this aggressive childhood cancer.
FUTURE PROSPECTS
Whole-genome sequencing offers the hope of identifying polymorphisms and other constitu- tional genetic alterations that influence tumor susceptibility in carriers of the p.R337H muta- tion. Genetically engineered mouse models with the equivalent germline p.R337H allele (p.R334H) are expected to advance our under- standing of how this mutation alters p53 re- sponses in a physiological manner. Whether the p.R337H mutation will selectively compro- mise responses to some cellular stresses (e.g., DNA damage, hyperproliferation, and hypoxia) but not others, and whether cell-fate outcomes
(e.g., cell-cycle arrest, apoptosis, senescence, DNA repair, metabolism) will be differentially affected in a tissue-specific manner will be im- portant to determine. These efforts may shed light onto why childhood adrenocortical tu- mors are so prevalent in families with a consti- tutional p.R337H mutation. The establishment of induced pluripotent stem cells from carriers of the Brazilian p.R337H mutation also holds great potential for studying the functional con- sequence of this mutation on p53 in a physio- logical manner.
Neonatal screening for the p.R337H muta- tion in Southern Brazil has had clinical benefit for carriers whom are monitored for early signs of pediatric adrenocortical tumors (Custódio et al. 2013). Screening for other malignancies, in particular breast and brain cancers, may also bring clinical benefit for p.R337H mutation carriers. Finally, advancing our understanding of how p53 functions and the cooperating ge- netic alterations that influence tumor suscepti- bility will be essential for guiding geneticists in counseling their patients and for improving the clinical management of carriers of LFS/LFL- associated and low-penetrant germline TP53 mutations.
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CSH & PERSPECTIVES
Cold Spring Harbor Perspectives in Medicine
The Inherited p53 Mutation in the Brazilian Population
Maria Isabel Achatz and Gerard P. Zambetti
Cold Spring Harb Perspect Med 2016; doi: 10.1101/cshperspect.a026195 originally published online September 23, 2016
Subject Collection The p53 Protein
Targeting the MDM2-p53 Protein-Protein Interaction for New Cancer Therapy: Progress and Challenges
Shaomeng Wang, Yujun Zhao, Angelo Aguilar, et al.
Structural Evolution and Dynamics of the p53 Proteins
Giovanni Chillemi, Sebastian Kehrloesser, Francesca Bernassola, et al.
Exploiting the p53 Pathway for Therapy Chit Fang Cheok and David Philip Lane
The Regulation of Cellular Functions by the p53 Protein: Cellular Senescence
Crystal A. Tonnessen-Murray, Guillermina Lozano and James G. Jackson
The Transactivation Domains of the p53 Protein Nitin Raj and Laura D. Attardi
The Evolution of the Ribosomal Protein-MDM2- p53 Pathway
Chad Deisenroth, Derek A. Franklin and Yanping Zhang
Somatic TP53 Mutations in the Era of Genome Sequencing
Pierre Hainaut and Gerd P. Pfeifer
The Paradox of p53: What, How, and Why? Yael Aylon and Moshe Oren
Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres Caitlin M. Roake and Steven E. Artandi
Inherited TP53 Mutations and the Li -Fraumeni Syndrome
Tanya Guha and David Malkin
TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia
Evan Q. Comeaux and Charles G. Mullighan
Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53 Neil T. Pfister and Carol Prives
The Inherited p53 Mutation in the Brazilian Population
Maria Isabel Achatz and Gerard P. Zambetti TP53 Mutations in Breast and Ovarian Cancer Laxmi Silwal-Pandit, Anita Langerød and Anne-Lise Børresen-Dale
p53 and the Carcinogenicity of Chronic Inflammation
Andrei V. Gudkov and Elena A. Komarova
Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation Yoav Shetzer, Alina Molchadsky and Varda Rotter
For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/