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Departments of Surgery (C.D.M., G.W., M.S., D.M.M.), Medicine (C.D.M., B.T., V.J., A.A., D.M.M.), and Pathology (F.F.), and Center for Molecular Medicine (C.D.M., A.A., D.M.M.), University of Connecticut Health Center, Farmington, Connecticut 06030-1110
Address all correspondence and requests for reprints to: Carl D. Malchoff, M.D., Ph.D., Surgical Research Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1110.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Papillary thyroid carcinoma (PTC) is usually sporadic. However, evidence for a familial association of PTC (fPTC) in about 5% of cases comes from family studies, epidemiological evaluations, and pathology examinations (2). Characteristics of fPTC include an association with benign nodular thyroid disease and autosomal dominant inheritance with age-dependent partial penetrance. Women are affected more than twice as frequently as men (2, 3, 4, 5). There may be multiple susceptibility genes and/or modifying genes (2, 5, 6, 7). More recently, an epidemiological study reported an increased incidence of premenopausal breast cancer in women with PTC (8), suggesting a common genetic predisposition to both disorders in some subjects.
In efforts to identify the fPTC susceptibility gene by positional cloning, two loci have been identified. A putative gene predisposing to an unusual form of familial thyroid tumors with cell oxyphilia (TCO) was mapped to chromosome 19p.32 in a French kindred (3). A putative multinodular goiter susceptibility gene (MNG1) was mapped to chromosome 14q31 in a Canadian family (9). However, the majority of fPTC kindreds do not link to these two loci (3, 7, 9).
We recently described an unusually large three-generation fPTC kindred inherent with sufficient statistical power to be extremely useful in linkage analysis (10). As with other fPTC kindreds, nodular thyroid disease was an associated disorder, inheritance was autosomal dominant with age-dependent incomplete penetrance, and women were affected more frequently than men (10). As most familial tumor syndromes are characterized by more than a single type of neoplasm (1), and some individuals may harbor a predisposition to both premenopausal breast cancer and PTC (8), we first tested the hypothesis that there is a familial predisposition to neoplasms other than PTC in this kindred. Subsequently, we used linkage analysis to test the hypothesis that this familial cancer predisposition maps to a specific chromosomal location.
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Subjects and Methods |
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Subjects, pathology evaluation, and DNA preparation
This kindred has been described in part previously (10). Each family member submitting to testing was interviewed and examined by the authors (B.T. and/or C.D.M.). Abdominal computed tomographic scanning was used to screen for renal neoplasms. Patient age at the time of diagnosis of PTC was published previously (10). Patient age at the time of clinical evaluation by the authors was as follows: II-5 at age 78 yr, II:6 at 75 yr, II:9 at 69 yr, II:11 at 68 yr, II:12 at 67 yr, II:14 at 64 yr, III:4 at 46 yr, III:5 at 58 yr, III:7 at 54 yr, III:8 at 52 yr, III:9 at 40 yr, III:10 at 48 yr, III:11 at 45 yr, III:12 at 42 yr, III:13 at 46 yr, III:14 at 37 yr, III:15 at 35 yr, III:16 at 43 yr, III:17 at 41 yr, III:18 at 42 yr, III:19 at 38 yr, III:20 at 27 yr, and IV:1 at 31 yr.
The pathology slides from neoplasms of all of the affected subjects and the cytology slides from the thyroid nodule aspirations were examined by one of the authors (F.F.). The avidin-biotin-peroxidase complex method of Hsu et al. (11) with appropriate positive and negative controls was used to determine the presence of thyroglobulin in the neoplasms of interest.
Genomic DNA was prepared from whole blood mononuclear leukocytes (12).
Linkage analysis
To evaluate candidate genes for linkage, up to 31 members of the multigeneration fPTC kindred were genotyped using short tandem repeat polymorphisms in close proximity to the chromosomal location of the candidate genes of interest. The information describing primer sequences, band sizes, and number of alleles was obtained from Genethon (13, 14). The 31 subjects represented all affected subjects, all first degree relatives of affected subjects, and all available informative spouses. The markers were amplified by PCR, typically using 100 ng genomic DNA in a 25-µL volume containing 50 pmol of each primer, 200 µmol/L deoxy-NTPs, 50 mmol/L KCl, 10 mmol/L Tris (pH 8.8), 1.5 mmol/L MgCl2, 0.01% gelatin, 4% dimethylsulfoxide, and 0.35 U Taq polymerase (Perkin-Elmer Corp., Norwalk, CT). Amplifications were carried out in a GeneAmp 9600 thermocycler (Perkin-Elmer Corp.), most frequently using the following conditions: 2 min at 94 C; followed by 35 cycles of 30 s at 94 C, 30 s at 56 C, and 15 s at 72 C; followed by a final extension of 10 min at 72 C. Products were separated on an 8% PAGE gel and silver stained (15). Family members were genotyped, and haplotypes were constructed. The data obtained from the genotyping were entered into a dedicated computer program, checked for data errors and inconsistencies, and prepared for the LINKAGE program.
A genomewide screen was performed using the Weber/CHLC Linkage Mapping Set 9, consisting of approximately 380 fluorescently labeled markers spaced at approximately 10-cM intervals (Research Genetics, Inc., Huntsville, AL), to genotype the 16 most informative members of the kindred (II-1, II-5, II-6, II-9, II-11, II-12, II-14, II-15, II-16, III-1, III-3, III-5, III-6, III-20, and IV-2). PCR-amplified products were separated by PAGE using an ABI 377 DNA sequencer. The data were automatically collected and analyzed by GeneScan and Genotyper software (PE Applied Biosystems, Foster City, CA) with respect to TAMRA GeneScan 500 size standards. Results were analyzed by haplotype analysis and the LINKAGE program.
Penetrance was estimated from kindreds reported previously (7, 16, 17, 18, 19) and from the kindreds under investigation by our group. Only subjects with proven PTC were assigned a positive affection status. This evaluation identified 20 female obligate carriers, and, of these, 16 had PTC for an overall female penetrance of 80%. Of 11 male obligate carriers, 5 were affected. This was deemed an insufficient sample from which to estimate accurately male penetrance. As penetrance is age dependent, and PTC rarely occurs before age 10 yr (5), penetrance in women was calculated by assuming penetrance to be 0 at age 10 yr, to increase linearly with age to reach 80% by age 60 yr, and to reach a maximum of 95% at age 70 yr. Only women over age 30 yr, affected subjects, and obligate carriers were used to calculate log of likelihood ratio (LOD) scores. In men and subjects less than 30 yr of age, the penetrance is not accurately known and was so low that analysis of these genotypes is unlikely to contribute in a meaningful way to the calculation of LOD scores. Men in generations II and III were genotyped to provide information concerning unavailable parents. Women with thyroid nodules were assigned a 90% probability of being affected. Subjects II-12 and III-4 were excluded from the LOD score calculation. Although their tumors were potentially associated with the syndrome, an accurate estimate of their affection status could not be made.
DNA sequencing
Dideoxy-DNA sequencing of MET exons was performed after PCR amplification of genomic DNA from subject II-1 using the primers and conditions described by Duh et al. (20). PCR products were subcloned directly using the pMos Blue Blunt Ended Cloning Kit (Amersham Pharmacia Biotech, Arlington Heights, IL). At least eight separate subclones of each PCR product were sequenced to be certain that both alleles had been screened. Automated sequencing was performed using a PE373 DNA sequencer by the molecular biology core at University of Connecticut Health Center.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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To determine whether non-PTC neoplasms exist in the kindred,
kindred members were reviewed for thyroid neoplasms, premenopausal
breast carcinoma, and rare nonthyroidal neoplasms common to more than a
single subject. All living subjects in generation II, 28 of the 34
subjects in generation III, and 4 subjects in generation IV consented
to history and physical examination of the thyroid. All living subjects
in generation II and 9 subjects in generation III consented to
abdominal computed tomography scans. The 5 subjects with thyroid
carcinoma had been identified independently by different primary care
physicians without knowledge of the positive family history. The PTC
were all greater than 3 cm in diameter at the time of diagnosis. Table 1
lists the neoplasms identified in
kindred members. Thyroid neoplasms and rare neoplasms found in two or
more members of the kindred are most likely to be part of this
inherited tumor syndrome. As anticipated, there were thyroid nodules.
Subjects III-10 and III-12 had 1-cm thyroid nodules identified at 48
and 42 yr of age, respectively. These were determined to be benign by
aspiration biopsy. Aspiration biopsy of the 1.5-cm nodule in subject
III-20 (aged 27 yr) revealed suspicious cytology, but the patient
refused resection for definitive evaluation. Papillary renal neoplasms
(PRN) were present in subjects II-1 and II-7. In subject II-1 this was
a papillary renal carcinoma (PRC) discovered at age 76 yr. Subject II-7
had died due to unrelated medical problems, but before his death at age
68 yr one kidney had been resected for suspicion of malignancy. This
kidney contained multifocal papillary renal adenomas. With high
likelihood, both subjects with PRN carry the fPTC susceptibility gene.
Subject II-1 has papillary thyroid carcinoma, and subject II-7 is an
obligate fPTC carrier, as he has two daughters with thyroid
nodules.
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shows that a typical PTC from subject
II-15 stained positively for thyroglobulin, as expected. Figure 2 shows that the papillary renal
carcinoma from subject II-1 did not stain for thyroglobulin.
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MET protooncogene analysis
Germline mutations of the MET protooncogene confer a
genetic predisposition to the development of PRC (21). To test the
hypothesis that the kindred described here is a phenotypic variant of
fPRC, linkage analysis was performed using markers D7S523 and D7S486,
which flank MET and are separated from each other by 1.5 cM.
Both haplotype analysis and calculation of exclusion areas (Fig. 3) demonstrated that the fPTC/PRN
phenotype is not linked to MET. Furthermore, mutational
analysis by DNA sequencing was performed to test the hypothesis that
there are two cancer susceptibility genes in the kindred, and that only
the PRN are caused by germline mutations of MET. Using
genomic DNA from subject II-1 as substrate, MET exons 12, 13, 16, 17,
18, 19, and 20, which include all known sites of mutations that confer
fPRC susceptibility, were amplified and fully sequenced. No mutations
were identified.
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To determine the location of the fPTC/PRN susceptibility gene, the chromosomal locations of candidate genes were evaluated for linkage to the fPTC/PRN phenotype and a genome-wide screen was performed using markers spaced at approximately 10-cM intervals. Candidate genes specifically excluded were RET, PTEN,TCO, MNG1, and MET. The region of 1q21 was found to be linked to the fPTC/PRN phenotype, when NTRK1 and PRCC, both candidates in this region, were tested for linkage. The genome-wide screen identified this same region as a likely site of linkage.
The genome-wide screen was analyzed by LOD scores and haplotype construction. The two highest LOD scores were 2.35 and 1.29 at markers D22S685 and D1S534, respectively. No other LOD scores were greater than 0.9. Haplotype analysis and multipoint analysis using markers surrounding D22S685 suggested that this chromosomal region was unlikely to be linked to the disease phenotype. In contrast, investigation of markers surrounding D1S534 confirmed linkage and defined the limits of the chromosomal region harboring the susceptibility gene.
Table 2 shows the LOD scores of 10
separate markers in this region of chromosome 1, and Fig. 4 shows the most probable inherited
haplotypes. Marker D1S534 is not included, but is located between
markers D1S2881 and D1S514. The maximum LOD score was 3.15 at marker
D1S514. A maximum three-point LOD score of 3.58 was observed with
markers D1S2343 and D1S2345 and with markers D1S2343 and D1S305.
Haplotype analysis demonstrated that all affected subjects carry the
same haplotype within the region of linkage. Furthermore, critical
recombination events in subject III-1 limited the region of linkage to
about 20 cM, with a centromeric boundary at marker D1S3009 and a
telomeric boundary at marker D1S2721. The haplotype analysis
demonstrated that subjects II-12 (renal oncocytoma) and III-4
(premenopausal breast carcinoma) both carry the haplotype linked to the
fPTC/PRN phenotype.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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An association of fPTC with both nodular thyroid disease and PRN was observed in the kindred. The familial association of PTC and nodular thyroid disease has been observed in most studies of fPTC and is expected (4, 5, 10). It is not surprising that an inherited mutation conferring a susceptibility to thyroid cancer could result in no clinical thyroid disease or in progression to a benign or malignant thyroid neoplasm depending upon which additional cancer susceptibility genes are mutated or deleted. The familial association of PTC and PRN is a novel observation. It is most unlikely that PTC and PRN represent a single neoplasm that subsequently metastasized. PTC usually metastasizes to local lymph nodes, and the kidney is not a common site for distant metastasis. Conversely, although renal cell carcinoma can metastasize to the thyroid, PRC have not been reported to metastasize to the thyroid (22). Furthermore, the PRC did not stain for thyroglobulin, making it unlikely that it represents a thyroid cancer metastatic to the kidney.
Although the familial association of PTC and PRN has not been reported previously, there are multiple lines of evidence supporting the likelihood that PRN are part of the fPTC syndrome in the kindred. First, it is anticipated that fPTC will be characterized by more than one neoplasm, because multiple neoplasms characterize most familial tumor syndromes (1). Second, observations related to PRN support an inherited predisposition. Sporadic PRN are extremely rare, so the occurrence of PRN in two kindred members strongly suggests a genetic predisposition. An inherited predisposition in this kindred is further supported by the multifocality of papillary renal adenomas in subject II-7. A precedent for a familial form of PRN has been established, as germline mutations of the MET protooncogene cause fPTC (21). However, the disorder described here is not a phenotypic variant of fPTC. The fPTC/PRN phenotype did not link to MET, and DNA sequences of MET exons 12, 13, 16, 17, 18, 19, and 20, the sites of MET mutations in fPRC (21), were normal. Third, receptor-mediated activation of the tyrosine kinase signal transduction cascade is a known mechanism of tumorigenesis common to both PTC and PRN, which, interestingly, have similar pathological features. Germline mutations of MET probably initiate PRC by activating the tyrosine kinase cascade (21). Rearrangements of RET and NTRK1 effect both illicit expression and activation of these tyrosine kinases in the thyroid epithelial cell and initiate PTC (23). Thus, there is compelling evidence to support the hypothesis that papillary renal neoplasms are part of the fPTC syndrome in the kindred. The case for a familial association is further strengthened by the subsequent observation that the individuals with PRN carry the same haplotype as those individuals with fPTC. In the very unlikely event that PRN is not part of the fPTC syndrome, the linkage analysis for fPTC would be remain unaltered and valid, as one subject with PRN has PTC (II-1), and the other (II-7) is an obligate carrier of the fPTC susceptibility gene.
It is intriguing to postulate that the fPTC/PRN susceptibility gene may predispose to the development of renal oncocytoma and premenopausal breast cancer. The subjects in our kindred with these rather rare neoplasms carried the same haplotype as the fPTC/PRN subjects. It is probable that the fPTC/PRN susceptibility gene predisposes to renal oncocytomas. Renal oncocytomas are believed to originate from the intercalated cells of the collecting duct (24). Therefore, they are similar in origin to PRN, which are believed to originate from the renal tubular epithelium (25). Like benign thyroid nodules, the renal oncocytoma may represent progression to a nonmalignant neoplasm that is initiated by a germline susceptibility gene. This probability is further supported by the recent report of a familial association of papillary renal neoplasia and renal oncocytoma (26). It is possible that FPTC/PRN may predispose to premenopausal breast carcinoma. One epidemiological study carefully analyzed the incidence of both premenopausal and postmenopausal breast cancer in women with PTC and found an increased incidence of premenopausal breast cancer only (8). This association may be due to a common genetic predisposition to both disorders. Investigation of other kindreds and identification of the susceptibility gene will be necessary to prove these possible associations.
The LOD scores were calculated using highly conservative assumptions. The LOD score calculations incorporated the known characteristics of fPTC, allowed for the possibility that thyroid nodules may not be caused by FPTC/PRN, and excluded two potentially affected subjects (II-12 and III-4) that carry the affected haplotype. There is increased penetrance with increased age in fPTC. The penetrance in men is low, but not precisely known. Therefore, only affected subjects, obligate carriers, and women over age 30 yr were used in the LOD score calculations, because they have the highest and best defined penetrance. As thyroid nodules are relatively common in the general population, any given subject with a thyroid nodule may not carry the fPTC/PRN susceptibility gene. In women, the lifetime probability of developing a palpable thyroid nodule is about 10% (27). This probability increases with age. To allow for the possibility that a palpable thyroid nodule is sporadic and unrelated to FPTC/PRN, women with a thyroid nodule were assigned a 10% probability of being unaffected. This is a conservative estimate. The LOD score calculation excluded subjects II-12 (oncocytoma) and III-4 (premenopausal breast cancer). Although these subjects have neoplasms that are probable or possible manifestations of fPTC/PRN, an accurate estimation of the probability of positive affection status of these two subjects was unknown. Assigning a higher probability of positive affection status to the thyroid nodule subjects and/or assigning a probability of positive affection status to the premenopausal breast cancer and oncocytoma subjects would increase the statistical probability of linkage. Therefore, it is highly unlikely that these conservative assumptions inflated the LOD score estimates.
Palpation was selected over ultrasound as the screening methodology to identify thyroid neoplasms. Thyroid ultrasound is more sensitive than palpation for the identification of thyroid neoplasms, and both techniques identify more abnormalities in older individuals. However, ultrasound is less specific than palpation, as the incidence of small sporadic neoplasms (both benign and malignant) in the general population is relatively high (27, 28). Specificity is critical if linkage analysis is to identify the correct locus of the etiological gene. Therefore, we chose the most specific of the two screening methods. In this regard, it should be noted that all PTC had presented as large (>3 cm) thyroid masses before recognition of the familial relationship. Therefore, these tumors represent highly specific findings. Problems associated with low sensitivity were overcome by using appropriate penetrance estimates and evaluating a large number of subjects (42) in a single kindred. The statistically significant LOD scores validate these strategies.
A single large kindred is more easily analyzed for associated clinical features and linkage than are multiple small families. Therefore, we used a single large fPTC/PRN kindred to identify both the clinical features and the locus of the etiological gene. Subsequent investigations of other kindreds will further clarify the clinical features and refine the locus of the etiological gene.
The fPTC/PRN susceptibility gene has not been mapped previously. A putative gene for a multinodular goiter phenotype (MNG1) has been mapped to 14q31 (9), and a putative gene for an unusual phenotype of oncocytic thyroid neoplasms (TCO) has been mapped to 19p13.2 (3). However, neither of these clinical phenotypes is similar to the one that we and others have described, in which there are multiple typical PTCs. In an evaluation of 56 fPTC kindreds RET, MNG1, and TCO were excluded, and it was suggested that at least 1 other susceptibility gene must exist (7). We excluded these candidate loci as well as 2 others: PTEN, the susceptibility gene for Cowden’s disease, which is associated with follicular thyroid neoplasms (29, 30), and MET, the susceptibility gene for fPRC (21). Importantly, FPTC/PRN was mapped to 1q21 in the studies presented here.
Potential candidate genes located in the chromosomal region of linkage include N-RAS and NTRK1. Activating RAS mutations have been identified in both benign and malignant thyroid neoplasms. However, they are more common in follicular neoplasms than in papillary neoplasms (31, 32, 33, 34, 35). NTRK1 is rearranged in sporadic PTC, but it is not normally expressed in the thyroid (23, 36, 37). Therefore, it is unlikely that a germline mutation of NTRK1 would predispose to the development of PTC. A gene that is rearranged in sporadic papillary renal carcinomas, PRCC, is in the region of 1q21, although its precise location in this broad region has not yet been determined. This gene is expressed in multiple tissues (38) and would be a potential candidate gene if it lies within the chromosomal region of linkage.
We conclude that familial association of PTC with papillary renal neoplasia defines a distinct familial tumor syndrome with a susceptibility gene that maps to 1q21.
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Acknowledgments |
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Footnotes |
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Received October 20, 1999.
Revised December 29, 1999.
Accepted December 31, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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subunit genes in thyroid tumors. Jpn J Cancer Res. 86:737–742.[CrossRef][Medline]
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