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Section of Cancer Genetics, Institute of Cancer Research (S.B., H.G., J.W., G.B., M.R.S., R.S.H.), Sutton, Surrey, United Kingdom SM2 5NG; Department of Medicine, Women’s College Hospital, University of Toronto (T.P., S.A.N.), Toronto, Ontario, Canada; Section of Genetics and Metabolism, Health Sciences Center (C.R.G.), Winnipeg, Manitoba, Canada R3A 1R9; and Departments of Medicine, Oncology and Human Genetics, Montreal General Hospital, and Sir M. B. Davis-Jewish General Hospital, McGill University (W.D.F.), Montréal, Canada H3T 1E2
Address all correspondence and requests for reprints to: Dr. Richard S. Houlston, Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom SM2 5NG. E-mail: r.houlston{at}icr.ac.uk
Abstract
About 5% of nonmedullary thyroid cancer is familial. These familial nonmedullary thyroid cancer cases are characterized by an earlier age of onset, more aggressive phenotype, and in some families a high propensity to benign thyroid disease. Little is known about the genes conferring predisposition to nonmedullary thyroid cancer. Three loci have been identified through genetic linkage: MNG1 on 14q32, TCO1 on 19p13.2, and fPTC on 1p21. In addition to these putative genes, a number of loci represent candidate familial nonmedullary thyroid cancer predisposition genes by virtue of their involvement in sporadic disease (TRKA), their role in benign disease (TSHR), and because they underlie syndromes with a risk of nonmedullary thyroid cancer (PTEN). To evaluate the roles of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA in familial nonmedullary thyroid cancer, we have carried out a comprehensive mutation and linkage analysis of these genes in 22 families. One family was linked to chromosome 19q13.2, confirming that TCO1 underlies a subset of familial nonmedullary thyroid cancer. None of the families was linked to MNG1 or fPTC, and there was no evidence to support the roles of PTEN, TSHR, or TRKA. Familial nonmedullary thyroid cancer is an emerging clinical phenotype that is genetically heterogeneous, and none of the currently identified genes accounts for the majority of families.
MOST NONMEDULLARY thyroid cancer (NMTC) is sporadic. However, evidence from family (1, 2) and epidemiological (3, 4) studies indicates that a subset is familial. The pattern of inheritance in many reported families is compatible with an autosomal dominant model with incomplete penetrance (1, 2). Characteristics of familial NMTC (FNMTC) include an earlier age of onset, more aggressive phenotype-multifocal disease, and more frequent relapses (1, 2). In some families there is evidence that genetic susceptibility to NMTC and benign thyroid disease, typically multinodular goiter (MNG), are related (1). Three FNMTC loci have been mapped by genetic linkage analysis using single, multiple case families. These include MNG1 on chromosome 14q32 (5), TCO1 on chromosome 19p13.2 (6), and fPTC on chromosome 1p21 (7). In addition to these putative genes, a number of loci represent candidate FNMTC predisposition genes by virtue of their involvement in sporadic disease (TRKA) (8), their role in nonmalignant thyroid disease (TSHR) (9), and because they underlie a syndrome associated with a risk of NMTC (PTEN causing Cowden’s syndrome) (10).
To evaluate the contributions of MNG1, TCO1, fPTC, PTEN, TSHR, and TRKA to familial NMTC we undertook a linkage and mutation analysis of these loci in 22 FNMTC families.
Subjects and Methods
Twenty-two families with two or more members affected with NMTC
were studied (Table 1
). The average age
at diagnosis of NMTC was 39.7 yr (SD, 15.2 yr), with a male
to female ratio of 1:4.7. None of the affected individuals had clinical
features indicative of familial adenomatous polyposis or had features
meeting the operational criteria of the International Cowden Consortium
(11) for a diagnosis of Cowden’s syndrome. The relevant
institutional review boards approved the study. Blood samples were
collected from family members, and DNA was isolated using a standard
sucrose lysis protocol.
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3') were as follows: exon 1: ggggcgtcagagagtagg,
caaacaagcagcgagtcc; exon 2, gcctgagccctgtgactc, gccctccctgacctcctg;
exon 3, ctgagggactgggagaag, ggagaatggtgaggtgac; exon 4,
tcctcccctcctcattc, tccaacagacccaagtg; exon 5, gccctctccttgactctg,
ccccttacaccacctc; exon 6, ggagcagccccgcagtag, ctctttccccatctttgt; exon
7, ggctctccaaagacttca, tgacaagaccccaggact; exon 8, cctgacctcctgctgttg,
tcccgaaccaggcactc; exon 9, gtaggcaggggactcact, atctccctgctctgacca; exon
10, aaaatggcttactacagg, aaagccaggagaacagac; exon 11,
cggctgtgtctcctctct, gcccttgacccagcatag; exon 12, agtggggctaccgtctga,
cccactctgtccagatgt; exon 13, gacatggctggataccgg, tctccccttggtttgaa;
exon 14, ccctctccttttcttgtt, aaggcgttggggacaaag; exon 15,
cctggaattgatgcagtg, aggccagcaagaggtgac; and exon 16,
gtgggctttctcctctgt, cccagtattccggctaac. Samples with band shifts were
sequenced after reamplification of the appropriate exon from genomic
DNA in the PCR. Purified PCR products were sequenced using the ABI
Ready Reaction Dye Terminator Cycle Sequencing Kit and an ABI 377 Prism
sequencer. Families were included in a linkage analysis of
PTEN, TRKA, MNG1, TSHR,
TCO, and fPTC if DNA was available from two or
more affected individuals who were not simply parent and child.
Fluorescently labeled microsatellite markers situated in or near the
TSHR (D14S61, D14S606, D14S68), PTEN (D10S201,
D10S573, D10S541), and TRKA (D1S498, D1S1595, D1S2635) genes
and linked markers in the MNG1 (D14S498, D14S1030, D14S267),
TCO1 (D19S391, D19S916, D19S413, D19S865, D19S568), and
fPTC (D1S2881, D1S514, D1S498, D1S305) regions were used to
genotype family members. Dye-labeled PCR products were detected on ABI
377 DNA sequencers and analyzed using Genescan and Genotyper software
(Applied Biosystems, Cheshire, UK). In the absence of a precise
mode of inheritance for NMTC, the gene frequency, penetrance, and
phenocopy rate of a dominant model were constrained to fit the observed
familial relative risk of thyroid cancer of 8.0 (4) and a
population prevalence of 0.002 (15) (0.001, 0.018, and
0.0016, respectively). An estimation of the proportion of families
linked to each locus was obtained by a test of heterogeneity.
Nonparametric linkage (NPL) scores were also determined. Both
parametric and nonparametric multipoint analyses were performed using
the GENEHUNTER program (16). Distances between markers
were obtained from Genetic Location Database
(http://cedar.genetics.soton.ac.uk/public_html/). Marker
allele frequencies were derived from observed relative frequencies. Results
All affected family members with either MNG or NMTC in the 22
families were screened for constitutional mutations in PTEN,
TSHR, and TRKA. A nonsense polymorphism in TSHR
was detected (CT, Asn168Asn), but no
pathogenic mutations (novel, missense, or truncating) in
PTEN, TSHR, or TRKA were identified.
All 21 potentially informative families were used in the linkage study
of PTEN, TSHR, TRKA, TCO1,
MNG1, and fPTC loci. Linkage analysis was
undertaken imposing 2 criteria for defining affection status. Firstly,
only individuals with NMTC were classed as affected; family members
with benign thyroid disease were considered of unknown phenotype. Under
this criteria, analysis was undertaken using both parametric and
nonparametric approaches. Secondly, individuals were considered
affected if they had either NMTC or MNG. Under this criteria analysis
was only performed using a nonparametric approach. Table 2 shows the multipoint LOD and NPL scores
for all of the families under both models. LOD scores were negative for
TSHR, PTEN, MNG1, and
TRKA1. Only at the TCO1 locus was there any
evidence for linkage. This was principally seen in family 1680
(Fig. 1), which showed cosegregation
of the chromosome19p13.2 marker haplotype defined by
D19S391-D19S916-D19S413-D19S865-D19S586 and NMTC. The LOD score in this
family is 1.54, and the NPL score is 4.33 (P =
0.03).
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Although about 5% of NMTC patients have a family history of the disease, comparatively little is known about the genes underlying familial forms of the disease (1). In 1997 we mapped the gene for multinodular goiter (MNG1) to chromosome 14q31 in a Canadian family segregating 18 cases of MNG and 2 cases of papillary thyroid cancer (PTC) (5). Subsequently, a gene predisposing to an unusual form of thyroid tumor with cell oxyphilia (TCO1) was mapped to chromosome 19p13.2 in a French kindred containing 6 cases of MNG and 3 cases of PTC (6). More recently, the putative gene fPTC was mapped in a family with 5 cases of papillary thyroid cancer, 3 cases of thyroid nodules, and 2 cases of papillary renal neoplasia to chromosome 1q21 (7).
None of the families we examined in this study showed significant linkage to the putative FNMTC thyroid cancer genes MNG1 or fPTC. Two other reports have found that the majority of FNMTC kindreds are not linked to MNG1 (5, 17). One of the families did, however, show linkage of NMTC to chromosome 19p13.2, providing independent confirmation of TCO1 as a NMTC predisposition locus. In contrast to the family previously linked to TCO1 (6), the thyroid cancers in our family were papillary rather than Hurthle cell.
We evaluated TSHR as a candidate gene for FNMTC, as it is implicated in benign thyroid disease, and activating mutations may affect thyroid cellular differentiation (9, 18, 19). There is, however, no evidence from this study that mutations in TSHR are a cause of FNMTC. TRKA represents a candidate susceptibility locus because of its involvement in sporadic cancer and its localization to the fPTC locus. There was, however, no evidence from this study that germline mutations in TRKA cause FNMTC. There was also no evidence from our study to indicate that mutations in PTEN cause NMTC outside the context of Cowden’s syndrome.
This study in addition to other reports indicate that FNMTC is genetically heterogeneous, and the majority of NMTC kindreds are unlinked to the putative predisposition genes MNG1 (5), TCO1 (6), and fPTC (7). This has considerable implications for the localization of further FNMTC predisposition genes, as genetic heterogeneity severely reduces the power of linkage in a genomic search. The three putative FMTC predisposition loci that have been detected to date, MNG1, TCO1, and fPTC, were located in single, multiple case families, sufficiently large to detect linkage in isolation. Most FNMTC families encountered are relatively small. In the context of allelic heterogeneity, the detection of additional novel FNMTC genes may be problematic. It is, however, increasingly clear that FNMTC can be divided into a number of groups on the basis of pathology and clinical features. Multiple tumors of the same histological type within a family are compatible with a specific germline mutation. Subcategorization of NMTC families on the basis of phenotype therefore provides a powerful strategy for enhancing the power of future linkage studies, especially if the involvement of known genes can be excluded.
Acknowledgments
We thank the families and their clinicians for their participation in this study.
Footnotes
This work was supported by the Cancer Research Campaign. Sequencing was conducted in the Jean Rook Sequencing Laboratory within the Institute of Cancer Research, which is supported by BREAKTHROUGH Breast Cancer, Charity 328323.
Abbreviations: FNMTC, Familial nonmedullary thyroid cancer; MNG, multinodular goiter; NMTC, nonmedullary thyroid cancer; NPL, nonparametric linkage; PTC, papillary thyroid cancer.
Received December 1, 2000.
Accepted April 9, 2001.
References
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