Review

TP53 mutations as biomarkers for cancer epidemiology

in Latin America: Current knowledge and perspectives

Claudia Vitoria de Moura Gallo a,*, Gulnar Azevedo e Silva Mendonca b,Emanuela de Moraes a,c, Magali Olivier c, Pierre Hainaut c

a Departamento de Biologia Celular e Genetica, Instituto de Biologia Roberto Alcantara Gomes,

Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazilb Departamento de Epidemiologia, Instituto de Medicina Social, Universidade do Estado do Rio de Janeiro,

Rio de Janeiro, Brazilc Group of Molecular Carcinogenesis, International Agency for Research on Cancer, Lyon, France

Received 11 November 2004; received in revised form 28 January 2005; accepted 30 January 2005

Available online 31 March 2005

www.elsevier.com/locate/reviewsmr

Community address: www.elsevier.com/locate/mutres

Mutation Research 589 (2005) 192–207

Abstract

Due to particular social and economical development, and to the impact of globalization of lifestyles, Latin America shows a

superposition of cancers that are frequent in low resource countries (gastric, oesophageal squamous cell and cervical cancers)

and high resource countries (cancers of breast, colon and rectum, lung and prostate). Latin America thus offers opportunities for

investigating the impact on changing lifetsyle patterns on the occurrence of cancer. At the molecular level, mutations in the

tumor suppressor gene TP53 are common in many cancers and their distribution can be informative of the nature of the

mutagenic mechanisms, thus giving clues to cancer etiology and molecular pathogenesis. However most of the data available are

derived from studies in industrialized countries. In this review, we discuss current trends on cancer occurrence in Latin American

countries, and we review the literature available on TP53 mutations and polymorphisms in patients from Latin America. Overall,

a total of 285 mutations have been described in 1213 patients in 20 publications, representing 1.5% of the total number of

mutations reported wordlwide. Except for hematological cancers, TP53 mutation frequencies are similar to those reported in

other regions of the world. The only tumor site presenting significant differences in mutation pattern as compared to other parts

of the world is colon and rectum. However, this difference is based on a single study with 35 patients. Recently, a characteristic

TP53 mutation at codon 337 (R337H) has been identified in the germline of children with adrenocortical carcinoma in Southern

Brazil. Further and better focused analyses of TP53 mutation patterns in the context of epidemiological studies, should help to

improve our understanding of cancer etiology in order to develop appropriate health policies and public health programs in Latin

America.

# 2005 Elsevier B.V. All rights reserved.

Keywords: TP53 mutation; Latin America; Biomarkers; Molecular epidemiology

* Corresponding author. Tel.: +55 21 2587 7567; fax: +55 21 2587 7377.

E-mail address: cgallo@uerj.br (C.V. de Moura Gallo).

1383-5742/$ – see front matter # 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.mrrev.2005.01.002

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 193

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

2. Cancer epidemiology in Latin America: the global burden of cancer and regional variations . . . . . . . . . . . . . 194

3. TP53 mutations as markers in molecular epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

3.1. p53 Structure and functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

3.2. Mutations in cancer: mutagenesis versus selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

3.3. TP53 germline mutations and polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

4. TP53 mutation analysis in Latin America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

4.1. Somatic mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

4.2. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

4.3. Colon cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

4.4. Oesophageal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

4.5. Head and neck cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4.6. Bladder cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4.7. Germline TP53 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

4.8. TP53 polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

5. Perspectives: design of studies on TP53 mutations in LA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

1. Introduction

Worldwide, cancer is considered as the second

most common cause of mortality after cardiovascular

diseases. It is estimated that more than six million

people die of the disease every year, with marked

regional differences [1]. It is commonly accepted that

cancer is a major problem in high resource indus-

trialized regions, however it is becoming also a burden

in lower resource developing countries, especially in

Latin America (Fig. 1) (definition of high and low

resource countries according to the World Bank,

http://www.mapsofworld.com).

Latin America is a part of the American continent

formed by countries that were colonized by Spanish

and Portuguese, spanning a large area from Mexico

to Argentina. It represents a very interesting area to

monitor and control trends in cancer incidence and

mortality, as well as to study geographic variations in

cancer patterns. Due to wide sociological and

economical disparities, the global map of cancer in

Latin America shows a superposition of cancers that

are frequent in industrialized countries (breast, lung,

prostate, colon), and of cancers that are more

frequent in developing countries (cervix, oesopha-

gus, oral, bladder, liver) [2,3]. While the former are

likely to be associated with a number of lifestyle

factors (in particular diet, tobacco and lack of

physical exercise), many of the latter cancers may

reflect the interactions between malnutrition, region-

specific environmental exposures and, in several

cases, viral infections [4]. This very complex

situation makes it extremely difficult to develop

global health policies for cancer prevention, detec-

tion and monitoring. Moreover, these trends are

changing rapidly. Another element of complexity as

far as genetic susceptibility of cancer is concerned, is

the existence of multiple ethnic groups, some of

them affected by strong founder effects that may

explain the local or regional clustering of relatively

rare cancers. Thus, the use of molecular biomarkers

may be particularly helpful to identify the respective

roles of environmental, biological, lifestyle and

genetical risk factors in studies on cancer in Latin

America.

Many constitutive or acquired genetic traits are

potential biomarkers for molecular epidemiology

studies. In this review, we will focus the interest on

mutations in the TP53 tumor suppressor gene, as there

is good evidence that these mutations may be

informative on the nature of the mutagenic mechan-

isms at work in cancer causation. Moreover, these

mutations may represent phenotypic changes in

tumour cells, giving different pathological features

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207194

Fig. 1. (A) World cancer incidence in all sites but skin, in men (left panel) and women (right panel) per 100,000; from [10]. (B) Global map

showing the growth national index (GNI, http://www.mapsofworld.com) for the countries around the world.

to the cancer cell, turning to be important clues to

clinical decisions [5].

TP53 is the most commonly mutated gene in

human cancers and its product, the p53 tumour

suppressor protein, is a transcription factor activated in

response to stress signals, in particular to genotoxic

stress. Several observations lead investigators to

consider the TP53 mutation pattern as a useful

biomarker of mutagenesis: (1) mutations in TP53

are mostly missense and very diverse in their position

and nature, allowing compilation and comparison of

tumor-specific mutation spectra; (2) these point

mutations are clustered in exons 4–9 (more than

80%) which facilitates analysis; (3) there is a large

data set of mutation information on TP53, which is

compiled in a dedicated, central database (http://

www-p53.iarc.fr).

The purpose of this review is to discuss the

usefulness of studies on TP53 mutation patterns as a

tool to better understand the epidemiology of cancer in

Latin America.

2. Cancer epidemiology in Latin America: the

global burden of cancer and regional variations

The 20th century has witnessed two important

socio-economic changes throughout the world: glo-

balization and a historical shift in patterns of

production and consumption [6]. The consequence

of this global rearrangement is a different health

profile of the developing world. These changes of

health and disease patterns are known as epidemio-

logical transition, characterized by a modification in

the incidence and mortality profiles. Decreasing rates

of infectious diseases and the increment of chronic-

degenerative diseases, especially cancer and cardio-

vascular diseases are detected in countries where the

income by person is very low [7,8].

In Latin America the epidemiological transition is

not yet accomplished. In this region of the world the

degenerative diseases are increasing, while the

prevalence of infectious, respiratory and vector-borne

diseases as malaria and dengue, and overall malnutri-

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 195

tion, remains high [7,8]. This dual aspect is related to

the socio-economical class distribution in the region:

on one side the poor rural and peri-urban population,

including Indian people, and on the other side the

wealthy urban elites. In the middle, we found the poor

urbans living in urban slums known as ‘‘favelas,’’

‘‘suburbios’’ and ‘‘pueblos jovenes.’’ It is noteworthy

that differences in ethnic distribution follow this

social-economical class distribution. Currently, Latin

America is the most urbanized of the less developed

regions in the world, and this urban expansion has

been accompanied by massive urban poverty [7,9].

The impact of this situation on the global burden of

cancer is illustrated in Fig. 1. It is striking to observe

that high global cancer incidence (Fig. 1A) co-incides

with economic prosperity (Fig. 1B), with the highest

rates of cancer occurring in developed countries in the

Western hemisphere as well as in Australia and the

Southern part of Latin America. By contrast, the

lowest rates are observed in equatorial and inter-

tropical regions. This trend is noticeable both in men

and, spectacularly, in women. As a result, there is, in

Latin America, a North–South gradient in cancer

incidence, with the lowest global burden observed in

the relatively poor countries of Central America and of

the North- and Eastern ridge of South America. The

highest global incidences are observed in Chile,

Argentina and, typically, Uruguay, which are the most

‘‘Westernized’’ of the Latin American countries.

Brazil represents an intermediate situation, reflect-

ing the enormous local and socio-economical dis-

parities that are prevalent throughout the country [10–

12]. It should be emphasized that population coverage

by cancer registries is, at best, only partial [2,3,6].

While data from Porto Alegre, an industrialized area,

show a pattern of incidence compatible with ‘‘wes-

tern’’ profile, the data from Belem, a rural area, are

more similar to those of registries in the poorest

countries of Latin America.

Fig. 2 compares the distribution of incidence and

mortality for the six most common cancers in men and

in women in Northern, Central and Southern Americas

[1]. First, it appears that the global incidence of the

main cancers is much higher in Northern than in Latin

America. However, the two cancers that rank first in

incidence among men, prostate and lung cancers are

the same throughout the continent. Colorectal cancer

is also common to the three Americas. In Latin

America, however, a number of cancers that arise are

uncommon in Northern America, in particular cancers

of the stomach and oesophagus (squamous cell), as

well as pancreas and leukemia in Central America. In

women, the difference between Northern and Latin

America is even more striking. Cervical cancer, which

is rare in North America, appears in the first and

second position in, respectively, Central and South

America. Breast cancer, the dominant cancer in North

America, is also the most common among women in

South America. As observed in men, stomach cancer

also features among the top five cancers in Latin

America, but is much less frequent in Northern

America. In contrast, lung cancers, that are now the

second most frequent cancer in women in Northern

America (and the first in mortality rate), are relatively

rare in Latin America, with the exception of Brazil

where recent figures indicate that it has also become

the second main cause of cancer death among women

[13]. Fig. 2 also illustrates important disparities

between Northern and Latin Americas in mortality

for manageable cancers such as prostate, breast and

colorectal cancers. Thus, as a region of contrasts, Latin

America has important regional differences in

incidence and mortality patterns and trends. Among

the cancers listed above, there are well-documented

high incidence rates of stomach cancer in Latin

America. Costa Rica, Ecuador and Colombia have

three to four times higher rates than Paraguay and

Cuba [14]. The analysis of mortality by gastric cancer

in Brazil between 1979 and 2001, showed a decrease

in incidence for both male and female [15,16]. In the

State of Rio de Janeiro, this decrease is more marked

in metropolitan than in rural areas. This type of cancer

is linked to nutritional habits such as additives and

high-salt foods that cause mucosal inflammation.

Moreover, persistent infection with H. pylori, which is

more common in lower social-economic population, is

a decisive factor in the burden of this cancer in Latin

America [17]. Verdecchia et al. [18] evaluated the

gastric cancer survival in population-based registries

in four continents, including Campinas, Brazil, and

concluded that the large differences observed among

the four areas were almost totally explained by

differences in age, gender, period and stage, rather

than by differences in patient management. The high

incidence of squamous oesophageal cancers in

Southern (but not Central) America has been

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207196

Fig. 2. Age-standardized cancer incidence and mortality, per 100,000 in men (left panel) and women (right panel), in North (upper panels),

Central (middle panels) and South Americas (lower panels); from [10].

documented in several studies [19,20]. According to

Parkin et al. [3], the highest incidences in Latin

America are: Argentina-Concordia (ASR of 13.9/

100,000 men and 3.1/100,000 women), Brazil-

Goiania (ASR of 10.8/100,000 men and 3.0/100,000

women) and Uruguay (ASR of 10.7/100,000 men and

2.5/100,000 women). As in other areas of the world,

the geographic distribution of oesophageal squamous

cell cancers is extremely heterogenous, with high- and

low-incidence areas throughout the continent. Main

suspected risk factors include consumption of hot

beverages (such as mate) as well as food habits such as

charcoal grilled meat (‘‘churrasco’’). In addition to

these specific factors, tobacco smoking together with

alcohol drinking plays a major role, as observed in

many western countries [21–24].

In women, the burden of cervical cancer is

particularly high, as observed in countries such as

Bolivia and Nicaragua, where incidences are among

the highest registered anywhere (respectively, 58.1

and 61.1/100,00/year). These high incidence rates are

the consequence of the huge public health impact of

human papillomavirus (HPV) infections and other risk

factors and of the limited coverage of the women

population by cytology screening [25–29]. A recent

study conducted in the city of Sao Paulo, Brazil

showed a slight reduction in cervical cancer mortality

rates that may point to an increase in the coverage of

this cancer screening using the Pap smear [30].

In contrast, the patterns of incidence of breast

cancer are indicative of an association with indus-

trialization and adoption of a ‘‘Westernized’’ lifestyle.

In Latin America, incidence rates for breast cancer

have been consistently increasing for the past 40 years

[31], and the highest incidences are detected in areas

such as Uruguay, Argentina-Bahıa Blanca and

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 197

Argentina-Concordia, with ASR of 114.9, 86.1 and

55.1 per 100,000 women, respectively [3]. In Brazil,

the highest incidence rates are observed in Brasilia and

Sao Paulo [13]. In USA, Hispanic women with breast

cancer, especially first-generation, have tumor char-

acteristics associated to delayed detection in the

timeliness of their cancer diagnosis, such as a higher

percentage of tumors larger than one centimeter [32].

In addition to the above-discussed situations, we

should take into account that in some regions, as for

example, the Northeastern of Brazil, cancer registration

is nonexistent or incomplete due to many structural

problems, thus introducing over- or underestimations of

cancer rates in different regions. The differences in

cancer registries may be important even within Latin

American countries. However, these trends in cancer

incidence and mortality show the relevance of the

disease and the importance of increasing cancer

epidemiological studies that are essential in develop-

ment of health policies and public health programs.

3. TP53 mutations as markers in molecular

epidemiology

Molecular epidemiology utilizes molecular bio-

markers as intermediate end-points to solve epide-

miological questions. The added value of this

approach is that the results provide direct insights

into mechanisms of disease development and can

often be translated into therapeutic or public health

decisions. It is clearly observed in cancer [33,34]. In

this respect, accumulating evidence demonstrate that

TP53 mutations can be biomarkers of carcinogen

effect and cancer development, providing clues to both

natural history and clinical evaluation of cancer.

3.1. p53 Structure and functions

The TP53 tumor suppressor gene is a key gene in

carcinogenesis and impairment of the p53 protein

functions seems to be central in the multistep

development of cancer [5]. The human TP53 gene

is located on chromosome 17p13.1, spanning 20 kb. It

contains 11 exons, the first one being non-coding. This

gene belongs to a family of highly conserved genes

that contains at least two other members, P63 and

TP73 [35–37].

The TP53 gene product is a protein of 393 residues

with a structural organization typical of transcription

factors: it presents (1) an acidic N-terminal domain

containing a transcription activation domain (residues

1–44), and a proline-rich regulatory domain (residues

62–94), (2) a central sequence-specific well-conserved

DNA-binding domain (residues 110–292), (3) an

oligomerization domain (residues 325–363) (4) a C-

terminal domain that contains multiple regulatory

signals (residues 363–393) [38].

The recently described proteins p63 and p73 have

similar structural organization, their DNA-binding

domain presenting the highest similarity with p53

[38]. Although the three proteins regulate similar

groups of genes, p53 has a unique role in tumor

suppression, as illustrated by knock-out mice models

which are developmentally normal but show multiple

tumors at an early age [39]. In contrast, p63 or p73-

deficient mice show developmental defects but no

increase in tumor incidence.

The unique role of p53 in tumor suppression is

explained by its key role in cellular response to various

forms of stress. The p53 protein is expressed in almost

all tissues as a constitutively repressed protein. The

main mechanism of repression is protein-protein

interaction with the product of the oncogene

MDM2, which targets p53 protein to proteasome

degradation. Several classes of signals can lead to the

de-repression of p53 and to its accumulation by post-

translational modifications. These signals include

DNA-damaging agents (genotoxic stress), constitutive

activation of growth signaling cascades (oncogenic

stress), as well as other types of stress such as

depletion in ribonucleotides or hypoxia [40]. Thus,

p53 lies at the point of convergence of several, distinct

stress–response pathways [41]. Fig. 3 shows an overall

outline of the biological functions of p53. Activation

of p53 is induced in response to signals generated by

kinases such as ATM, ATR, Chk2 or JNK that

recognize and transduce DNA-damage as well as other

stress signals. Once activated, p53 regulates the

expression of several classes of genes, either through

sequence-specific DNA-binding or through protein-

protein interactions. P53-regulated genes (activated or

repressed) include genes involved in cell-cycle arrest

(P21WAF1, GADD45), apoptosis (PUMA, BAX,

FAS/CD95), DNA repair (Pol B, O6MGMT, MSH2)

and angiogenesis (TSP1). Their coordinated regula-

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207198

Fig. 3. Schematic view of main signaling pathways regulated by p53, showing selected transactivated target genes.

tion by p53 results in anti-proliferative effects,

allowing the preservation of genomic integrity [42].

3.2. Mutations in cancer: mutagenesis versus

selection

TP53 alterations in human cancers include loss of

alleles, gene mutations (mostly missense) and

inactivation of the protein by sequestration by viral

or cellular proteins. The most frequent alterations are

mutations in the coding sequence which are found in

almost every kind of human cancer. A database of

mutations reported in human cancer is maintained at

the International Agency for Research on Cancer

(http://www-p53.iarc.fr). The overall mutation fre-

quencies range from 5 to 50% depending on the tumor

type and stage. Malignancies with high mutation

frequencies (40–55%) include ovarian, esophageal,

colorectal, head and neck and lung cancers. Tumors of

the brain, breast, stomach and liver show an

intermediate mutation frequency (20–35%). Malig-

nancies with low mutation frequency include leuke-

mia, sarcoma, testicular cancer, malignant melanoma

and cervical cancer. In the latter cancers, p53 is

thought to be inactivated by alternative mechanisms,

such as HPV protein E6 that eliminates p53 by rapid

degradation.

TP53 mutations cluster within the DNA-binding

domain of the protein, between exons 5 and 8 [38].

Although most studies have screened only exons 5–8

after the observation that mutations clustered in this

region, subsequent studies that have analyzed the

entire coding sequence have shown that 80% of all

mutations are located between exons 5 and 8. About

30% of these mutations fall at five ‘‘hotspot’’ codons

(175, 245, 248, 273, 282) and have been found in

almost every type of cancer. The other 70% of the

mutations are distributed over more than 200 codons.

The nature, position, and relative prevalence of

mutations vary among cancer types and population

groups [38]. Two main factors contribute to the

shaping of a tumor-specific ‘‘mutation pattern’’. The

first is mutagenesis: the type of damage caused by a

mutagen can be specific in its nature and DNA

sequence context, and the rate of mutation formation is

limited by the cell’s capacity to repair DNA lesions.

Specific mutation patterns have been observed in

studies on populations exposed to high levels of

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 199

mutagens. Well-documented examples include hepa-

tocellular carcinoma in individuals chronically

infected by HBV and exposed to dietary aflatoxins,

lung cancers in smokers and non-melanoma skin

cancers in individuals exposed to solar UV. In several

other cancers, such as bladder and oesophageal

carcinomas, specific mutation profiles have been

observed, but the mutagens have not been clearly

identified. For the most frequent types of TP53

mutations, namely transitions (purine to purine or

pyrimidine to pyrimidine) at cytosines within CpG

sites, it is considered that spontaneous deamination of

methylated cytosine, leading to a substitution to

thymine is the main mechanism involved. This process

is greatly enhanced by oxyradicals, in particular nitric

oxide (NO), which is generated endogenously during

conditions such as inflammation or bacterial infection

[43,44]. In colon cancer, NO production has been

correlated with the presence of transition mutations at

CpG sites in TP53 [45]. Overall, looking at specific

TP53 mutation patterns may thus help to generate

hypotheses on the mutagenic processes involved.

The second is biological selection: only mutants

that have significant changes in their functional

properties will induce a proliferative advantage and

contribute to cancer. The fact that TP53 mutations

cluster in the central DNA-binding domain indicates

that transcriptional activation through specific

response elements is the essential biological mechan-

ism for tumor suppression [46–48]. However, TP53

mutations may result in the over-expression of the

mutant protein, which is retained throughout cancer

progression. Even in distant metastasis that mutant

protein may exert some pro-oncogenic effects. These

effects may vary from one tissue to another, resulting

in the selection of different mutants.

A list of mutants with their biological activities,

tested in human cells or yeast assays, and reported in

the literature is available on the IARC TP53 website

(TP53 function database at http://www-p53.iarc.fr).

3.3. TP53 germline mutations and polymorphisms

Inherited TP53 mutations are associated with a rare

autosomal dominant disorder, the Li–Fraumeni syn-

drome (LFS). LFS is clinically defined by a familial

clustering of tumors diagnosed before 45 years of age,

mostly sarcomas, breast, brain and adrenocortical

cancers [49]. About 70% of LFS families have been

shown to carry a mutant TP53 allele [50,51]. LFS

patients are heterozygous for TP53 mutation, but

cancer cells developing in these patients loose the

wild-type allele. The penetrance of the mutant allele is

close to 100%, suggesting a causal link between the

constitutive mutation and the subsequent somatic

inactivation of the wild-type allele. This hypothesis is

consistent with the fact that normal cells from

individuals with germline TP53 mutations show

altered genomic stability [52]. In TP53 mutation

carriers, 80% of the tumors are sarcomas, breast

cancer, brain tumors and adrenocortical carcinomas,

breast cancers and sarcomas representing 50% of all

tumors [53].

Several TP53 polymorphisms have been identified

in human populations, most of them being localised in

introns, outside consensus splicing sites (list available

at http://www-p53.iarc.fr/Polymorphism.html). Only

two polymorphisms, serine to proline at residue 47 and

arginine to proline at residue 72, alter the amino acid

sequence of p53. The Pro47 variant is a rare

polymorphism affecting a codon well conserved in

evolution [54]. For residue 72, sharp ethnic differences

of allele frequencies have been observed [55].

Numerous studies have investigated the associations

of codon 72 polymorphism with increased risk for

different cancers related or not to HPV, but the

associations that have been found in some studies have

always been challenged by subsequent studies [56,57].

Recently, Langerod et al. [58] observed that in breast

tumors the presence of TP53 mutation was signifi-

cantly more often found on the Arg72 allele than the

Pro72 allele, suggesting a role of the Arg72 allele in

the mechanism of breast cancer development. So far,

evidence that TP53 polymorphisms may have a role in

cancer susceptibility remains to be established.

4. TP53 mutation analysis in Latin America

4.1. Somatic mutations

The list of all studies that have been published so

far on TP53 somatic mutations in Latin America is

presented in Table 1. This list shows that only 20

studies have been published and they come mainly

from Brazil (12/20 studies) (Table 1). Moreover, most

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Table 1

List of studies on TP53 mutation in samples from Latin America

Tumor site Country Reference Year Method Region analysed Mutation frequency

Bladder Argentina/Chile [67] 2003 Dir.Seq. Exons 5–8 35.7% (45/126)

Bone Brazil [84] 2001 SSCP Exons 5–8 na (1/1)

Brain Brazil [85] 1997 Dir. Seq. Exons 5–8 na (1/1)

Breast Brazil [59] 2002 SSCP Exons 5–8 20% (24/120)

Breast Brazil [60] 2003 SSCP Exons 4–9 17% (50/294)

Cervix Uteri Brazil [86] 2001 SSCP Exons 5–8 3.2% (4/122)

Colorectum Brazil [87] 1996 SSCP Exons 5–8 38.5% (15/39)

Colorectum Chile [88] 2000 Dir. Seq. Exons 5–9 60% (21/35)

Esophagus Brazil [89] 2000 Dir. Seq. Exons 5–8 na (2/2)

Esophagus Brazil [90] 2002 SSCP Exons 5–9 34.8% (47/135)

Esophagus Uruguay [91] 1991 Dir. Seq. Exons 5–8 44.1% (6/19)

Gallbladder Chile [92] 1998 Dir. Seq. Exons 5–8 52.4% (22/42)

Gallbladder Chile [93] 2000 Dir. Seq. Exons 5–8 52% (13/25)

Head& Neck Brazil [94] 1998 SSCP Exons 5–8 53.3% (48/90)

Hematol Argentina/ Brazil/ Chile [95] 1992 SSCP Exons 5–8 40.7% (11/27)

Hematol Brazil [96] 2003 SSCP Exons 5–9 22.5% (11/49)

Liver Mexico [97] 1996 Dir. Seq. Exon 7 18.7% (3/16)

Naso-pharynx Mexico [98] 2001 DHPLC Exons 5–8 23.8% (5/21)

Penis Brazil [99] 1998 SSCP Exons 5–8 28.6% (6/21)

Stomach Brazil [100] 1996 Dir. Seq. Exons 5–8 32.1% (9/28)

studies are small, with only 6 studies having analyzed

more than 50 samples. The largest studies are on breast

(total of 414 samples), oesophagus (total of 156

samples), bladder (total of 126 samples), cervix (total

of 122 samples), head and neck (total of 90 samples)

and colorectum (total of 74 samples). Only one study

has been reported for stomach cancer, which is the

fourth most frequent cancer in Latin America, and no

study has been found on lung and prostate cancers,

which are among the most frequent cancers. In

Uruguay, where the overall incidence of cancer is the

highest in Latin America, there is only one small study

on cancer of the oesophagus. It is also of note that most

studies performed in Latin America are recent (after

1998), compared to studies from the US or Europe,

which started in the early 1990s. Although the number

of studies seems to increase, 55% were done since

2000, the overall coverage of TP53 mutation in Latin

America is thus very sparse.

In these studies, TP53 mutations have been screened

by SSCP or direct sequencing and have mainly

analyzed exons 5–8. Mutation frequencies are similar

to frequencies reported worldwide (see IARC TP53

database at http://www-p53.iarc.fr), except for hema-

tological cancers which show a higher frequency of

mutation (22–40% versus 10% in IARC TP53

database).

The detailed mutation data of studies listed in

Table 1 are available through the IARC TP53 database

(http://www-p53.iarc.fr). Below, we analyze the

mutation patterns of cancers for which the largest

data sets are available. Almost all samples from Latin

America have been screened from exons 5–8 and

because the type of mutations in these exons differ

significantly from the type of mutation outside these

exons, we only analyzed mutations located in exons 5–

8. TP53 mutations in cancer from Japan, Europe, and

Northern America were used as comparison groups.

4.2. Breast cancer

Two studies are available on breast cancer, both

from Brazil: Rio de Janeiro [59] and Sao Paulo [60].

The overall pattern of mutations reported in the studies

from Brazil showed a higher proportion of insertions/

del and G:C > T:A transversions than any other area

(Fig. 4). In contrast, the proportion of G:C > A:T

transitions at non-CpG was lower than in other areas.

In Japan and Northern America, insertions and

deletions have been reported to be more common in

elderly women. In contrast, G:C > T:A transversions

were more common among younger women in

Europe. While the significance of these trends remains

to be determined, it is possible that they may

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 201

Fig. 4. Proportion of specific types of TP53 mutations in breast cancers from Latin America (LA); Japan; Europe (EU) and North America (NA).

Mutation data were selected from the R8 release of the IARC TP53 database (June 2003). The total number of mutations in primary tumors are 63

for LA, 154 for Japan, 810 for EU and 516 for NA.

Fig. 5. Proportion of specific types of TP53 mutations in esophageal

esquamous cell carcinoma from Latin America (LA), and high

incidence areas in China and Europe (EU). Mutation data from

LA were selected from the R8 release of the IARC TP53 database

(June 2003). Figures for China and EU were taken from [84]. The

total number of mutations in primary tumors are 54 for LA, 314 for

China and 144 for EU.

correspond to differences in mutagenic processes that

remain to be identified.

4.3. Colon cancer

Two studies have reported TP53 mutations in

cancer of the colon and rectum, one from Brazil and

one from Chile (Table 1). The pattern of mutations

reported for these two studies differ significantly from

the pattern in other areas (not shown, p < 0.001).

However, the difference is exclusively due to the

Chilian study which reports a very unusual spectrum

of mutation, while the data on the Brazilain patients

are similar to those of the comparison groups. Most

studies on cancer of colon and rectum report a high

frequency of G:C > A:T transitions at CpG sites (45–

50%) and low levels of deletions or mutations on A:T

bases. This is the case for the Brazilian cohort, but in

the Chilian series, there are only 20% G:C > A:T

transitions at CpG sites, whereas deletions and

mutations on A:T bases are over-represented (16%

versus 8% and 26% versus 14%, respectively). The

reasons for this unusual pattern of mutation are thus

unknown and would need further investigation. In

particular, there is no evidence that patients had a

history of past exposure to well-defined risk factors.

4.4. Oesophageal cancer

The three studies on oesophageal cancer in LA

have analysed squamous cell carcinoma (SCC) cases

from high incidence areas in Southern Brazil and

Uruguay (Table 1). Striking geographic variations in

incidence rates, TP53 mutation prevalence and

proportion of certain TP53 mutation types have been

reported for SCC [61–64]. In Europe, high prevalence

of mutations on A:T bases have been linked to

exposure to metabolites of alcohol, and in high

incidence areas of China, a high prevalence of

transition mutations at G:C has been tentatively

correlated with various dietary habits including

exposure to nitrosamines and consumption of scalding

hot tea. In most cancers of the upper-aerodigestive

tract, transversions at G:C base pairs have been

interpreted as possible ‘‘signatures’’ of tobacco

carcinogens. Fig. 5 compares the proportion of these

various types of mutations in the three studies from

LA with those observed in high incidence areas of

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207202

Western Europe and central China. The pattern of

mutations in SCC from LA tends to be more similar to

the one observed in China than in Europe. This

similarity may underline the role of comparable risk

factors between the two areas, including in particular

thermal injury inflicted by hot beverages. Interest-

ingly, the proportion of A:T mutations in LA is

intermediate between China and Europe, suggesting a

possible contributioin of alcohol to TP53 mutagenesis

in SCC from LA. Further analysis on cohorts of

patients with very well defined data on individual

exposure should help to better identify the causes of

these mutations.

4.5. Head and neck cancer

One study has been performed on head and neck

squamous cell carcinoma (HNSCC) from Brazil

(Table 1). The pattern of mutation described is

characterized by a high frequency of insertions/

deletions and G:C > A:T transitions (not shown),

which is similar to the pattern observed in other

countries. It has been previously reported that

deletions and insertions leading to frameshift muta-

tions were more frequent in a sub-group of patients

exposed to both alcohol and tobacco, the two major

risk factors for HNSCC [65,66]. It is thus possible that

the combined effect of tobacco and alcohol favor the

formation of frameshift mutations. However, no

experimental evidence supports these observations.

4.6. Bladder cancer

The LA study on bladder cancer has been

conducted on individuals exposed to tobacco and

arsenic [67]. Tobacco smoking, occupational exposure

to chemical dyes and inflammatory reactions to

parasitic or other infections account for the majority

of the bladder cancer cases in the world and specific

TP53 mutation patterns have been linked to these

exposures. G:C > A:T transitions at non-CpG sites are

over-represented in patients exposed to tobacco and/or

aromatic amines. These mutations cluster between

codons 271 and 285 and in particular at codons 280

and 285 (4.3 and 4.9% of all mutations, respectively)

which are in the same DNA sequence context (AGAG

for codon 280 and AGAG for codon 285). It has been

suggested that this sequence may represent a

preferential target for specific carcinogens, such as

aromatic amines [68]. In contrast, bladder tumors

from regions of endemic parasitic infections show a

high prevalence of G:C > A:T transitions at CpG sites

[69], which is suspected to be an effect of nitric oxide

(a common mediator of inflammation) on the rate of

deamination of 5-methylcytosine. For arsenic expo-

sure, no study is available in the IARC TP53 database

on arsenic-exposed bladder cancer patients, but a case-

control study of bladder cancer and drinking water

arsenic performed in Western United States has found

an increased risk of bladder cancer for smokers who

ingest arsenic [70].

Authors from the Latin American study did not find

any association between arsenic exposure and specific

types of mutations, but found an increase in

G:C > A:T transitions at CpG sites in smokers with

>20 pack year of exposure and a significant

association between a hotspot codon at position 273

and tobacco consumption. Five mutations were found

at codons 280/285. Because of the epidemiological

evidence linking arsenic and tobacco in the risk of

developing bladder cancer, it would be interesting to

further investigate if this unusual spectrum of

mutation could be due to the combined effect of

arsenic and tobacco.

4.7. Germline TP53 mutations

The only report of germline TP53 mutation in Latin

America represents a very special situation where one

specific mutation has been described in several

unrelated children from Southern Brazil who were

affected by childhood adrenocortical carcinoma.

Interestingly, the mutation was described in 35 of

the 36 analyzed cases and the patients were not

related, as shown by intragenic polymorphic markers,

ruling out a possible founder effect [71]. This situation

is the only example of a TP53 mutation that would

lead exclusively to one type of cancer. This mutation is

a missense mutation at codon 337 (R337H) located in

the oligomerisation domain of the protein. Functional

analysis has shown that this mutant protein is pH-

sensitive, i.e. inactive (mutant-like) at pH >7.7 and

active (wild-type-like) at pH <7.7 [72]. The protein

may thus adopt a mutant phenotype only under

particular physiological conditions leading to a rise in

intracellular pH. Although this effect does provide a

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207 203

clear explanation for the tissue-specificity of the

R337H mutant, this example illustrates the fact that

mutant p53 protein function may depend on the

cellular context. The reason why such a particular,

familial mutation has not been found in other parts of

the world deserves further attention.

4.8. TP53 polymorphisms

Over 14 different polymorphisms have been

described in TP53 (http://www-p53.iarc.fr/Polymor-

phism.html). The most studied is the Arg/Pro

polymorphism in codon 72, which impact on the

coding sequence and may be associated with cancer

risk. Eight studies have addressed this issue in Latin

America: one in Argentina [73], one in Peru [74], one

in Mexico [75] and five in Brazil [76–80]. All studies

were done using PCR-based techniques and the Arg72

allele was described to be the most common in all

populations except in the study from Peru, where the

Pro72 allele was more frequent. Six studies analysed

the association between codon 72 genotypes and

papillomavirus-induced cervical cancer [73,75] and

none of them supported the existence of an association

with a risk of HPV-induced cancer. Three studies, all

from Brazil, address the possible association between

codon 72 polymorphism and risk of skin-cancer [78],

oral squamous cell carcinoma [79] and thyroid cancer

[80]. Studies have also been conducted to compare the

frequency of three distinct polymorphisms (BstUI and

MspI RFLPs in exon 4 and intron 6, respectively, and a

16 bp duplication in intron 3) in 114 Amerindians

from different Brazilian Indian Tribes, 95 Euro-

Brazilians and 70 Afro-Brazilians [81]. This analysis

helped to identify populations of the same ethnic

group. In one tribe, the Wai–Wai people, a rare

haplotype was found which was only described in a

Chinese study. TP53 polymorphisms are, therefore,

interesting markers to understand population distribu-

tion in Latin America.

5. Perspectives: design of studies on TP53mutations in LA

Studying cancer aetiology and implementing

prevention measures are complex challenges in Latin

American countries due to the inherent genetic

complexity of the populations, the wide socio-

economic discrepancies and, the rapidly changing

trends in lifestyles throughout the continent, illu-

strated by the development of huge urbanized areas.

Within this complex pattern, genetics can provide a

useful tool to compare populations and assess gene-

environment interactions that underlie cancer devel-

opment. Analysis of TP53 mutations in normal and

cancer tissues represents an affordable, easy to

manage approach to gather important information

on cancer aetiology. Formation of mutations in TP53

is the consequence of a succession of processes

involving DNA damage, DNA repair and biological

selection of mutants that confer a selective growth

advantage. All these processes are, to some extent,

dependent upon genetic susceptibility, nature of DNA

damaging agents, local DNA sequence context and

impact of the mutation upon protein structure and

function. Thus, the pattern of TP53 mutation may

show wide differences, not only among pathologies,

but also among groups of subjects, depending upon

their genetic background, environmental exposures, or

socio-economic status. Therefore, it would be of great

interest to develop systematic collections of tumor

specimens (surgical specimens or biopsies) in studies

comparing the position and type of TP53 mutations in

patients positive- or negative for a specific risk factor.

This case–case design would be more appropriate than

most current studies that are based on the evaluation of

mutation patterns in consecutive, unselected groups of

patients. An example of the power of this approach is

given in the recent study by Dai et al. [82], who have

shown significant differences in the prevalence and

pattern of TP53 mutations in matched, human

papilloma virus 16 positive and negative patients

with oral squamous cancer. We would like to advocate

that close interactions between epidemiologists,

pathologists and molecular biologists in the develop-

ment of such studies might result in rapid and

important advances in understanding the aetiology of

common cancers in Latin America. The information

from TP53 mutation pattern can be of particular

interest in the context of studies addressing the

statistical significance of polymorphisms in cancer

susceptibility genes. Recent studies have shown that

such polymorphism may influence not only the

prevalence but also the type of mutations, in relation

with susceptibility to specific DNA-damaging agents.

C.V. de Moura Gallo et al. / Mutation Research 589 (2005) 192–207204

For example, a polymorphism at codon 399 in the

DNA excision-repair enzyme XRCC1 is associated

with higher frequency of adenine to guanine TP53

mutations in lung cancers of smokers, suggesting a

role of this gene in the repair of cigarette smoking-

induced DNA damage [83]. By means of a carefully

matched study design, it may be possible to rule out

the role of a number of confounding factors and to

obtain significant results rapidly that would impact on

the development of focused and appropriate preven-

tion strategies.

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