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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 11 5307-5312
Copyright © 2001 by The Endocrine Society

Endocrine Care

Increased Risk for Nonmedullary Thyroid Cancer in the First Degree Relatives of Prevalent Cases of Nonmedullary Thyroid Cancer: A Hospital-Based Study

Tuya Pal, Florian D. Vogl1, Pierre O. Chappuis, Richard Tsang, James Brierley, Helene Renard, Kevin Sanders, Tania Kantemiroff, Sabira Bagha, David E. Goldgar, Steven A. Narod and William D. Foulkes2

Center for Research in Women’s Health, Sunnybrook and Women’s College Health Sciences Center (T.P., S.B., S.A.N.), Toronto, Ontario, Canada M5G 1N8; Unit of Genetic Epidemiology, International Agency for Research on Cancer (F.D.V., H.R., D.E.G.), 69008 Lyon, France; Division of Medical Genetics, Department of Medicine, Montréal General Hospital and Cancer Prevention Research Unit, Sir Mortimer B. Davis-Jewish General Hospital, McGill University (P.O.C., K.S., T.K.), Montréal, Québec, Canada H3G 1A4; Department of Radiation Oncology, Princess Margaret Hospital, University Health Network (R.T., J.B.), Toronto, Ontario, Canada M5G 2M9; and Program in Cancer Genetics, Departments of Oncology and Human Genetics (W.D.F.), McGill University, Montréal, Québec, Canada H2W 1S6

Address all correspondence and requests for reprints to: W. D. Foulkes, M.B., Ph.D., Division of Medical Genetics, Montréal General Hospital/Room L10-120, 1650 Cedar Avenue, Montréal, Québec, Canada H3G 1A4. E-mail: william.foulkes{at}mcgill.ca

Abstract

The genetic basis for nonmedullary forms of thyroid cancer (NMTC) is less well established than that of medullary thyroid cancer. However, epidemiological and family studies suggest that a proportion of NMTC may be due to inherited predisposition. To estimate the familial risk of thyroid cancer, we conducted a hospital-based case-control study at the Princess Margaret Hospital in Toronto, Ontario, Canada, and at 2 university hospitals in Montréal, Québec, Canada. We obtained pedigrees from 339 unselected patients diagnosed with NMTC and from 319 unaffected ethnically matched controls. Family histories of cancer were obtained from the cases and controls for 3292 first degree relatives of cases and controls. Seventeen cases (5.0%) and 2 controls (0.6%) reported at least one first degree relative with thyroid cancer.

In relatives of patients with thyroid cancer, the incidence of any type of cancer (including NMTC) was 38% higher than in relatives of controls (incidence rate ratio, 1.4; 95% confidence interval, 1.1–1.7). The relative risk for thyroid cancer was 10-fold higher in relatives of cancer patients than in controls (incidence rate ratio, 10.3; 95% confidence interval, 2.2–47.6).

Our findings suggest that hereditary or other familial factors are important in a small proportion of NMTC. Molecular studies are needed to determine the genetic basis of cancer susceptibility in these families.

THE INCIDENCE OF thyroid cancer in Canada is 3/100,000 in males and 9/100,000 in females (1) and is increasing at an average rate of more than 2%/yr. An increased ability to detect thyroid cancer may be part of the reason for this increase, but other factors may also be important. The rate of increase is less pronounced in men, and mortality rates for both men and women have remained quite stable. Nonmedullary thyroid cancer (NMTC) refers to malignancies arising from the epithelial cells of the thyroid and accounts for 80–90% of malignant thyroid tumors (2, 3). The main subtypes of NMTC include papillary thyroid carcinoma and follicular thyroid carcinoma. Papillary thyroid carcinomas account for 80% of NMTCs, and follicular thyroid carcinomas account for a further 15%.

Although most NMTC are thought to be sporadic, several studies have reported a 4- to 9-fold increased risk of thyroid cancer in relatives of patients (4, 5, 6, 7, 8). The prevalence of familial cases among all NMTCs ranges between 3.5–6.2% (5, 7, 9, 10, 11). The clustering of NMTC in a family may be the result of a known cancer predisposing syndrome, such as familial adenomatous polyposis (FAP) or Cowden disease (12, 13). Conversely, several families have been reported with clustering of NMTC without evidence of an identifiable familial cancer syndrome. The NMTCs in these families are often bilateral or multifocal, occur at an earlier age than the sporadic forms, are often associated with benign thyroid pathologies (5), and may have a more aggressive course (14). Several published pedigrees suggest an autosomal dominant mode of inheritance with incomplete penetrance and variable expressivity (5, 15, 16, 17, 18, 19).

The purpose of this study was to estimate relative risks (RR) for the occurrence of cancer of all types in first degree relatives of unselected cases of NMTC compared with first degree relatives of cancer-free controls in a hospital-based setting.

Subjects and Methods

Study subjects

The study protocol was approved by the ethics committees of the University of Toronto and the Princess Margaret Hospital in Toronto and the Montréal General and Sir Mortimer B. Davis-Jewish General Hospitals in Montréal. Informed consent was obtained from all the subjects. In Ontario, patients were recruited from the thyroid cancer clinic at the Princess Margaret Hospital from December of 1997 to June of 1999. The study included patients with pathologically confirmed NMTC diagnosed between 1986 and 1998. There were a total of 198 patients approached, of whom 163 agreed to participate (82.3% participation rate). In Québec, patients were recruited by studying the medical records of all cases of NMTC from the offices of the 3 surgeons who performed the majority of thyroid operations at the McGill University-affiliated hospitals. All cases were diagnosed between 1986 and 1996. After review of all potential cases, 206 NMTC patients were contacted, of whom 176 agreed to participate (85.4% participation rate).

Controls were matched for ethnicity with the cases. In Ontario, this matching was performed by using the patient’s spouse as the source of the pedigrees in 116 cases. Spousal controls have been used in other studies and are an effective way to match for age and ethnicity (20). In 8 cases where a spouse was not available, a control pedigree was obtained from a friend of the patient. Spouse or friend controls could not be found for the remaining 39 cases. In Québec, 195 control subjects without thyroid disease or cancer were recruited through the otorhinolaryngology clinic at the Sir Mortimer B. Davis-Jewish General Hospital.

Pedigree information was obtained for participating cases (n = 339) and for controls (n = 319). The family history included current age or age at death, age of diagnosis of cancer, and site of cancer in first degree relatives (parents and siblings) of the proband. Offspring could not be considered for analysis because spousal controls were used in Ontario. No attempts were made to verify the diagnosis of cancer in the first degree relatives; however, the diagnosis of cancer reported in first degree relatives is very likely to be accurate (21, 22, 23).

Statistical analysis

The analysis was performed using a historical cohort approach, with the exposed group being the relatives of the thyroid cancer cases and the unexposed group being the relatives of the controls. Parents and siblings of the cases and controls were considered as study subjects in this analysis. Person-years of first degree relatives were accumulated until age at death or current age at the time of interview of the proband, or until age at diagnosis if the relative had developed cancer.

The cumulative incidence of cancer at various sites was compared between relatives of cases and controls using incidence rates. The point estimate and 95% confidence interval (CI) for the incidence rate ratio (IRR) was calculated for thyroid cancer and cancer sites where overall more than 10 cases had been reported. Where applicable, cancers were grouped into broad categories of hormone-related (breast, ovarian, endometrium, prostate), smoking-related (larynx, lung, bladder), and gastrointestinal (esophagus, stomach, pancreas, liver, small intestine, colorectal) types. Reported IRRs are adjusted for place of enrollment (Ontario/Québec). Additionally, sex-specific IRRs are given where they varied considerably across strata.

With a retrospective study design, we would expect to ascertain fewer of the more aggressive cases of thyroid cancer, resulting in a potential survival bias. However, if hereditary cases were found to have more aggressive disease, as has previously been reported (14, 16, 24), we would expect to ascertain fewer hereditary cases, which would result in an underestimate of the actual risk.

Results

Among the 339 patients with NMTC in the study, 95 (28.0%) were male and 244 (72.0%) were females (sex ratio female/male, 2.6:1). The mean age at diagnosis of thyroid cancer was 44.8 yr (range, 15–90). In total, 1711 first degree relatives of NMTC patients were included in the study (including parents and an average of 3.1 siblings/proband) who contributed a total of 93,986 person-yr of follow-up. A total of 228 cancers at different sites were reported among the relatives of NMTC patients.

There were 319 control subjects, of whom 146 (45.8%) were male and 173 (54.2%) were female. In total, 1581 first degree relatives (including parents and an average of 3.0 siblings/subject) contributed a total of 89,530 person-yr of follow-up. A total of 160 cancers were reported in control relatives. Characteristics of study participants and their relatives are shown in Table 1Go.


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  		Table 1. Descriptive statistics of study participants and their first-degree relatives

 
The most frequently reported cancer sites in first degree relatives were the following (in decreasing order, with n being the number of cancers): colon (n = 64), breast (n = 53), lung (n = 43), prostate (n = 28), stomach (n = 23), thyroid (n = 22), melanoma (n = 14), and endometrium (n = 11).

The RR for any cancer in first degree relatives of NMTC cases was 1.4 (95% CI, 1.1–1.7; Table 2Go). Thyroid cancer accounted for most of the excess cancer risk (IRR, 10.3; 95% CI, 2.2–47.6). However, the IRR for any cancer remained significantly elevated when thyroid cancer was excluded (IRR, 1.3; 95% CI, 1.1–1.7). The IRR for thyroid cancer in female relatives was markedly higher than that in the male relatives (17.1 vs. 3.1, respectively). An elevated RR of at least 50% in relatives of cases was also found for cancer of the prostate (IRR, 2.0), endometrium (IRR, 1.8), breast (IRR, 1.7), and lung (only in males; IRR, 1.6), but these risks were not statistically significant. When grouping hormone-related cancers together, a significantly elevated risk was found (IRR, 1.8; 95% CI, 1.2–2.7).


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  		Table 2. Incidence rate ratios (IRR) and 95% confidence intervals (CI) for different cancer sites in relatives of cases with thyroid cancer and of controls

 
Twenty thyroid cancers occurred in first degree relatives of 17 NMTC cases. The sex ratio for affected relatives was 5.7:1 (female/male). In three families, 2 first degree relatives had thyroid cancer (Fig. 1Go). Among individuals with familial NMTC, one proband had been diagnosed with cutaneous malignant melanoma (2 yr before NMTC) and cervical cancer (7 yr after NMTC). The mother of an individual with NMTC was reported to have been diagnosed with breast cancer as well as NMTC. No other individual affected with NMTC in NMTC families reported a second cancer. In first degree relatives of controls, only 2 thyroid cancer cases were reported. Clinical review of the 17 thyroid cancer families showed that none of the pedigrees was suggestive of a known familial cancer syndrome (i.e. FAP or Cowden syndrome) as the underlying etiology. Further review of the clinico-pathological features of familial NMTC indicated that the mean age at diagnosis was 47.0 yr (range, 26–69), which is not statistically significantly different from that observed in nonfamilial cases (P = 0.48, by Wilcoxon test). Other features are indicated in Table 3Go. Notably, all cancers were of papillary subtype, and 10 were multicentric/multifocal, but goiter and/or nodular hyperplasia was rarely identified.



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  		Figure 1. In each of the pedigrees (A, B, and C), the proband is indicated by an arrow. Black-shaded symbols indicate a diagnosis of cancer. Ages are shown directly below the symbol. Cancer diagnoses are followed by the age at diagnosis. PTC, Papillary thyroid cancer; PFTC mixed papillary and follicular thyroid cancer.

 

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  		Table 3. Clinico-pathological characteristics of the nonmedullary thyroid carcinoma cases with a positive family history of thyroid carcinoma

 
Discussion

In our study we found that 17 of 339 (5.0%) patients with NMTC had at least one first degree relative affected with thyroid cancer. This is consistent with previous reports that found that familial NMTC accounts for approximately 6% of patients with papillary thyroid cancer (18, 25). Familial follicular thyroid cancer appears to be less common than familial papillary thyroid cancer (14). We have not been able to exclude the possibility that some of the excess NMTC observed in relatives is due to attendance at a thyroid clinic because of a possible thyroid mass and subsequent diagnosis of very small invasive NMTC. Although this remains a possibility, it is interesting to note that no familial cases reported goiter, suggesting that nonspecific thyroid enlargement (a possible reason for clinic attendance by a relative, in the context of diagnosis of NMTC in a close relative) was not common in our series of familial NMTC probands. Also, the genetic contribution to NMTC incidence does not seem to have changed very much over the decades (19), whereas if a referral bias were operating, one might expect it to become more common as imaging improves.

NMTC is associated with both FAP and Cowden disease, which are due to mutations in the APC and PTEN genes, respectively. FAP is characterized by multiple adenomatous polyps of the gastrointestinal tract and a high risk of colon cancer. The prevalence of papillary thyroid cancer in patients with FAP is about 2%, and the RR is estimated to be between 5–10 times greater than that of the general population (26); however, in female FAP patients under age 35 yr, the RR of mainly papillary thyroid cancer may be as high as 160-fold that of the general population (27). Sporadic thyroid tumors have previously been analyzed for APC gene mutations, and no significant mutations have been found (28, 29). Cowden disease is characterized by multiple hamartomatous lesions of the skin, mucous membranes, breast, and thyroid. Thyroid cancer has been described in 10% of cases (19). Sporadic thyroid tumors have been analyzed for PTEN mutations, and no mutations have been observed (30). Both FAP and Cowden disease are rare syndromes; thus, their effects would probably not be seen in the present type of study.

Familial RR of cancer have been estimated using the Utah Population Database. Goldgar et al. (6) reported that first degree relatives of patients with thyroid cancer had a RR of 8.6 (95% CI, 4.7–13.7) for developing the same type of cancer. The corresponding risk in our study was 10.3 (95% CI, 2.2–47.6). An increased familial risk of thyroid cancer was also reported in a recent study by Hemminki et al. (8). Seventy-eight families were identified in the Swedish Family-Cancer Database with a parent and child having thyroid cancer. The standardized incidence ratios for NMTC in offspring was 7.8 (95% CI, 3.9–13.2) for sons and 2.8 (95% CI, 1.5–4.5) for daughters. However, we found a higher risk of thyroid cancer in female first degree relatives compared with male first degree relatives (IRR, 17.1 vs. 3.1, respectively).

A relationship between thyroid cancer and other malignancies has not been clearly established. A familial association of breast and thyroid cancer was reported by Goldgar et al. (6), but not in other epidemiological studies (31, 32). Goldgar et al. (6) found a significant excess of breast cancer in relatives of thyroid cancer patients (RR, 1.7; 95% CI, 1.3–2.2). Our study yielded a comparable result with an IRR for breast cancer of 1.7 (95% CI, 1.0–3.0). Other cancers associated with thyroid cancer in the Utah study included soft tissue sarcoma (RR, 2.9; 95% CI, 0.9–4.0), leukemia (RR, 2. 7; 95% CI, 1.1–5.5), and prostate cancer (RR, 1.4; 95% CI, 1.1–1.9). The corresponding RR for prostate cancer in our study was 2.0 (95% CI, 0.9–4.3). Stoffer et al. (5) found a high incidence of colon cancer in the parents of patients with familial papillary thyroid cancer. The increased risk of colorectal cancer in our study was not statistically significant (IRR, 1.3; 95% CI, 0.8–2.1).

To date, linkage studies have identified the locations of three genes for familial NMTC: MNG1 (33), TCO (34), and PTC (35). A large Canadian family of German origin showed linkage of MNG1 to chromosome 14q (33). This family included 18 cases of nontoxic multinodular goiter with 2 individuals having papillary lesions suggestive of papillary thyroid cancer. Subsequently, in a French family, TCO was linked to chromosome 19p13.2 (34). This family contained multiple cases of thyroid carcinomas and adenomas, multiple or isolated, with cell oxiphilia (as seen in Hurthle cell tumors) and a compound architecture of follicular, papillary, and solid structures not resembling any of the typical subclasses of thyroid tumors. Adenomas and carcinomas shared the same properties and were believed to represent different stages of progression to malignancy. More recently, a 3-generation family with 5 cases of papillary thyroid cancer, 3 cases of thyroid nodules, and 2 cases of papillary renal neoplasia was linked to 1q21 (putative gene PTC) (35). The papillary renal cancer seen in the 2 family members included 1 individual who was also affected with papillary thyroid cancer and the other who was an obligate carrier.

Apart from a genetic predisposition, an increased risk of thyroid cancer may be due to shared environmental etiological agents. Several environmental risk factors have been implicated in thyroid cancer. The most important of these is ionizing radiation. A marked increase in papillary thyroid cancer has been documented in children after exposure to radioactive fall-out from accidents at nuclear power plants (36, 37) and testing of nuclear weapons (38, 39). One of the Montréal thyroid cancer patients reported living near Chernobyl during the nuclear accident, but she did not have any affected relatives.

Therapeutic radiation exposure has been studied by Bhatia et al. (40) through investigation of women treated for Hodgkin’s disease with mantle irradiation. Thyroid cancer was the second most commonly observed solid tumor seen in this study (standardized incidence ratio, 32.7; 95% CI, 15.3–55.3) after breast cancer. Radiation exposure for the treatment of acne has also been associated with thyroid cancer (41) with an overall incidence of 31% for those treated during adolescence (42). The results of a study performed at the Princess Margaret Hospital reviewing the records of 382 patients with differentiated thyroid carcinoma showed 14% of the patients to have a history of previous exposure to radiation (43).

Prognostic differences have been noted between familial and sporadic NMTC. Familial NMTC has been suggested to have a more aggressive phenotype in several (14, 16, 24), but not all (25), studies. Individuals with familial NMTC seem to have a high rate of local recurrence (14, 16, 24). The tumors tend to be multifocal and may invade locally and metastasize to regional lymph nodes while they are relatively small (14, 24).

Our study displays the importance of obtaining a family history for patients with NMTC, as hereditary factors are important in a small proportion of these patients. Careful follow-up for patients with a family history of thyroid cancer is indicated through routine physical examinations, as clinical differences between sporadic and familial cases may be present. Molecular studies are necessary to determine the inherited predisposition to cancer in these families.

Acknowledgments

We thank Andrée MacMillan and Drs. Black, Mitmaker, Tabah, and Frenkiel for their help in ascertaining cases and controls in Montréal for this study.

Footnotes

The work in Montréal was supported by the Fonds de la Recherche en Santé du Québec (Québec Family Cancer Network) and the Thyroid Foundation of Canada.

1 Recipient of a Special Training Award from the International Agency for Research on Cancer. Back

2 Chercheur Boursier Clinicien JII of the Fonds de la Recherche en Santé du Québec. Back

Abbreviations: CI, Confidence interval; FAP, familial adenomatous polyposis; IRR, incidence rate ratio; NMTC, nonmedullary thyroid cancer; RR, relative risk.

Received March 12, 2001.

Accepted July 23, 2001.

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals