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Clinical Cancer Research Vol. 6, 1819-1825, May 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Association of Allelic Loss on 1q, 4p, 7q, 9p, 9q, and 16q with Postoperative Death in Papillary Thyroid Carcinoma1

Yutaka Kitamura, Kazuo Shimizu, Shigeo Tanaka, Koichi Ito and Mitsuru Emi2

Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, Kawasaki 211-8533 [Y. K., M. E.]; Department of Surgery II, Nippon Medical School, Tokyo 113-8602 [Y. K., K. S., S. T.]; and Ito Hospital, Tokyo 150-8308 [K. I.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Papillary thyroid carcinomas, most of which are characterized by slow growth and good prognosis, account for the majority of thyroid carcinomas. To provide appropriate postoperative management, it is important to classify them by prediction of their prognosis. To find genetic markers associated with poor prognosis, allelic loss at all 39 nonacrocentric chromosome arms was compared in 24 deceased cases and 45 age-, sex-, stage-, and type-matched survived cases. Allelic loss was examined in primary tumors from both groups using highly polymorphic microsatellite markers on 39 nonacrocentric autosomal arms. Age at diagnosis, sex, stage, and types of tumors were matched between the two groups. No recurrent tumor was used for DNA analysis. Mean fractional allelic loss in the deceased and survived cases was 0.10 ± 0.08 and 0.03 ± 0.05 (P < 0.001). The survived cases showed marginal frequencies of allelic loss throughout all chromosome arms except 22q. The deceased cases showed frequent allelic losses on chromosomes 1q (37%), 4p (21%), 7q (20%), 9p (36%), 9q (31%), and 16q (29%), with significant difference (P < 0.05). These chromosome regions may include tumor suppressor genes whose inactivation is associated with aggressive phenotypes of papillary thyroid carcinoma.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Papillary thyroid carcinoma is the major histological type of differentiated thyroid carcinoma and accounts for ~90% of all thyroid carcinomas. Although papillary thyroid carcinoma is characterized by slow growth and good prognosis in general, a proportion of patients have an unfavorable outcome postoperatively because of local recurrence and distant metastasis or anaplastic transformation of the differentiated tumor (1, 2, 3, 4, 5) . Previous clinicopathological studies have suggested older age, extrathyroidal invasion, distant metastasis, and poorly differentiated histological type at initial treatment as predictive of poor prognosis (1 , 2 , 4, 5, 6, 7, 8, 9, 10) . However, accurate prediction of postoperative outcomes based on these conventional indicators is difficult because of their limited power of prediction. Some institutes use simple thyroidectomy as a standard operation for this type of cancer, whereas others consider neck dissection together with thyroidectomy. In fact, some nonaggressive papillary thyroid carcinomas have been managed by thyroidectomy or simple tumor resection without any further complication, whereas more aggressive forms require extensive operations, including systematic neck dissection and adjuvant therapy to avoid unfavorable outcomes. Thus, it is clear that more precise predictions of postoperative prognoses for patients with papillary thyroid carcinoma are important to clinicians making treatment decisions.

Although rearrangements of the RET gene have been described in a proportion of papillary thyroid carcinomas (11 , 12) , genetic alteration associated with the development and progression of this type of carcinoma in general remains largely unknown. Allelic loss (LOH3 ) of a particular chromosomal region in a tumor is thought to indicate that a tumor suppressor gene normally resident there has been deleted (13) . Although frequent allelic losses have been reported in various cancers, including follicular thyroid carcinoma (another type of differentiated thyroid carcinoma; Ref. 14 ) and anaplastic thyroid carcinoma (15) , no characteristic loss or clinical features associated with such loss has been noted in papillary thyroid carcinomas (16, 17, 18, 19) .

To study allelic loss in association with specific clinical outcomes in papillary thyroid carcinoma, it is necessary to recruit a large panel of patients and to follow them up in a long postoperative period because patients who underwent surgery for this type of cancer generally exhibit a low mortality rate and a long postoperative survival period. In the present study, we examined 39 loci representing all 39 nonacrocentric chromosome arms for allelic losses in DNA from primary tumors using a polymorphic marker for each locus. To identify specific allelic losses that might predict postoperative outcome in primary papillary thyroid carcinoma, we attempted to correlate allelic loss at each of the tested markers with postoperative prognosis by comparing frequencies of each allelic loss among 24 deceased cases and 45 survived cases matched for age at diagnosis, sex, stage, and types of tumors who have been monitored for 10 years after their operation.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Over 7500 patients with thyroid carcinoma were treated at Ito Hospital between 1954 and 1997. The study population of papillary thyroid carcinoma consisted of 24 deceased cases and 45 survived cases. Histological diagnosis was made according to the criteria by the Japanese Society of Thyroid Surgery (21) . Clinical features and treatments performed on the deceased and survived patients are shown in Table 1Citation . The 24 deceased papillary thyroid carcinoma patients consisted of 20 women and 4 men whose primary tumors were operated on between 1954 and 1997 and who died of thyroid carcinoma between 1985 and 1998.


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  		Table 1

Clinical features of the deceased and survived papillary thyroid carcinoma patients

 
A summary of the clinical characteristics of the deceased patients in comparison with those of the survived patient group is shown in Table 1Citation , and a summary of the clinical characteristics of individual deceased patients is shown in Table 2Citation . For the deceased group, mean age at diagnosis of primary tumors and at death was 57.3 (range, 22–86) and 68.3 (range, 47–87), respectively. Mean survival period from the primary surgery was 11.5 years (range, 0.3–36). Clinical stage of the deceased cases at the initial diagnosis of primary tumors by the TNM classification were stage I in 3 cases, stage II in 2 cases, stage III in 16 cases, and stage IV in 3 cases. For those deceased cases, immediate causes of death included respiratory failure attributable to remarkable pulmonary metastasis, massive bleeding from the recurrent local tumor, circulatory failure attributable to compression of the vena cava by mediastinal lymph node metastasis, and gastrointestinal bleeding (Table 2)Citation .


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  		Table 2

Clinical characteristics and allelic losses of each deceased papillary thyroid carcinoma patient

 
The 45 age- and sex-matched survived patients were selected from patients who underwent surgery for papillary thyroid carcinoma in 1987 and 1988. All patients of the survived group were followed for >10 years and were clinically confirmed to be without recurrence and distant metastasis by the end of 1998. The survived patients consisted of 40 women and 5 men. Mean age at initial treatment was 56.2 (range, 21–80). Sex, age at diagnosis, stage, and types of tumors were not significantly different between the deceased group and survived group. Clinical stage of survived cases was stage I in 5 cases, stage II in 10 cases, and stage III in 30 cases (Table 1)Citation . Hemithyroidectomy or total thyroidectomy together with neck dissection were carried out in all patients of the survived group. Thyroxin was given to suppress thyrotropin for at least 5 postoperative years. Informed consent in the formal style of the hospital was obtained from each patient before surgery.

Specimens and DNA Preparation.
Formalin-fixed paraffin-embedded tissue blocks containing both primary tumor and corresponding nontumor tissue were obtained from each case. Both in the deceased cases and survived cases, tumor DNA were obtained from the tissue blocks of primary tumors prepared at initial surgery. From each tissue block, 10–15 slides of 10-µm sections were prepared. Both papillary thyroid carcinoma and nontumor tissue were isolated and compared with a H&E-stained slide by microdissection. Tumor and nontumor DNA were extracted by using DEXPAD (Takara, Tokyo, Japan) according to manufacturer’s instructions and purified by phenol-chloroform extraction.

LOH Analysis.
Allelotyping was carried out in both panels of papillary thyroid carcinomas, deceased and survived, by PCR-based LOH analyses using 39 highly polymorphic microsatellite markers consisting of one marker from each of the nonacrocentric autosomal arms. The loci of markers used in this study are listed in Table 3Citation . Markers were amplified in tumor and corresponding nontumor DNA as previously described (22) . Briefly, PCR was performed in a total volume of 10 µl containing 20 ng of DNA, 10 mM Tris-HCl (pH 8.4), 50 mM KCl, 1.5 mM MgCl2, 0.01% of gelatin, 200 µM dNTPs, 2.5 pmol of [{gamma}-32P] ATP-end-labeled forward primer, 2.5 pmol of reverse primer, and 0.25 units of Taq polymerase. Cycle conditions, in a Gene Amp PCR 9600 System (Perkin-Elmer Cetus Instruments, Norwalk, CT), were 94°C for 3 min, then 30 cycles of 94°C for 30 s, appropriate annealing temperature (55–64°C) for 30 s, and 72°C for 30 s with a final extension of 72°C for 3 min. PCR products were resolved by electrophoresis on denaturing (36% formamide and 8 M urea) 6% polyacrylamide gels at 2000 V for 2–3 h. Size-separated alleles were then visualized by autoradiography.


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  		Table 3

Microsatellite markers used in this study and comparison of the frequency of LOH between the survived and deceased cases of papillary thyroid carcinomaa

 
Definition of LOH.
LOH was assessed by visual inspection of autoradiographs and by measuring signal intensities of polymorphic alleles. Signal intensities were quantified by a Hoefer GS-300 scanning densitometer; peak areas corresponding to each signal were calculated by electronic integration using the GS-370 electrophoresis data system (Hoefer Scientific Instruments, San Francisco, CA). When the signal intensities of alleles of tumor-tissue DNA were compared with those of corresponding nontumor DNA, a reduction in signal intensity >50% was interpreted as LOH. Our PCR-LOH and procedures can distinguish neither trisomy of individual chromosomes and trisomy of the whole chromosomal set nor LOH and reduplication and retention. Also, a possibility that allelic imbalances detected as LOH might represent aneuploidy or allelic amplification remains undistinguished in the present procedure.

Statistical Analysis.
Clinical parameters, FAL, and frequencies of LOH on each chromosome arm between the deceased and survived groups of papillary thyroid carcinoma were compared by the student t test, {chi}2 test, or Fisher’s exact test. Ps of <0.05 were considered statistically significant. All calculations were performed using StatView version 4.5 software (SAS Institute Inc., San Francisco, CA).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Comparison of allelic loss features were performed in DNA of primary tumors between survived cases (good prognosis) and deceased cases (bad prognosis) of papillary thyroid carcinomas. No recurrent tumor was used for DNA analysis. Age at diagnosis, sex, stage, and types of tumors were matched between the two groups. Allelotyping of primary tumors in both the deceased and survived patient groups of papillary thyroid carcinoma was measured by LOH analyses using 39 highly polymorphic microsatellite makers located on each of the nonacrocentromeric chromosome arms. Representative autoradiograms of samples demonstrating LOH at several marker loci are shown in Fig. 1Citation . Table 3Citation summarizes the frequency of LOH observed at each marker locus. Fig. 2Citation displays the LOH frequency schematically. Percent heterozygosity (informativeness) of the polymorphic markers ranged from 38 to 96%, with an average of 73%. Twenty-one of 24 deceased cases and 19 of 45 survived cases showed LOH on at least one chromosome arm. LOH on each arm was observed at frequencies of 0–37% and 0–19% in the deceased and survived cases, respectively. Mean percentages of LOH on each chromosome arm in the deceased and survived cases were 10.4% and 3.1%, with SDs of 11.4 and 4.0, respectively (P < 0.001). In the survived cases, frequent LOH was detected only on 22q where LOH was detected in 6 of 31 cases (19%) with D22S284 at 22q13.1–13.2. In the deceased cases, whereas LOH frequencies were also low on a majority of the chromosome arms (less than 10% LOH in 21 of 39 chromosome arms), high frequencies of LOH were found on chromosome arms 1q, 4p, 7q, 9p, 9q, 16q, and 22q; they were detected on 1q with D1S213 at 1q32–43 (7 of 19; 37%), 4p with D4S2946 at 4p15 (3 of 14; 21%), 7q with D7S2431 at 7q21–22 (2 of 10; 20%), 9p with D9S161 at 9p21 (5 of 14; 36%), 9q with D9S1776 at 9q32–33 (4 of 13; 31%), 16q with D16S3123 (5 of 17; 29%), and 22q with D22S284 at 22q13.1–13.2 (6 of 18; 33%).



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  		Fig. 1. Representative autoradiographs of allelic loss revealed by microsatellite analysis in papillary thyroid carcinoma. Arrowheads, the alleles lost in tumor DNA. N, nontumor DNA. T, tumor DNA.

 


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  		Fig. 2. Frequencies of allelic loss shown for each chromosome arm among both the deceased and survived papillary thyroid carcinoma cases. , the short arms (p); {square}, the long arms (q). *, significant difference in LOH frequency between the deceased and survived cases (P < 0.05).

 
Statistical comparison of the frequency of LOH on each chromosome arm between the both groups (shown in Table 2Citation and Fig. 2Citation ) revealed that the LOH frequency on chromosome arms 1q, 4p, 7p, 9p, 9q, and 16q was significantly higher in the deceased cases than those detected in the survived cases on each respective arm (P < 0.05).

FAL was calculated by dividing the number of chromosomal arms on which allelic loss occurred by the number of chromosomal arms for which allelic markers were informative (23) . Allelic losses, FALs, and clinical features of each deceased papillary thyroid carcinoma patient are shown in Table 2Citation . The mean FALs of the deceased and survived cases were 0.10 (range, 0–0.30) and 0.03 (range, 0–0.22), respectively, with SDs of 0.08 and 0.05, respectively, showing a significant difference (P < 0.001).


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Frequent allelic loss was reported in follicular thyroid carcinomas; the mean rate of LOH was 20% and the mean FAL was 0.20 (14) . In contrast to follicular thyroid carcinoma, papillary thyroid carcinoma has been reported to show a very low rate of LOH by several authors (16, 17, 18) . Our panels of papillary thyroid carcinoma, especially the survived cases, also revealed infrequent allelic loss in most chromosome arms: 3.1% and 10.4% of the mean LOH rate and 0.03 and 0.10 of the mean FAL in the survived and deceased cases, respectively. However, we have here identified several chromosome regions showing a high rate of LOH in papillary thyroid carcinomas. Frequent allelic loss at one locus on chromosome arm 22q was detected in both the survived and deceased cases, whereas the other loci indicating frequent allelic loss were specific for the deceased cases. Loss of 22q may occur as an early genetic event in the development of papillary thyroid carcinoma. Furthermore, frequent allelic loss of 22q has been reported in follicular thyroid carcinoma by microsatellite and comparative genome hybridization analyses (14 , 19) . We have also identified frequent allelic loss on 22q in 6 of 16 anaplastic thyroid carcinomas (15) . Loss of 22q can be observed throughout the carcinomas derived from the follicular cells in the thyroid, suggesting that loss of chromosome 22q plays a basic role in the development of thyroid carcinomas.

The clinical course of papillary thyroid carcinomas after surgery varies from rapid progression with a short length of survival to a completely disease-free interval of >10 years (5) . Thus, prognostic indicators that could determine grade of malignancy, predict postoperative prognosis accurately, and guide adjuvant therapy would be important (20) . To find genetic markers associated with poor prognosis of papillary thyroid carcinoma that are independent of conventional clinicopathological parameters, we compared the frequency of LOH on each chromosome arm between the survived and deceased cases, representing the tumors with favorable and virulent behavior, respectively. In the previous studies (14 , 17 , 24) , a correlation between LOH and clinical outcome was not found in differentiated thyroid carcinomas. Owing to the examination of a large number of deceased cases of papillary thyroid carcinoma, chromosomal loci on 1q, 4p, 7q, 9p, 9q, and 16q were found to reveal significantly higher frequencies of LOH in the deceased cases. Allelic losses on these loci may be associated with poor prognosis in papillary thyroid carcinoma. Moreover, these chromosome regions may implicate potential tumor suppressor genes associated with the aggressive phenotype of papillary thyroid carcinoma.

Chromosomal imbalances that we described as LOH in the present study may sometimes reflect aneuploidy or allelic amplification in addition to allelic loss; chromosome amplifications were not always distinguished from chromosome loss by the PCR-based LOH analysis used in the present study. Thus, a possibility of an involvement of oncogenes, whose activation would be associated with the progression of such tumors in the regions with high rate of allelic imbalance may have to be considered, although Hemmer et al. (19) did not find specific gains of chromosomal regions in 26 papillary thyroid carcinomas by comparative genome hybridization analysis.

Putative tumor suppressor genes on and around the chromosomal loci indicating high frequency of LOH in this study have been described: metastasis suppressor gene KISS1 on 1q32–41 (25) , CDKN2A (26 , 27) and CDKN2B (26) on 9p21, and NF2 (28 , 29) and hSNF5/INI1 (30) on 22q. However, Tung et al. (31) reported infrequent CDKN2A alteration in differentiated thyroid carcinomas. Other candidate loci for tumor suppressors on 1q, 4p, 7q, 9p, 9q, 16q, and 22q were also reported in a variety of tumors (32, 33, 34, 35, 36, 37, 38) , including thyroid carcinomas: 1q in Hürthle cell carcinomas (39) , 7q31.2 (24) and 22q (14) in follicular thyroid carcinomas, and 1q, 11p, and 22q in anaplastic thyroid carcinomas (15) .

Making detailed deletion maps is necessary to determine whether the tumor suppressor genes or loci noted above are related to the development and progression of papillary thyroid carcinoma. Although further prospective study is clearly necessary, allelic losses of the chromosome regions specifically identified in the deceased cases may be a prognostic factor for papillary thyroid carcinoma, the most common type of thyroid malignancy.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Grant-in-Aids for the priority areas of "Cancer Research" and "Genome Science" from the Ministry of Education, Science, Sports, and Culture of Japan and by a Research Grant for Cancer Research from the Ministry of Health and Welfare of Japan. Back

2 To whom requests for reprints should be addressed, at Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan. Phone: 81-44-733-5230; Fax: 81-44-733-5192; E-mail: memi{at}nms.ac.jp Back

3 The abbreviations used are: LOH, loss of heterozygosity; FAL, fractional allelic loss. Back

Received 6/24/99; revised 1/10/00; accepted 2/16/00.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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