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Genetic predisposition to papillary thyroid cancer

Authors:

Abstract

Approximately 5% of differentiated thyroid cancers are hereditary. Hereditary non-medullary thyroid cancer may occur as a minor component of familial cancer syndromes (e.g. familial adenomatous polyposis) or as a primary feature (familial non-medullary thyroid cancer [FNMTC]). Among FNMTC, PTC is the most common. Although a hereditary predisposition to non-medullary thyroid cancer is well established, the susceptibility genes are poorly known. Up to now, by linkage analysis using microsatellite markers, several putative loci have been described - 1q21, 6q22, 8p23.1-p22, and 8q24; however, validation studies have been unsuccessful. In the present review we discuss the results of linkage analysis and the most recent results of genome wide association studies (GWAS) with high resolution SNP (single nucleotide polymorphism) arrays.
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PRACE POGLĄDOWE/REVIEWS
Endokrynologia Polska/Polish Journal of Endocrinology
Tom/Volume 61; Numer/Number 5/2010
ISSN 0423–104X
Dorota Kula M.D., Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Centreand
Institute of Oncology, Gliwice Branch, 44–100 Gliwice, Wybrzeże Armii Krajowej St. 15, tel.: +48 32278 97 20, fax: + 48 32 278 94 57,
e-mail: dkula@io.gliwice.pl
Genetic predisposition to papillary thyroid cancer
Badanie predyspozycji genetycznej do raka brodawkowatego tarczycy
Dorota Kula, Michał Kalemba, Beata Jurecka-Lubieniecka, Zbigniew Puch,
Małgorzata Kowalska, Tomasz Tyszkiewicz, Monika Kowal, Daria Handkiewicz-Junak
Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie Memorial Cancer Centre and Institute
of Oncology, Gliwice Branch
Abstract
Approximately 5% of differentiated thyroid cancers are hereditary. Hereditary non-medullary thyroid cancer may occur as a minor com-
ponent of familial cancer syndromes (e.g. familial adenomatous polyposis) or as a primary feature (familial non-medullary thyroid cancer
[FNMTC]). Among FNMTC, PTC is the most common. Although a hereditary predisposition to non-medullary thyroid cancer is well
established, the susceptibility genes are poorly known. Up to now, by linkage analysis using microsatellite markers, several putative loci
have been described — 1q21, 6q22, 8p23.1-p22, and 8q24; however, validation studies have been unsuccessful. In the present review we
discuss the results of linkage analysis and the most recent results of genome wide association studies (GWAS) with high resolution SNP
(single nucleotide polymorphism) arrays. (Pol J Endocrinol 2010; 61 (5): 486–489)
Key words: papillary thyroid carcinoma, familial non-medullary thyroid cancer, genetic predisposition, SNP
Streszczenie
Około 5% zróżnicowanych raków tarczycy wykazuje predyspozycję dziedziczną. Dziedziczny nierdzeniasty rak tarczycy może występo-
wać jako składowa niektórych dziedzicznych zespołów nowotworowych, na przykład rodzinnej polipowatości jelit oraz jako rodzinny
zróżnicowany rak tarczycy (FNMTC, familial non-medullary thyroid cancer), gdzie najczęściej obserwuje się raka brodawkowatego. Choć
predyspozycja dziedziczna do nierdzeniastych raków tarczycy jest dobrze znana, to jednak geny warunkujące jej występowanie nie
zostały jeszcze poznane. Wykonane jak dotąd badania zidentyfikowały kilka loci — 1q21, 6q22, 8p23.1-p22 oraz 8q24, jednak wyniki te nie
zawsze były jednoznaczne. W niniejszej pracy omówiono rezultaty badań sprzężenia oraz ostatnio uzyskane wyniki badań związku
całego genomu (GWAS, genome wide association study) wykonano przez badania polimorfizmu pojedynczego nukleotydu (SNP, single
nucleotide polymorphism) z wykorzystaniem techniki mikromacierzy wysokiej gęstości. (Endokrynol Pol 2010; 61 (5): 486–489)
Słowa kluczowe: rak brodawkowaty tarczycy, rodzinny zróżnicowany rak tarczycy, predyspozycja genetyczne, SNP
This work was supported by Ministry of Science and Higher Education grant number N N519 579938.
Introduction
Papillary thyroid carcinoma (PTC), follicular thyroid
carcinoma (FTC), poorly differentiated (insular) thyroid
carcinoma (PDTC), and undifferentiated (anaplastic)
thyroid carcinoma are all non-medullary thyroid can-
cer histotypes (NMTC) which originate from thyroid
epithelial cells [1]. Among them, 5% constitute heredi-
tary cases (HNMTC). Very rarely NMTC may occur as
a component of familial cancer syndromes: Cowden’s
disease, familial adenomatous polyposis (FAP), Gard-
ner’s syndrome, Carney’s complex type 1, Werner’s
syndrome, and papillary renal neoplasia, or as a famil-
ial non-medullary thyroid cancer (FNMTC) [2]. FNMTC
is characterized by the presence of differentiated thy-
roid cancer of follicular cell origin in two or more first-
degree relatives [2].
Among FNMTC, PTC is the most common; howev-
er, kindred with follicular and poorly differentiated thy-
roid cancer have also been reported [2]. The pathogen-
esis of papillary thyroid carcinoma (PTC) involves al-
terations in the RET/PTC-RAS-BRAF signalling path-
way, most frequently by BRAF-activating somatic
mutations and RET/PTC rearrangements [3, 4]. The loss
of heterozygosity at the TCO and NMTC1 locus (loci
linked with FNMTC) was demonstrated in some, but not
all, tumour specimens from patients with FNMTC [2].
Genetic predisposition to PTC, which is the highest
of all cancers not displaying Mendelian inheritance [5–7],
is suggested by case-control studies, which show a 3- to
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PRACE POGLĄDOWE
10-fold higher risk in first degree relatives [3, 5, 6]. The
risk is higher for first-degree male relatives of male
probands than for first-degree female relatives of female
probands [7]. Genes responsible for PTC /FNMTC are
poorly known — genetic predisposition is expected to
be multigenetic with low- to moderate-penetrance
genes [4, 6] interacting with each other and with the
environment determining individual susceptibility [6].
Up to the present, by linkage analysis using microsatel-
lite markers, several putative loci have been described:
TCO locus (thyroid tumours with cell oxyphilia) on
19p13.2 (first identified in a family with oxyphilic thy-
roid neoplasms), NMTC1 in 2q21 (identified in a family
with hereditary transmission of the follicular variant of
PTC), MNG1 (multinodular goiter) on 14q32 (a family
with 18 cases of nontoxic multinodular goiter with
2 PTC individuals), and PRN1 locus on 1q21 (identified
in a family with PTC, nodular benign thyroid disease,
and papillary renal neoplasia) [2, 8–10]; however, in part,
the results are contradictory. The reason for this are
multiple: probably the imprecise FNMTC definition
(two or more family members affected) and, as a conse-
quence, dilution of the linkage studies with sporadic
cases plays a role here. The heterogeneity of FNMTC
syndrome also has to be considered [2].
The above-mentioned studies were performed on
individual families, which were not necessarily repre-
sentative of the vast majority of inherited cases, so val-
idation of the results was unsuccessful [10]. Recently,
new techniques — high resolution SNP arrays — have
been used in genetic predisposition studies. Using this
technique, genome-wide linkage analysis performed in
a large family (11 members affected by nodular goiter
and follicular thyroid adenoma, and 5 patients with
thyroid cancer) revealed the linkage of region 8p23.1-
-p22 with familial thyroid epithelial neoplasia [11]. The
same technique, used for linkage analysis performed
on a large, broad sampling of 38 FNMTC families, dis-
covered two distinct loci on chromosome 1q21, the first
one described earlier as a PRN1 (papillary renal neo-
plasia) locus, and the second one previously unknown
[10]. High density SNP arrays were also used to per-
form a genome-wide linkage study (large family with
PTC and melanoma), which revealed the linkage of 8q24
locus with PTC. By using microsatellites markers the
results were confirmed in 25 additional PTC families.
Further analysis of the 8q24 locus implicated a putative
non-coding RNA gene (AK023948) as a candidate gene
for PTC [5].
In the absence of large pedigrees of related individ-
uals, and to discover the chromosomal regions associ-
ated with common disease, SNP array-based techniques
can be used to perform genome-wide association stud-
ies (GWAS) [10]. Association study seems to be an ap-
propriate approach in multigenic disease as linkage
analysis does not have sufficient power to identify low-
penetrance genes [6]. Recently, a GWAS has been per-
formed on 192 Icelandic patients with PTC or FTC and
37,196 healthy controls, in which 304,983 SNPs were
tested for association [7]. The strongest signals were
obtained for two SNP: rs965513 (Aallele) on 9q22.33 and
rs944289 (T allele) on 14q13.3. The results were con-
firmed in case control groups of European descent:
342 cases and 384 controls from the United States and
90 cases and 1343 controls from Spain. Combination of the
results from Iceland, the United States, and Spain result-
ed in OR 1.75 for A allele of rs965513 (p = 1.7 × 10–27) and
1.3 for T allele of rs944289 (p = 2.0 × 10–9). In the gener-
al population, almost 11% of individuals were homozy-
gous for rs965513 A allele, 32% for rs944289 T allele, and
3.7% were homozygous for both variants. Homozygous
carriers of rs965513 A allele had a 3.1-fold higher risk
for thyroid cancer then non-carriers, and a 1.9-fold high-
er for rs944289 T allele, respectively. The risk for dou-
bly homozygous individuals was 5.7-fold greater. For
the combined data, the frequency of rs965513 A allele
carriers was higher among patient diagnosed at
a younger age (rs944289 had no effect) [7]. There were
no differences observed between males and females for
rs965513 or for rs944289. Subsequently, the effects of
two SNPs were analyzed in the combined data in the
main histotypes of thyroid cancer (~ 85% of the Span-
ish and Icelandic cases were PTC, ~ 12% were FTC,
whereas all of the United States cases were PTC). For
rs956613 A allele the OR for PTC was 1.8 (p = 4.7 × 10–23)
and for FTC OR was 1.55 (p = 0.016), and for rs944289 T
allele OR was 1.32 (p = 2.0 × 10–6) and 1.63 (p = 0.007),
respectively. This demonstrated that two SNPs in-
creased the risk of two main histotypes of thyroid can-
cer (the numbers of other histotype cases in the com-
bined data were too small to be considered) [7].
The SNP rs965513 lies on 9q22.33 within the linkage
disequilibrium (LD) region where XPA, FOXE1, C9orf156,
and HEMGN genes are localized, and the FOXE1 (fork-
head box E1, formerly TTF2, Thyroid Transcription
Factor 2) is the closest gene. FOXE1 is a centre of the
regulatory network of transcription factors, which ini-
tiate thyroid differentiation at the embryonic stage. It is
also important for the maintenance of the thyroid dif-
ferentiated state in adults as it is involved in regulating
the transcription of thyroglobulin and thyroperoxidase
(TPO) gene, which are pivotal for thyroid hormone syn-
thesis [6, 7]. The expression of FOXE1 has been shown
to be abnormal in thyroid tumours, and its mutations
among other phenotypes cause human syndromes as-
sociated with thyroid agenesis.
The SNP rs944289 on 14q13.3 is localized in the LD
region where no RefSeq genes are present and the clos-
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est genes are BRMS1L, MBIP, SFTA3, and NKX2-1
(TTF1). The best candidate as a source of the associa-
tion signal obtained for the 14q13.3 locus is NKX2-1,
which has a prominent role in thyroid development.
Its expression is altered in thyroid tumours [7]. As both
FOXE1 and NKX2-1 genes are involved in the biology
of the thyroid gland, in the next step the effects of
rs965513 and rs944289 on the TSH, free T3 and T4 serum
levels were assessed. The measurement was taken over
a period of 11 years on the material from Icelanders not
having thyroid cancer. Both rs966513 A and rs944289 T
alleles were associated with a decreased TSH serum
concentration (p = 2.9 × 10-14 and p = 0.03, respectively).
rs965513 A allele was associated with an increase in T3
levels and with a decrease in T4 levels (p = 0.003 and
p = 6.1 × 10–5, respectively). For rs944289, no effects on
either T3 or T4 were observed [7]. These data showed
the influence of at least the rs945513 in the 9q22.33 lo-
cus on the thyroid function.
An independent, recently performed candidate gene
association study also revealed the association of FOXE1
with PTC [6]. The study comprised “tag SNP” (used to
infer LD blocks according to the HapMap project) and
putative functional SNP in genes involved in thyroid
cell differentiation and proliferation, and in genes found
to be differentially expressed in thyroid carcinoma (as
described in public databases CGAP-SAGE). A total of
615 Spanish cases and 525 controls were genotyped for
768 SNPs localized in 97 genes. The strongest evidence
of association with PTC was observed for SNP in an LD
block spanning the entire FOXE1 gene. The results were
validated in an independent Italian series of 482 cases
and 532 controls. The strongest association was ob-
served for rs1867277 A allele localized in the promoter
sequence, which was a different SNP to that observed
in the Icelandic GWAS study. The combined OR (per
allele) for rs1867277 was 1.49 (p = 5.9 × 10–9). The
FOXE1 in this study was particularly associated with
the classic PTC variant. Functional assays revealed the
recruitment of USF1 and USF2 transcription factors by
rs186277 A allele, while both alleles, G and A, formed
a complex in which DREAM, CREB, and aCREM partici-
pated. Transient transfection study assays revealed that
CREB, and strongly aCREM, activated FOXE1 promot-
er, while DREAM reduced aCREM dependent-tran-
scriptional induction. USF factors also induced signifi-
cant increases in FOXE1 transcription activity when
rs1867277 A allele was present. Transcriptional activation
of the FOXE1 gene by binding transcription factors
aCREM and CREB was regulated by hormonal factors,
particularly by TSH via cAMP. The authors concluded
that in this way transcription factors could regulate
FOXE1 expression in response to TSH in a physiological
situation, but also indicated that FOXE1-specific studies
were needed to understand its role in thyroid tumour
development. FOXE1 gene belongs to the forkhead fam-
ily of transcriptional factors, which has recently been
identified as a molecular signature for epithelial to mes-
enchymal transition in human colon cancer.
The authors hypothesized that increased FOXE1
expression in thyroid carcinomas (which has been ob-
served to parallel the differentiation process of thyroid
carcinomas) could be related to a motile advantage of
malignant thyroid cells, which would be enhanced by
the presence of the rs1867277 A risk predisposing allele
[6]. Until now, no data are available on the expression
of FOXE1 in PTC.
As mentioned previously, PTC may be caused by
the interaction of multiple genes, either protein-encod-
ing genes or regulatory genes. Recently, microRNA
(miRNA) genes have been implicated in contributing
to the pathogenesis of PTC. MicroRNAs are small non-
coding RNA molecules which negatively regulate the
expression of other genes. MicroRNAs are transcribed
from endogenous DNA and they inactivate specific
mRNAs and interfere with the translation of target pro-
teins [4]. Thus, microRNAs regulate many processes like
development, apoptosis, cell proliferation, and hae-
matopoiesis; they also act as tumour suppressor genes
and oncomirs. Expression of microRNAs has been found
to vary between cancers and normal cells and among
different types of cancers [4]. For example, miR-221,
miR-222, and mir-146 are upregulated in PTC compared
with unaffected thyroid tissue [3]. Recently it has been
found that common G/C polymorphism (rs2910164)
within the pre-miR-146a sequence is associated with
PTC [4]. In material coming from 608 sporadic PTC pa-
tients and 901 controls from Finland, Poland, and the
United States the frequency of genotype differed sig-
nificantly (p = 0.000002). The G/C heterozygosity was
associated with an increased risk of PTC (OR = 1.62;
p = 0.0000007) in comparison with homozygosity, while
both homozygous states were protective (OR = 0.42,
p = 0.0027 for CC v. GG + GC; OR = 0.69, p = 0.0006
for GG v. CC + GC; OR = 0.5, p = 0.024 for CC v. GG).
It was shown that this polymorphism reduced the
amount of pre- and mature miR-146a from the C allele
compared with the G allele. By evaluation of a com-
bined group of DNA samples obtained from the blood
of PTC patients and from normal thyroid tissue in pa-
tients with PTC, it has been found that 3.6–6.1% of PTC
cases exhibit mutation from GG or CC in the germ-line
DNA toward GC heterozygosity in the tumour. The
authors concluded that polymorphism in pre-miR-146a
might play a role in tumourigenesis. The effects of miR-
NA polymorphism were expected to be mediated by
target genes whose expression was affected by the SNP
status. miR-146a is known to be involved in NF-kappa
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PRACE POGLĄDOWE
B regulation and the reduction in miR-146a leads to less
efficient inhibition of target genes: RET-PTC1 (frequent
rearranged proto-oncogene in PTC), TRAF6, and IRAK1
(involved in the Toll-like receptor and cytokine signal-
ling pathway). The role of Toll-like receptors and
NF-kappa B in thyroid tumourigenesis is well estab-
lished [4]. It was also shown that miR-146a GC heterozy-
gotes produced three mature microRNAs: one from the
leading strand (miR-146a), and two from the passenger
strand (miR-146a*G and miR-146a*C), each with its dis-
tinct set of target genes, whereas each homozygote pro-
duced two microRNAs (one from leading strand, the
second from passenger strand). As shown by microar-
ray and TaqMan real time PCR data, the difference in
expression of miR-146a and other transcript between
the tumour and unaffected parts of the thyroid from
GC and GG patients can be observed. These data sug-
gested that altered microRNAs might be early factors
playing a role in the tumourigenesis of PTC [12].
To sum up, although many studies have been per-
formed, up to the present the genes predisposing to
FNMTC still seem not to be sufficiently identified. FN-
MTC tends to be more aggressive than sporadic cancer,
is characterized by early age at onset, is often bilateral,
and may have mixed PTC and FTC features [13]. Many
medical centres recommend more aggressive treatment
of FNMTC cases [2, 8, 10]. Identification of the suscepti-
bility genes would enable FNMTC screening, early di-
agnosis, and as a result prophylactic treatment and im-
proved patient outcome [2]. However, because of mul-
tigenetic predisposition to FNMTC due to the existence
of heterogenous groups of histological variants, the is-
sue is still a challenge and multicenter analysis would
be necessary to reach the final goal [2].
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... The incidence of the disease has increased from 10.8 to 15.3 per 100,000 in 2008, representing approximately a 1.5-fold increase in Turkey [2]. Papillary thyroid carcinoma (PTC), which originate from thyroid epithelial cells, is the most common histopathological subtype of thyroid cancer and it is responsible for 80% of all thyroid cancers and it is usually metastase to lymphatic vessels [3][4][5][6]. ...
... In this study, no significant difference has been detected between patients and controls for FOXE1 variant incidences since the relatively small sample size of patient and control group. [4]. Previous studies mentioned many unfavorable prognostic factors such as, capsular infiltration, extrathyroidal extension and lymph node metastases, which are critical for recurrence, are strongly associated with poor thyroid cancer prognosis [6,22,23]. ...
Article
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Background: Recent reports indicated that incidence of thyroid carcinoma is increasing throughout the worldwide. The aim of our study was to determine a possible relationship between Forkhead box E1 (FOXE1) gene variants and histopathological features of papillary thyroid carcinoma. Methods: FOXE1 gene variations; rs894673, rs1867277 and rs3758249 were analyzed in 57 Papillary thyroid carcinoma patients and 51 age matched healthy control subjects. Restriction fragment length polymorphism (RFLP) technique was used to specifically detect the variations. Results: There was a significant difference in the distribution of rs894673 genotypes in Papillary thyroid carcinoma cases (P=0.01). AA genotype presence of rs1867277 was more significantly associated with several histopathological parameters such as focal and diffuse capsular invasion, lymphatic invasion, P3 with P4 tumor grade and surgical margins. AA genotype presence in rs1867277 variation was significantly associated with the classical variant which is subtype of papillary thyroid carcinoma. Furthermore, the presence of the allel A was found to be related with lymph node invasion risk by 2.46 fold, capsular invasion risk by 2.97 fold, and pT3 with pT4 pathological stage risk by 4.13 fold and the presence of allele A in rs1867277 was significantly associated with classic variants. The presence of allele A in rs1867277 was more significantly associated with several histopathological parameters in classic variant in papillary thyroid carcinoma cases such as, the presence of the A allele was found relationship with lymph node invasion risk by 2.0 fold, capsular invasion risk by 2.39 fold , and pT3 with pT4 pathological stage risk by 3.57 fold. In addition, AATT, AAAA and GATT haplotypes (rs1867277 and rs894673) were evaluated for association with papillary thyroid carcinoma cases. Our results indicate that the significant difference according to two-allele haplotype distribution between papillary thyroid carcinoma cases and control groups. Conclusion: Our findings suggest that FOXE1 variations generate a higher risk for poor histopathological features of papillary thyroid carcinoma.
... Furthermore, in another study, A allele reported significantly related to TC and they showed that FOXE1 polymorphisms were associated with risk of PTC (Somuncu et al., 2015). Further, Kula et al., (2010) showed, A allele was probably associated with TC in the metastatic form. FOXE1 is necessary for proliferation and migration of thyroid cells during morphogenesis. ...
Article
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Thyroid cancer (TC) is the mainly frequent endocrine cancer by different incidence rate in worldwide. However, early prediction of this cancer is still challenging due to the unclear pathogenicity. In this study with the aid of systems biology approach, performed a holistic study on GSE65144 dataset containing anaplastic thyroid carcinoma tissues. Co-expression network analysis by WGCNA suggested that highly preserved turquoise module with 1,480 genes was significantly correlated to TC. Most of the top 54 hub-genes of this module are functionality correlated to thyroid hormone generation (GO:0006590). Of these 54 hub-genes, FOXE1 has been reported previously to contain mutation asosiated to TC and chosen for experimental validation step. To this end, we conducted a case-control study including 81 TC patients and 165 controls individuals to evaluate the effects of FOXE1 functional polymorphisms (rs1867277) on the development of TC in Sistan and Balouchestan province of Iran. The polymorphisms of FOXE1 gene (rs1867277) assessed by tetra-ARMS PCR technique. Homozygous (GG) and (AA) variant of rs1867277 polymorphism were detected in 26 (32.1%) and 15 (18.5 %) of TC patients, and 66 (40.0%), and 15 (9.1%) in controls, respectively (p-value= 0.03, OR= 2.53). The A allele frequency was 70 (43.2%) in TC patients and 114 (34.5%) in controls (p-value= 0.06, OR= 1.44). Overall, our results suggested that FOXE1 gene could be used as a prognostic marker in TC and also provides information related to FOXE1 functional polymorphisms (rs1867277) in Sistan and Balouchestan province of Iran. .
... Papillary thyroid cancer (PTC) is the most frequently diagnosed differentiated thyroid cancer (DTC) [1,2]. Genetic predisposition to PTC is the highest of all cancers not displaying Mendelian inheritance [3][4][5][6]. This predisposition is expected to be multigenetic, with interactions among genes and environmental factors determining individual susceptibility [2,4]; however, the genes responsible for PTC are poorly known. ...
Article
Full-text available
Introduction: Papillary thyroid cancer (PTC) shows familial occurrence, and some susceptibility single nucleotide polymorphisms (SNPs) have been identified in FOXE1 and near the NKX2-1 locus. The aim of our study was to analyse the association of PTC risk with SNPs in FOXE1 (rs965513, rs1867277, rs1443434) and near the NKX2-1 locus (rs944289) in a Polish population, and, in the second step, the interac-tion between SNPs and patient-related factors (age at diagnosis and gender). Material and methods: A total of 2243 DNA samples from PTC patients and 1160 controls were included in the study. The SNP analysis was performed with the allelic discrimination technique. Results: There were significant associations of all SNPs with PTC (rs965513 odds ratio [OR] = 1.72, p = 8 × 10-7; rs1867277 OR = 1.59, p = 1 × 10-6; rs1443434 OR = 1.53, p = 1 × 10-5; rs944289 OR = 1.52, p = 4 × 10-5). Logistic regression analysis revealed an increased PTC risk in the interaction of rs944289 with age at diagnosis (OR = 1.01 per year, p = 6 × 10-4) and a decreased PTC risk in the interaction of male gender with the GGT FOXE1 protective haplotype (OR = 0.69, p = 0.01). Conclusions: the association between PTC and all analysed SNPs was confirmed. It was also shown that patient-related factors modify the predisposition to PTC by increasing the risk for rs944289 per year of age, and by enhancing the protective effect of the FOXE1 GGT haplotype in men.
... Both genetic predisposition and environmental factors have been implicated in the aetiology of thyroid cancer. However, most cases are sporadic and only around 6 % of cases can be attributed directly to genetic predisposition [36]. Known risk factors for thyroid cancer include exposure to ionizing radiation (especially of the head and neck) and iodine deficiency [37][38][39][40][41]. ...
Article
Objective To examine temporal trends in the incidence of primary thyroid cancers diagnosed in 0–49 year olds in parts of Great Britain (GB) during the period 1976–2005. We specifically aimed to analyse age, period and cohort effects. Design Population-based descriptive analysis of cancer registry data. Setting Parts of Great Britain. Participants Case data on thyroid cancer were obtained from four regional cancer registries in GB (i. Northern and Yorkshire, ii. North West, iii. Wales and iv. Scotland). Main outcome measures Age-standardised incidence rates (ASRs) and 95% CIs were calculated. Negative binomial regression was used to examine the effects of age, sex, drift (linear trend), non-linear period and non-linear cohort. Results The study analysed 4327 cases of thyroid cancer aged 0–49 years at diagnosis. For males, the overall ASR was 3.9 per million persons per year (95% CI 3.6 to to 4.1). For females, the overall ASR was 12.5 per million persons per year (95% CI 12.0 to to 12.9). The best fitting negative binomial regression model included age (p<0.001), sex (p<0.001) and drift (p<0.001). Non-linear period (p=0.42) and non-linear cohort (p=0.71) were not statistically significant. For males aged 0–14 years, the ASR increased from 0.2 per million persons per year in 1976–1986 to 0.6 per million persons per year in 1997–2005. For males aged 15–29 years and 30–49 years the ASRs increased from 1.9 to 3.2 and from 7.3 to 12.6 per million persons per year, respectively. For females aged 0–14 years, the ASR increased from 0.3 to 0.5 per million persons per year. For females aged 15–29 years and 30–49 years the ASRs increased from 7.0 to 12.3 and from 21.2 to 40.0 per million persons per year, respectively. Conclusions There has been a linear increase in the incidence of thyroid cancer, which has led to a doubling of the number of cases diagnosed over a 20 year time span. The reasons for this increase are not well understood, but it is consistent with findings from other countries.
... Both genetic predisposition and environmental factors have been implicated in the aetiology of thyroid cancer. However, most cases are sporadic and only around 6 % of cases can be attributed directly to genetic predisposition [36]. Known risk factors for thyroid cancer include exposure to ionizing radiation (especially of the head and neck) and iodine deficiency [37][38][39][40][41]. ...
Article
Increases in the incidence of thyroid cancer have been previously reported. The purpose of the present study was to examine temporal trends in the incidence of primary thyroid cancer diagnosed in 0-49 year olds in parts of Great Britain during 1976-2005. Data on 4,337 cases of thyroid cancer were obtained from regional cancer registries. Age-standardized incidence rates (ASRs) were calculated. Negative binomial regression was used to examine effects of age, sex, drift (linear trend), non-linear period and non-linear cohort. The best fitting negative binomial regression model included age (P < 0.001), sex (P < 0.001) and drift (P < 0.001). Non-linear period (P = 0.648) and non-linear cohort (P = 0.788) were not statistically significant. For males aged 0-14, the ASR increased from 0.2 per million persons per year in 1976-1986 to 0.6 in 1997-2005. For males aged 15-29 and 30-49 the ASRs increased from 1.9 to 3.3 and from 7.4 to 12.7, respectively. For females aged 0-14, the corresponding ASR increased from 0.3 to 0.5. For females aged 15-29 and 30-49 the ASRs increased from 6.9 to 12.4 and from 21.2 to 42.3, respectively. For all age groups, there has been a linear increase in incidence of thyroid cancer, which has led to a doubling of the number of cases diagnosed over a twenty year span. The reasons for this increase are not well understood, but it is consistent with findings from other countries.
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Thyroid cancers are largely divided into medullary (MTC) and non-medullary (NMTC) cancers , depending on the cell type of origin. Familial non-medullary thyroid cancer (FNMTC) comprises about 5–15 % of NMTC and is a heterogeneous group of diseases, including both non-syndromic and syndromic forms. Non-syndromic FNMTC tends to manifest papillary thyroid carcinoma , usually multifocal and bilateral . Several high-penetrance genes for FNMTC have been identified, but they are often confined to a few or single families, and other susceptibility loci appear to play a small part, conferring only small increments in risk. Familial susceptibility is likely to be due to a combination of genetic and environmental influences. The current focus of research in FNMTC is to characterise the susceptibility genes and their role in carcinogenesis. FNMTC can also occur as a part of multitumour genetic syndromes such as familial adenomatous polyposis , Cowden’s disease , Werner’s syndrome and Carney complex . These tend to present at an early age and are multicentric and bilateral with distinct pathology. The clinical evaluation of these patients is similar to that for most patients with a thyroid nodule. Medullary thyroid cancer (MTC) arises from the parafollicular cells of the thyroid which release calcitonin. The familial form of MTC accounts for 20–25 % of cases and presents as a part of the multiple endocrine neoplasia type 2 (MEN 2) syndromes or as a pure familial MTC (FMTC). They are caused by germline point mutations in the RET oncogene on chromosome 10q11.2. There is a clear genotype–phenotype correlation, and the aggressiveness of FMTC depends on the specific genetic mutation, which should determine the timing of surgery.
Article
Background: Familial non-medullary thyroid cancer (FNMTC) mandates family screening with ultrasound; however, the need for screening paediatric thyroid cancer with no family history has not been addressed. Methods: This study conducted a retrospective cohort study in a tertiary hospital. The study group is composed of patients ≤18 years undergoing surgery for papillary thyroid cancer (PTC) from 2008 to 2014. Results: During the study period, 15 paediatric patients had PTC. Only one patient had a prior family history of PTC involving two second-degree relatives. Of the 30 parents, four were lost to follow-up, with the remaining 26 undergoing screening thyroid ultrasound. Nodular thyroid disease was documented in eight ultrasounds performed. Subsequently, one has not undergone fine-needle biopsy, five were benign and two underwent surgical resection: one having a benign follicular adenoma and the other a papillary microcarcinoma with nodal micrometastasis. Conclusions: Routine ultrasound screening of parents of children presenting with PTC and no family history do not demonstrate an increased incidence of FNMTC. Screening of affected families is likely to demonstrate the expected background incidence of nodular thyroid disease and incidental papillary microcarcinoma. As such, it is unlikely to be useful.
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In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.
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Learning Objectives Apply the principles of genetics to heritable aspects of thyroid cancer. Explain and discuss presymptomatic gene testing with family members of patients with familial thyroid cancer. Proactively manage patients presenting with a family history of thyroid cancer. This article is available for continuing medical education credit at CME.TheOncologist.com.
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In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
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Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.
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Papillary thyroid carcinoma (PTC) displays higher heritability than most other cancers. To search for genes predisposing to PTC, we performed a genome-wide linkage analysis in a large family with PTC and melanoma. Among several peaks the highest was at 8q24, with a maximum nonparametric linkage (NPL) score of 7.03. Linkage analysis was then broadened to comprise 25 additional PTC families that produced a maximum NPL score of 3.2, P = 0.007 at the 8q24 locus. Fine mapping with microsatellite markers was compatible with linkage to the 8q24 locus in 10 of the 26 families. In the large family, a approximately 320 Kb haplotype was shared by individuals with PTC, melanoma, or benign thyroid disease, but not by unaffected individuals. A 12 Kb haplotype of 8 SNP markers within the larger haplotype was shared by 9 of the 10 families in which the 8q24 locus was compatible with linkage. The shared haplotype is located within 2 known overlapping protein-coding genes, thyroglobulin (TG) and Src-like adaptor (SLA). Resequencing of the coding and control regions of TG and SLA did not disclose putative mutations in PTC patients. Embedded in the TG-SLA region are three likely noncoding RNA genes, one of which (AK023948) harbors the 8-SNP haplotype. Resequencing of AK023948 and one of the other RNA genes did not reveal candidate mutations. Gene expression analysis indicated that AK023948 is significantly down-regulated in most PTC tumors. The putative noncoding RNA gene AK023948 is a candidate susceptibility gene for PTC.
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Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.
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It is well‐known that medullary thyroid carcinoma occurs in a familial form as part of the multiple endocrine neoplasia (MEN) 2 syndromes. However, it is less well‐recognized that nonmedullary thyroid carcinoma (NMTC) sometimes is familial. Arising from the thyroid epithelial cell, the NMTCs include papillary, follicular, and anaplastic thyroid carcinoma. Although most NMTC are sporadic, there is increasing evidence for a familial form. When inherited, NMTC is autosomal dominant with partial penetrance, and it is not associated consistently with other malignancies. The average age of onset is about 38 years, and in some cases, it may be more aggressive than sporadic PTC; up to 5% of subjects with NMTC have a family history positive for the same disorder. The etiologic gene(s) have not been identified, although positional cloning of these genes may be possible. The evidence for and characteristics of familial NMTC will be reviewed, and the clinical and research implications will be discussed. Semin. Surg. Oncol. 16:16–18, 1999. © 1999 Wiley‐Liss, Inc.
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Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families.
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Familial nonmedullary thyroid cancer (FNMTC) is associated with earlier onset and more aggressive behavior than its sporadic counterpart. Although candidate chromosomal loci have been proposed for isolated families with variants of FNMTC, the etiology of most cases is unknown. We aimed to identify loci linked to FNMTC susceptibility using single-nucleotide polymorphism (SNP) array-based linkage analysis in a broad sampling of affected families. We enrolled and pedigreed 38 FNMTC families. Genomic DNA was extracted from the peripheral blood of 110 relatives, and hybridized to Affymetrix SNP arrays. We performed genotyping and linkage analysis, calculating exponential logarithm-of-the-odds (LOD) scores to identify chromosomal loci with a significant likelihood of linkage. Forty-nine affected and 61 unaffected members of FNMTC families were genotyped. In pooled linkage analysis of all families, 2 distinct loci with significant linkage were detected at 6q22 and 1q21 (LOD=3.3 and 3.04, respectively). We have identified 2 loci on chromosomes 1 and 6 that demonstrate linkage in a broad sampling of FNMTC families. Our findings suggest the presence of germline mutations in heretofore-undiscovered genes at these loci, which may potentially lead to accurate genetic tests. Future studies will consist of technical validation and subset analyses of higher-risk pedigrees.