Single nucleotide polymorphisms of the FTO gene and cancer risk:an overview

Marta Elena Hernandez-Caballero •

Jose Alfredo Sierra-Ramırez

Received: 13 November 2013 / Accepted: 5 November 2014

� Springer Science+Business Media Dordrecht 2014

Abstract The FTO (fat mass and obesity-associated)

gene has a strong linkage disequilibrium block, within

which SNPs have been identified that are involved in the

development of obesity. Recently some of these variants

have also been associated with cancer. However, identifi-

cation of the possible mechanisms that could explain these

associations has proven to be elusive. It has been found that

FTO polymorphisms can regulate the expression of genes

at large kilobases of distance as well as the expression of

the FTO gene itself, and regions for transcription factor

binding. To date it has been observed that variants

rs9939609, rs17817449, rs8050136, rs1477196, rs6499640,

rs16953002, rs11075995 and rs1121980 are associated

with the risk of developing cancer. Some studies have

produced negative results when comparing the same

polymorphisms, but make a simple association between

polymorphic variants and cancer, have proved difficult

because this relation is by nature multifactorial. A certain

degree of variation resulting from the improper design of

studies or processing of data can lead to erroneous con-

clusions. However, it is now unquestionable that certain

FTO polymorphisms regulate genetic expression related to

cancer susceptibility, although this field is just beginning to

be understood.

Keywords SNP � FTO � Cancer risk factors � Obesity

Introduction

The use of new technology has revolutionized the way of

finding genetic disorders. For example, thanks to genome

wide association studies (GWAS) it has been established

that there is an association of more than 150 loci with

increased susceptibility to cancer [1] and of other loci with

susceptibility to obesity. It is now known that the FTO

gene, originally identified as a susceptibility gene for type

2 diabetes, has multiple single nucleotide polymorphisms

(SNPs) present in intron 1 that are associated with obesity

in a robust manner. The association of SNPs to cancer has

been both positive and negative, possibly because cancer is

a complex multifactorial entity. Interestingly, SNPs

involved in carcinogenesis are commonly located outside

of the protein-coding sequences that are known to affect

the direct regulation of gene expression. However, it is

likely that this regulation is combined with nutritional and

environmental factors to trigger cancer development. In

this review, we described recent insights into the associa-

tion of FTO SNPs with various types of cancer.

Obesity and cancer

There has been a very notable change in lifestyle in

developed as well as developing countries in the last

20 years. The tendency in both cases is to excessive con-

sumption of high-calorie foods together with increasing

sedentariness, which has led to a three-fold increase in the

prevalence of overweight and obesity [2, 3].

Obesity is a polygenic disease influenced by inherited

and environmental factors. This condition tends to trigger

different types of diseases, such as metabolic syndrome,

fatty liver, heart disease and bone problems. Of particular

M. E. Hernandez-Caballero (&)

Facultad de Medicina, Benemerita Universidad Autonoma de

Puebla, C.P. 72420 Puebla, Mexico

e-mail: ehdezc@yahoo.com

J. A. Sierra-Ramırez

Seccion de Estudios de Posgrado e Investigacion, Escuela

Superior de Medicina, Instituto Politecnico Nacional,

C.P. 11340 Mexico, Mexico

123

Mol Biol Rep

DOI 10.1007/s11033-014-3817-y

interest in the present review is its role in increasing the

risk of developing certain cancers. It has been shown that

the risk of cancer is 50 % higher in obese women than

those with normal weight [4] and is age-dependent [5]. Of

all cancer deaths in the U.S. in 2003, 14 % in men and

20 % in women were attributable to overweight and

obesity, especially colon, rectum, esophagus, kidney,

pancreas, gallbladder, ovary, endometrium, liver, prostate

and hematological malignancies [6]. There are various

mechanisms that may explain the association between

obesity and increased cancer risk. Obesity is associated

with insulin resistance and the hyperinsulinemia compen-

satory increase in the production of growth factors, which

in turn stimulates mitogenesis and consequently carcino-

genesis [7], multiple signaling pathways, oxidative stress

and inflammatory processes.

For example, it has been suggested that obesity is clo-

sely associated with breast cancer, which is now the disease

with the highest mortality rate among women worldwide.

Among postmenopausal women obesity is considered a

risk factor in up to 30–50 % of the cases of this type of

cancer [8, 9]. Several epidemiological studies linking

weight and cancer have shown that obesity correlates with

poor prognosis, greater tumor size, faster metastasis to the

lymph nodes, and high tumor grade [4]. Although obesity

promotes hormone-dependent tumors, it does not affect

local levels of estrogen in postmenopausal breast tissue.

Recently it was shown that, regardless of the BMI, there is

a decreased risk of breast cancer in postmenopausal women

receiving estrogen orally [10].

Biology of FTO polymorphisms

Through a GWAS in 2007 it was discovered that there are

obesity susceptibility loci [11]. The genes present in these

sites may be of two types: those that affect the function of

the central nervous system and those acting at a peripheral

level through adipose tissue [12].

Among the genes present in obesity susceptibility loci is

the fat mass and obesity-associated (FTO) gene. This gene,

located in chromosome 16q12.2, encodes for a 2-oxoglu-

tarate (2-OG) Fe2?-dependent dioxygenase, which also acts

as a DNA-demethylase. FTO has a *40-kb linkage dis-

equilibrium (LD) block in intron 1, which has been conclu-

sively associated with an increased risk of obesity in people

with European ancestry [13, 14]. The FTO protein is

expressed in many tissues: mesenteric fat, adipose, pancre-

atic, liver, and especially hypothalamus. It contributes to the

regulation of the global metabolic rate, energy expenditure,

energy homeostasis [15], body size and body fat accumula-

tion. Mutations in FTO that lead to a loss of function cause

severe growth retardation, leanness, increased metabolic rate

and hyperphagia. The loss of a functional copy can be

compatible with being lean or obese [16, 17].

FTO has SNPs in non-coding regions, which like those

present in coding regions can affect RNA processing,

interrupt the start and end of transcription, and alter the

stability and translation impact on promoter sequences,

enhancers and silencers. An SNP in the transcription factor

binding site may increase or decrease the binding of tran-

scription factors, leading to allele specific gene expression

[18].

The first attempt to elucidate the function of FTO SNPs

was reported by Stratigopoulous et al. [15]. They found

that rs8050136 is in a regulatory region that is a cut-like

homeobox 1(CUTL1) binding site and that rs8050136A,

associated with lower body mass, preferentially binds to

CUTL1 in human fibroblast DNA. Silencing of the tran-

scriptional factor CUTL1 caused decreased FTO expres-

sion in fibroblasts. A couple of years later, Jowett et al. [19]

showed that rs8050136 does not influence FTO expression

but instead expression of retinoblastoma-like 2 (RBL2)

gene *270 kb proximal to FTO. Moreover, given the

finding of this research group of a strong correlation of

allele rs8050136A and RBL2 expression levels, there is a

potential role for RBL2 in the mediation of biological

consequences of this genetic variant. Later, Berulava and

Horsthemke [20] analyzed allelic transcript levels of RBL2

in individuals heterozygous and homozygous for

rs8050136, but did not find any influence from variants at

FTO on RBL2 gene expression. In another study they

demonstrated that FTO SNPs affect the expression of the

gene itself. In a study of skin fibroblasts and peripheral

blood, they analyzed the expression level of risk allele A of

SNP rs9939609 and non-risk allele T. The results show that

the presence of the risk allele is associated with increased

levels of the FTO transcript, suggesting that in intron 1

there may be a cis-regulatory site that regulates FTO [21].

Recently Smemo et al. [22] published evidence that sup-

ports previous studies. They found that intron 1 of FTO

interacts with the promoter sequence of the iroquois

homeobox 3 (IRX3) gene (located 500 kb away) and could

regulate its expression when certain variants are present

within FTO. Hence, it is clear that FTO SNPs have the

ability to alter the binding site for transcriptional factors

and regulate gene expression.

FTO polymorphisms and cancer

Two years after the first publications showing an associa-

tion between variants in the FTO gene and obesity-related

traits, researchers began to explore the possible association

between these variants and cancer risk in obese people of

various ethnic groups. Brennan et al. [23] attempted to

Mol Biol Rep

123

minimize the bias generated by linking overweight and

cancer that result from weight changes during a lifetime

and age-related incidence of disease. They used genetic

variant SNP rs9939609 FTO in a study of 7,000 people

from Central and Eastern Europe, finding that variant A

was associated with a lower risk of lung cancer and a

minimal increase in risk for kidney cancer. Furthermore,

Lewis et al. [24] suggested that the rs9939609A allele is a

protective factor against the risk of prostate cancer, reduces

the likelihood of low-grade cancer, and may increase the

probability of high grade cancer, but statistical significance

for this study is very weak.

Subsequently, the search for an association between

FTO variants and other cancers intensified. Nock et al. [25]

analyzed a Caucasian and an African-American population

and found that in the Caucasian population strong LD

variants were associated with increased BMI between the

ages of 30 and 40, but were unrelated to colorectal ade-

noma. Among the African Americans in the study, there

was an association between colorectal adenoma and the

presence of one or two copies of the FTO SNPs

rs8050136A and rs17817449G. The presence of two copies

of these variants was associated with BMI. However, an

analysis of FTO variants rs17817449 and rs9939609 in

Slavs, Italians, African Americans, Japanese Americans,

Latinos, Native Hawaiians and Whites in three other

studies failed to find any association between these variants

and colorectal cancer or colorectal adenoma [26–28].

Tang et al. [29] proposed that there is a relationship

between the risk of pancreatic cancer and polymorphic

variants of FTO in obesity and diabetes. Analyzing a

majority non-Hispanic white population, they associated

rs9939609A and rs8050136A variants with a reduced risk

of pancreatic cancer in people with normal BMI (less than

25 kg/m2, P = 0.001) and an increased risk in patients

with a higher than normal BMI (C25 kg/m2, P = 0.0015),

which suggests that BMI is a determining factor. A month

later Pierce et al. [30] showed a significant association

(OR = 1.12, CI: 1.02–1.23, P = 0.02) between the

rs8050136A variant and pancreatic cancer based on a case

study in European populations. However, they concluded

that it is necessary to examine a broader sample to give

greater power to their discovery.

Interestingly, a meta-analysis performed by Li et al. [31]

involving studies of different cancer types and FTO poly-

morphism associations gave no positive results, except for

pancreatic cancer based on the results of Tang et al. and

Pierce et al. When polymorphisms were analyzed in a

Japanese population, Lin et al. [32] found a 1.5-fold greater

risk of pancreatic cancer with the TT genotype than with the

rs9939609TA genotype. In addition, with rs9939609AA

and a history of diabetes there was a significantly elevated

risk, but the association with BMI was not statistically

significant (in contrast with findings in Western countries).

Hence, the association between developing of cancer and

being overweight and/or having certain FTO polymor-

phisms appears to be closely related to ethnicity.

Observational epidemiological studies have established

a link between thyroid cancer risk and obesity. However,

attempts to unravel the biological mechanisms by which

this link is established have not produced any clear results.

Kitahara et al. [33] analyzed 575 tag SNPs in 23 obesity-

related gene regions in a case–control study and found no

association between obesity-related FTO genetic poly-

morphisms and the risk of papillary thyroid cancer.

Regarding an association of FTO variants with endo-

metrial and breast cancer, Delahanty et al. [34] studied

seven loci that included FTO SNPs. Trying to establish a

relationship between obesity and endometrial cancer risk in

Chinese women, they found that FTO SNPs had no asso-

ciation with BMI, but a strong association with endometrial

cancer. This suggests a possible role of FTO in this cancer

through a pathway other than obesity. Lurie et al. [35] had

similar results in a case–control analysis of the variant

rs9939609AA in 3,601 non-Hispanic women. Interestingly,

Gaudet et al. [36] had previously analyzed 189 FTO tag

SNPs in endometrial cancer and found no association in

417 Polish patients.

Due to the alarming increase in the prevalence of

obesity and breast cancer, an association has been sug-

gested between this cancer and poor nutritional status. High

values of BMI and WC are considered risk factors for this

type of cancer [37]. In an attempt to establish a connection

between FTO polymorphic variants and breast cancer,

seven studies have been conducted in different populations.

A positive association was found only in the case of

African American women [38]. Despite the fact that Ka-

klamani et al. [39] reported a significant association

between FTO rs1477196 and breast cancer risk in pre-

dominantly Caucasian patients, Kusinska et al. [40] found

no such relation with the FTO variants rs993909 and

rs9930506 in a sample of 134 Polish women. The same

negative result was obtained by Brooks et al. when they

tried to find a relationship between FTO variants associated

with BMI and the subsequent risk of second primary breast

cancer [41]. This is probably because the mechanisms for

the development of metastasis do not involve the same risk

factors as first tumor emergence.

In a meta-analysis of ER-negative breast cancer, Garcia-

Closas et al. [42] found that FTO variant rs11075995,

which is in an enhancer region of intron 1, appears to be

activated in normal cells and in triple-negative cancer

tumor cells. This variant has been associated with BMI, but

the relation with etiological pathways for ER-negative

breast cancer is unknown. However, when analyzing SNPs

in 67 breast cancer susceptibility loci, Long et al. [38]

Mol Biol Rep

123

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Mol Biol Rep

123

observed an association between FTO and breast cancer

only with ER-positive (OR = 1.32, CI: 1.09–1.60,

P = 0.004) breast cancer, finding no association with the

ER-negative cancer subtype. They attribute the distinct

results of these two studies to the size of the sample, which

was further reduced when stratifying patients by tumor

subtypes.

Finally, in a Brazilian population it was found that when

FTO SNPs rs1121980 and rs9939609 were analyzed in

combination with the presence of SNP rs17782313 in the

melanocortin-4 receptor (MC4R), a 4.9-fold higher risk of

developing breast cancer was observed [43]. Recently, Iles

et al. [44] found that other FTO SNPs present in an intron

(e.g., intron 8) not associated with obesity may be associ-

ated with the risk of developing cancer (Table 1 summa-

rizes all FTO SNPs positively associated with some type of

cancer).

Conclusions

Making a simple association between polymorphic variants

of FTO and cancer has proven difficult; indeed, it seems

that such an association is multifactorial. There have been

failures in study design that make some results of ques-

tionable reliability. One factor is the sample size, which in

some studies is too small to allow for good stratification

and data analysis. For example, the way that variables are

stratified in the comparison of genders may hide differ-

ences between men and women within an ethnic group.

Meta-analyses have important limitations as the heteroge-

neity among studies included and how data are pooled.

Therefore, even if these analyses yield a more accurate

approximation than individual studies, they can produce

biased estimates and thereby erroneous conclusions can

result. Other factor is ethnic background, especially com-

paring populations with great genetic differences such as

people of African and European/Asian ancestry. Another

factor is the genetic origin of tumors compared; for

example in the case of breast cancer studies, in the same

group of study are included spontaneous and hereditary

tumors and the tumor ER status, this last is tightly related

with ethnicity as already demonstrated by the work of

Garcia-Closas et al. and Long. In fact, based on results

obtained from obesity studies, FTO is an important obesity

gene in populations of Caucasian or Asian ancestry, but in

African populations the phenotypic variation is so high that

it made difficult to establish the association of the gene as

an important obesity factor.

The factor history of obesity is important as well, although

excess adiposity may be more related to the promotion of

tumor growth rather than with onset. Although a strong block

of linkage disequilibrium in intron 1 seems to be implicated

in obesity, more research is needed to explore the relation-

ship of this factor with cancer. On the other hand, a new field

of study has opened in regard to FTO SNPs in intron 8 that are

not associated with obesity but could be a risk factor for the

development of cancer. Large-scale fine mapping studies

may be useful for identifying other cancer susceptibility loci

unrelated to obesity, but it is well known how difficult is to do

fine-mapping regions of LD like in FTO gene. In the case of

GWAS finding an association between a susceptibility loci

and cancer, it has been difficult to identify the molecular

mechanism responsible. Just as emerging evidence has

supported an association of FTO and its intronic variants

with obesity, it is likely that FTO polymorphisms have a

pivotal role in cancer as well.

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