Risk of Thyroid Cancer in Relatives of Patients with Medullary Thyroid Carcinoma by Age at Diagnosis

M Fallah et al. Familial risk of medullary 20:5 717–724 Research thyroid carcinoma

Risk of thyroid cancer in relatives of patients with medullary thyroid carcinoma by age at diagnosis

Mahdi Fallah1, Kristina Sundquist2 and Kari Hemminki1,2 Correspondence should be addressed 1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, to M Fallah 69120 Heidelberg, Germany Email 2Center for Primary Health Care Research, Lund University, Malmo¨ , Sweden [email protected]

Abstract

The familial risk of medullary thyroid carcinoma (MTC alone or as part of multiple endocrine neoplasms, MEN2A/MEN2B) is high, so we aimed to answer open questions about the lifetime cumulative risk of thyroid cancer (LCRTC at 0–79 years) among relatives of MTC patients by age and sex. For this nationwide study, a cohort of 3217 ﬁrst-/second-degree relatives (FDRs/SDRs) of 389 MTC patients diagnosed in 1958–2010 in the Swedish Family-Cancer Database was followed for the incidence of thyroid cancer. The LCRTC in female relatives of patients with early-onset MEN2B (diagnosis age !25 years) was 44–57%, representing 140–520 times increase over the risk in their peers without a family history of endocrine tumors (men: LCRTCZ22–52%, 320–750 times) depending on the number of affected FDRs/SDRs. The LCRTC in female relatives of patients with late-onset MEN2B

Endocrine-Related Cancer (diagnosis age R25 years) was about 15–43% (menZ24%). The LCRTC among relatives of early-onset MTC-alone patients was 3–20%. The LCRTC among relatives of late-onset MTC-alone patients was 5–26%. The LCRTC in female relatives of MEN2A patients was 16–63% (menZ52%). The relatives of patients with early-onset MTC exhibited a high tendency to develop early-onset thyroid cancer. Simply available data on the number of FDRs and even SDRs affected with MTC and their age at diagnosis were quite informative for the estimation of the risk of thyroid cancer in probands. In settings where genetic testing is not available or affordable for all, evidence-based cumulative risks reported

in this nationwide study may help physicians to identify very high-risk individuals. Endocrine-Related Cancer (2013) 20, 717–724

Introduction

The incidence of thyroid cancer, the most common extends beyond the nuclear family (Amundadottir et al. endocrine malignancy, continues to increase with over 2004). Medullary thyroid carcinoma (MTC) is the third 213 000 new thyroid cancer cases being diagnosed in the most common thyroid neoplasm (3–10%) after papillary world per year and 48 020 new cases in the USA (6.4% (50–80%) and follicular (10–40%) carcinomas (Hundahl annual percentage increase during 1997–2008; Ferlay et al. et al. 1998, Boyle 2008, Pacini et al. 2010). A strong genetic 2010, Khan et al. 2010, Howlader et al. 2011). The familial component is known for medullary carcinoma, so that risk of thyroid cancer is known to be highest among cancer up to 25% of the cases are estimated to be heritable, sites (Goldgar et al. 1994), for which the increased risk caused by a gain-of-function germline mutation in the

http://erc.endocrinology-journals.org q 2013 Society for Endocrinology Published by Bioscientiﬁca Ltd. DOI: 10.1530/ERC-13-0021 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 05:54:32PM via free access Research M Fallah et al. Familial risk of medullary 20:5 718 thyroid carcinoma

RET proto-oncogene (multiple endocrine neoplasia (MEN) Proband/MTC/MEN2A/MEN2B/MTC alone definitions type 2A and MEN2B and familial MTC (FMTC)) with an In this paper, by probands we mean relatives (FDRs/SDRs) autosomal dominant mode of inheritance (Negri et al. of a patient with MTC, for whom we estimate the familial 2002, DeLellis et al. 2004, Nose 2011). Despite the rarity of risk. ICD-10 code C73 and ICD-O-3 morphology codes these syndromes and MTC in general, early diagnosis is 8510–8511 and 8345–8347 were used to identify MTC especially important, since MTC is a lethal disease if not cases. MEN2B cases (nZ49) were defined as those with promptly and appropriately treated (Sakorafas et al. 2008). MTC and adrenal tumor without parathyroid tumor in A limited number of population-based epidemiolog- the extended family (patients or any of their FDRs or ical studies have been able to quantify the familial risk of SDRs). MEN2A cases (nZ11) were defined as those with histological types of medullary and non-medullary carci- MTC (or unspecified thyroid cancer) and both parathyroid nomas separately, but none had a large sample size to and adrenal tumors in the extended family. MTC-alone analyze the risk stratified by age and sex (Hemminki & cases (nZ329) were defined as those with MTC without Dong 2000, 2001, Hemminki et al. 2005) and none any non-thyroid endocrine tumor (adrenal, parathyroid, reported any clinically relevant absolute risk estimate pituitary, pancreatic insulinoma, or other specified (cumulative risk). One study on MTC has reported only endocrine gland tumors; ICD-10 codes C74–75 and parent–child familial risk (did not report the familial risk among siblings; Hemminki & Dong 2000), and another C25.4) in the extended family. FMTC patients were study has reported that relatives of less than half of 65 defined as those with MTC alone and MTC alone in at cases of MTC have concordant MTC (Hemminki & Dong least four FDRs or SDRs. Only 16 MTC cases that did not 2001). Therefore, in this study, the latest updated version match our above-mentioned definitions were excluded C of the Swedish Family-Cancer Database (FCD) was used, (e.g. MTC only endocrine tumors other than parathyroid which is an unbiased, high-quality nationwide family- or adrenal tumors). cancer database, to be able to comprehensively quantify the familial risk ratio and, for the first time, cumulative Statistical analyses risk of all MTC subtypes by age and sex. Standardized incidence ratios (SIRs adjusted for sex, age, and period of diagnosis of thyroid cancer) were used to Subjects and methods compare thyroid cancer risk in individuals with a family Endocrine-Related Cancer The Statistics Sweden maintains the Multi-generation history of MTC with the risk in their peers without a family Register that covers offspring born in or after 1932 along history of endocrine tumors (ICD-10 C73–75 or C25.4). with their parents and siblings. This Register was linked Follow-up started for parents of the MTC cases at the birth to the Swedish Cancer Registry (1958–2010) to create the of the MTC child and for others at birth, at immigration, Swedish FCD, which is a unique resource in terms of size or on 1st January 1961, whichever was latest. Follow-up (world’s largest of its kind) and validity of data on family was terminated on the date of death, at emigration, or on relationship and cancer. The nationwide cancer registry the date of study completion (31st December 2010). The records all the cancer diagnoses (including thyroid SIRs were calculated as the ratio of observed (O) to cancer) in the country. The 2013 update of these data expected (E) number of cases. The expected numbers includes a total population of over 14.7 million individ- were calculated from sex-, 5-year age group-, and period- uals and more than 1.7 million cancer patients. The data specific (5-year bands) background incidence rates of are organized into child–mother–father triplets; the thyroid cancer in those without a family history of parents were registered at the time of birth of their child, endocrine tumors multiplied by the corresponding allowing tracking of biological parents. For this study, person-years for those with a family history of MTC in we recoded ICD-7, Pathological Anatomic Diagnosis (PAD the study population. 95% CIs were calculated assuming a or C24/Hist), and ICD-O-2 codes to their corresponding Poisson distribution. The SAS Software (by SAS Institute, ICD-10 and ICD-O-3 morphology codes. There was Inc., Cary, NC, USA) version 9.3 was used for data analysis. information on 405 MTC patients in the database. For simplicity, SIRs O50 are rounded off to the nearest Information on 389 (215 women and 174 men) well- order of 10 (e.g. 667–670) in this paper and exact numbers defined MTC patients (about 3% of all thyroid cancer are presented in the tables. patients in the database) and their first-/second-degree The lifetime cumulative risk (assumed to be 0–79 relatives (FDRs/SDRs, nZ3217) was used for this study. years, which is close to the average life expectancy in

Sweden, 81 years, and close to the maximum age of the finding was that in the absence of MEN2B in young second generation in the FCD, 78 years) was calculated FDRs, the presence of MEN2B in young SDRs was also based on the following formulas: age-specific annual associated with an increased LCRTC in probands (one incidence rateZnumber of cases for each 5-year age group affected SDR 41–44% and R2 SDRs 52–55%, depending on divided by person-years of that age group (0–4,., 74–79); sex). The LCRTC in relatives of patients with late-onset age-specific cumulative rateZ5!age group-specific annual MEN2B (diagnosis age R25 years) was generally high, but incidence rate; lifelong cumulative rateZsum of age- lower than the risk in relatives of early-onset MEN2B specific cumulative rates; and cumulative riskZ1Kexp patients (one FDR 21%, R2 FDRs 43%, and SDRs 8–13%). (Kcumulative rate). The 95% CIs for cumulative rate were calculated as follows: cumulative rateG(1.96!5!square MTC alone root of ‘sum of each contributing age-specific cumulative rate divided by its corresponding person-years’). Then, the The LCRTC in female FDRs of patients with MTC alone 95% CIs for cumulative rates were converted to 95% CIs diagnosed at young ages (!25) was 30% (Table 2), which for cumulative risks using a formula the same as the represents about 180-fold increase over the risk in their above. To avoid overestimation of cumulative risk due to peers without a family history of endocrine tumors (men: ignorance of competing causes of death, in all the LCRTCZ10%, about 210-fold). When there were one or calculations, individual person-years were used, so that more SDRs with early-onset MTC alone in a family, the the person-year calculation was stopped in the year of LCRTC in other relatives was 2–6%, depending on death if the person had died during the study period. proband’s sex and age. The LCRTC in relatives of patients The age-specific incidence of thyroid cancer among with MTC alone diagnosed at older ages (R25) was relatives of MEN2/MTC-alone patients peaked at age generally higher than the population risk, but lower 15–19 years in this study and dropped at age 25–29 years than the risk in relatives of early-onset MTC-alone patients and again increased with some other drops due to small (one FDR 6% in women and 4% in men). sample size in older ages. Therefore, we used the cutoff age of 25 years to distinguish between early-onset and Multiple endocrine neoplasia type 2A late-onset familial thyroid cancers. The LCRTC in FDRs of patients with MEN2A was 40%, representing about 290-fold increase over the risk in their Endocrine-Related Cancer Ethics peers without a family history of endocrine tumors The Lund regional Ethics Committee approved the (Supplementary Table 1, see section on supplementary study protocol. data given at the end of this article).

Risk trend by age Results The age-speciﬁc cumulative risk of thyroid cancer (CRTC) by The lifetime cumulative risk of thyroid cancer (LCRTC) family history of MEN2B is shown in Fig. 1 (upper panels). among individuals without a family history of any In general, the CRTC in a proband with a family history endocrine tumor was 0.4% in women and 0.2% in men. of MEN2B at younger ages (!25) started to increase at The familial risks of MTC by subtype of MTC younger ages, while the CRTC when a relative was diagnosed (MEN2B/MTC alone/MEN2A), age at diagnosis (!25 or with MTC at older ages started to increase at older ages. R25 years), number (1 or R2) and type of relationship A similar pattern was observed for the CRTC in relatives (FDR or SDR only) of affected relatives, and proband’s age of MTC-alone patients (lower panels, Fig. 1). More detailed and sex were as follows: information on the CRTC of MEN2A/MEN2B/MTC alone is given in Supplementary Tables 2, 3 and 4, see section Multiple endocrine neoplasia type 2B on supplementary data given at the end of this article. The LCRTC in female FDRs of patients with early-onset MEN2B (diagnosis age !25 years) was 55% (Table 1), Discordant cancer sites which represents about 420-fold increase over the risk in their peers without a family history of endocrine tumors Among all the non-endocrine discordant cancers, only the (men: LCRTCZ42%, about 750-fold). An interesting risk of colorectal cancer (SIRZ3.2, 95% CIZ1.1–7.6, nZ5)

http://erc.endocrinology-journals.org q 2013 Society for Endocrinology Published by Bioscientiﬁca Ltd. DOI: 10.1530/ERC-13-0021 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 05:54:32PM via free access Endocrine-Related Cancer O:1.50EC1-01Pitdi ra Britain Great in Printed 10.1530/ERC-13-0021 DOI: http://erc.endocrinology-journals.org Research

Table 1 SIRs and CRs of thyroid cancer in relatives (probands) of MEN2B patients

Family history of MEN2B

Proband’s info 1 FDR R2 FDRs 1 SDR only R2 SDRs only alhe l aiilrs fmedullary of risk Familial al. et Fallah M

q Sex Age (years) n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI 03SceyfrEndocrinology for Society 2013 Patient’s info Age at MEN2B diagnosis in the family, any

All All 28 229 (152–331) 40 (26–51) 8 316 (136–622) 46 (17–65) 14 165 (90–277) 28 (13–40) 9 266 (122–506) 51 (18–71) !25 15 1889 (1057–3115) 21 (11–30) 2 1247 (151–4506) 15 (0–31) 4 546 (149–1399) 6 (0–12) 2 653 (79–2360) 9 (0–21) R25 13 114 (61–195) 24 (10–36) 6 253 (93–550) 37 (8–57) 10 129 (62–237) 23 (8–35) 7 228 (92–470) 46 (11–68) Women All 17 198 (115–317) 43 (24–58) 5 295 (96–689) 51 (8–74) 6 101 (37–219) 31 (5–49) 5 193 (63–451) 56 (4–80) !25 9 1393 (637–2645) 23 (9–36) 1 771 (20–4296) 13 (0–34) 2 350 (42–1264) 6 (0–15) 1 390 (10–2175) 8 (0–23) R25 8 101 (44–198) 26 (7–41) 4 256 (70–655) 44 (1–68) 4 74 (20–190) 26 (0–45) 4 171 (47–439) 52 (0–77) Men All 11 303 (151–542) 35 (15–51) 3 356 (74–1042) 41 (0–67) 8 317 (137–624) 26 (7–40) 4 507 (138–1299) 42 (0–67) !25 6 4048 (1485–8810) 18 (4–30) 1 3262 (83–18 172) 16 (0–40) 2 1245 (151–4499) 6 (0–14) 1 2002 (51–11 153) 10 (0–27) R25 5 144 (47–335) 21 (1–37) 2 247 (30–891) 30 (0–57) 6 254 (93–552) 21 (3–36) 3 406 (84–1187) 36 (0–62) Age at MEN2B diagnosis !25 years

All All 22 490 (307–742) 50 (32–64) 3 431 (89–1260) 39 (0–66) 12 259 (134–452) 42 (20–59) 8 284 (123–559) 57 (21–76) !25 13 2591 (1380–4431) 29 (15–41) 1 1209 (31–6738) 14 (0–37) 3 1459 (301–4265) 12 (0–25) 1 947 (24–5275) 11 (0–28) hri carcinoma thyroid

ulse yBocetﬁaLtd. Bioscientiﬁca by Published R25 9 226 (103–429) 30 (10–45) 2 326 (40–1178) 29 (0–56) 9 203 (93–386) 34 (12–51) 7 258 (104–532) 52 (16–72) Women All 15 422 (236–697) 55 (31–71) 2 522 (63–1885) 57 (0–88) 4 143 (39–365) 44 (0–68) 4 189 (52–484) 55 (0–80) !25 8 1872 (808–3688) 30 (10–45) 1 1542 (39–8591) 25 (0–58) 1 722 (18–4022) 9 (0–25) 0 R25 7 224 (90–462) 36 (9–55) 1 314 (8–1749) 43 (0–81) 3 113 (23–329) 38 (0–64) 4 196 (54–502) 55 (0–80) Men All 7 749 (301–1543) 42 (11–62) 1 320 (8–1783) 22 (0–52) 8 437 (189–862) 41 (13–60) 4 569 (155–1456) 52 (1–77) !25 5 6737 (2187–15 721) 28 (4–45) 022985 (362–10 782) 13 (0–28) 1 3442 (87–19 176) 18 (0–45) R25 2 232a (28–840) 20a (0–42) 1 339 (9–1891) 22 (0–52) 6 340 (125–741) 32 (5–51) 3 445 (92–1301) 42 (0–69) Age at MEN2B diagnosis R25 years

All All 6 78 (29–169) 21 (3–36) 3 193 (40–563) 43 (0–70) 2 52 (6–187) 8 (0–18) 1 228 (6–1269) 13 (0–34) !25 2 684 (83–2470) 6 (0–15) 01190 (5–1058) 2 (0–7) 1 853 (22–4754) 13 (0–34) R25 4 54 (15–138) 16 (0–30) 3 201 (42–588) 43 (0–70) 1 30 (1–167) 6 (0–15) 0 Women All 2 40 (5–143) 17 (0–37) 3 229 (47–669) 43 (0–70) 2 63 (8–229) 15 (0–33) 1 281 (7–1567) 24 (0–56) !25 1 458 (12–2550) 7 (0–19) 01231 (6–1286) 5 (0–13) 1 1019 (26–5677) 24 (0–56) R25 1 21 (1–116) 11 (0–29) 3 241 (50–704) 43 (0–70) 1 37 (1–205) 11 (0–29) 0 Downloaded fromBioscientifica.com at09/28/202105:54:32PM Men All 4 148 (40–380) 24 (0–43) 000 !25 1 1351 (34–7528) 6 (0–17) 000 R25 3 114 (24–335) 19 (0–38) 000

FDR, ﬁrst-degree relative; SDR only, second-degree relative with no affected FDR; bold type standardized incidence ratio (SIR), 95% CI did not include 1.00. Italic numbers represent cumulative risk (CR). CR at 25–79 years was reported for proband’s age R25 years and CR at 0–79 years for ‘all’ ages. a Example: CR of thyroid cancer at 25–79 years in a man (proband) with a family history of early-onset MEN2B (diagnosis age !25 years) only in his mother (1 FDR) is 20%, representing a 232-fold higher 20

risk than the risk in his peers without a family history of endocrine tumors. :5 720 via freeaccess Endocrine-Related Cancer O:1.50EC1-01Pitdi ra Britain Great in Printed 10.1530/ERC-13-0021 DOI: http://erc.endocrinology-journals.org Research

Table 2 SIRs and CRs of thyroid cancer in relatives (probands) of MTC-alone patients

Family history of MTC alone

Proband’s info 1 FDR R2 FDRs 1 SDR only R2 SDRs only alhe l aiilrs fmedullary of risk Familial al. et Fallah M Sex Age (years) n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI n SIR 95% CI CR% 95% CI q

03SceyfrEndocrinology for Society 2013 Patient’s info Age at MTC diagnosis in family, any

All All 27 24 (16–35) 8 (5–11) 5 135 (44–314) 24 (3–40) 4 4 (1–11) 0.4 (0–0.9) 1 10 (0–58) 2 (0–7) !25 9 239 (109–454) 3 (1–5) 2 1174 (142–4239) 10 (0–23) 3 23 (5–66) 0.3 (0–0.6) 0 R25 18 17 (10–26) 5 (3–8) 3 85 (17–247) 15 (0–30) 1 1 (0–7) 0.2 (0–0.5) 1 11 (0–61) 2 (0–7) Women All 19 23 (14–36) 10 (5–14) 3 103 (21–301) 29 (0–52) 2 3 (0–10) 0.5 (0–1.2) 0 !25 5 161 (52–376) 3 (0–6) 2 1582 (192–5714) 21 (0–43) 1 9 (0–51) 0.2 (0–0.5) 0 R25 14 18 (10–30) 7 (3–11) 1 36 (1–200) 10 (0–27) 1 2 (0–9) 0.3 (0–0.9) 0 Men All 8 27 (12–53) 6 (2–10) 2 248 (30–894) 20 (0–41) 2 9 (1–33) 0.4 (0–0.9) 1 31 (1–175) 5 (0–13) !25 4 608 (166–1558) 3 (0–6) 0286 (10–311) 0.4 (0–0.9) 0 R25 4 14 (4–35) 3 (0–6) 2 262 (32–946) 20 (0–41) 0 1 32 (1–180) 5 (0–13) Age at MTC diagnosis !25 years

All All 11 173 (86–310) 20 (8–30) 2 131 (16–472) 17 (0–35) 3 12 (2–34) 3.4 (0–7.2) 1 15 (0–82) 3 (0–9)

!25 8 983 (425–1938) 13 (4–20) 2 1811 (219–6543) 17 (0–35) 2 179 (22–646) 2.5 (0–5.9) 0 carcinoma thyroid ulse yBocetﬁaLtd. Bioscientiﬁca by Published R25 3 54 (11–158) 8 (0–17) 0 1 4 (0–23) 0.9 (0–2.7) 1 15 (0–85) 3 (0–9) Women All 8 176 (76–348) 30 (8–46) 2 175 (21–630) 33 (0–61) 1 5 (0–29) 1.7 (0–4.9) 0 !25 5 753 (244–1757) 15 (2–26) 2 2431 (294–8783) 33 (0–61) 00 R25 3 78 (16–227) 17 (0–34) 0 1 5 (0–31) 1.7 (0–4.9) 0 Men All 3 164 (34–480) 10 (0–20) 0230 (4–108) 5.9 (0–13.4) 1 45 (1–249) 6 (0–16) !25 3 2010 (414–5873) 10 (0–20) 021045 (127–3777) 5.9 (0–13.4) 0 R25 000146 (1–254) 6 (0–16) Age at MTC diagnosis R25 years

All All 16 15 (9–25) 5 (2–8) 2 130 (16–470) 26 (0–51) 1 1 (0–8) 0.1 (0–0.3) 0 !25 1 34 (1–189) 0 (0–1) 0 1 8 (0–46) 0.1 (0–0.3) 0 R25 15 15 (8–24) 5 (2–7) 2 133 (16–481) 26 (0–51) 00 Women All 11 14 (7–26) 6 (2–9) 1 82 (2–459) 22 (0–52) 1 2 (0–11) 0.2 (0–0.6) 0

Downloaded fromBioscientifica.com at09/28/202105:54:32PM !25 0 0 1 10 (0–56) 0.2 (0–0.6) 0 R25 11 15 (7–26) 6 (2–9) 1 84 (2–469) 22 (0–52) 00 Men All 5 18 (6–42) 4 (0–8) 1 310 (8–1725) 28 (0–63) 00 !25 1 197 (5–1096) 1 (0–2) 000 R25 4 14a (4–37) 3a (0–7) 1 318 (8–1770) 28 (0–63) 00

FDR, ﬁrst-degree relative; SDR, second-degree relative; bold type standardized incidence ratio (SIR), 95% CI did not include 1.00. Italic numbers represent cumulative risk (CR). CR at 25–79 years was reported for proband’s age R25 years and CR at 0–79 years for ‘all’ ages. 20 aExample: CR of thyroid cancer at 25–79 years in a man (proband) with a family history of late-onset MTC alone (diagnosis age R25 years) only in his mother (1 FDR) is 3%, representing a 14-fold higher :5 risk than the risk in his peers without a family history of endocrine tumors. 721 via freeaccess Research M Fallah et al. Familial risk of medullary 20:5 722 thyroid carcinoma

70 ≥2 FDRs age <25 MEN2B women MEN2B men ≥2 SDRs ≥2 SDRs 1 FDR age <25 60 1 SDR age <25 1 FDR age <25 ≥ ≥ 2 FDRs age 25 ≥2 FDRs 1 FDR age ≥25 1 SDR age <25 50 1 SDR age ≥25 No FDR/SDR 1 FDR age ≥25 No FDR/SDR 40

0 0 10203040506070800 1020304050607080 By age (years) By age (years)

60 ≥ MTC-alone women MTC-alone men 4 FDRs/SDR ≥2 FDRs ≥2 FDRs age <25 1 FDR age <25 1 FDR age <25 ≥ 50 ≥2 FDRs age ≥25 2 SDRs ≥ 1 FDR age ≥25 1 FDR age 25 1 SDR 1 SDR No FDR/SDR No FDR/SDR 40

Endocrine-Related Cancer 20

10 Cumulative risk of thyroid cancer (%) Cumulative risk of thyroid cancer (%)

0 0 10203040506070800 1020304050607080 By age (years) By age (years)

Figure 1 Cumulative risk of thyroid cancer in relatives (probands) of MEN2B (upper panels) and MTC-alone (lower panels) patients by proband’s sex and age. FDR, ﬁrst-degree relative; SDR, second-degree relative with no affected ﬁrst-degree relative.

was significantly increased when a FDR had MEN2B sex- and age-specific estimates for cumulative risk by (data not shown), which can be a chance finding. No case family history status and age at diagnosis of relatives. of non-medullary thyroid cancer was found among the The familial risk is usually presented as a risk ratio (e.g. relatives of MTC patients. SIR), which needs to be converted to absolute risk to be meaningful in clinical practice. This is the first time that the CRTC in relatives of MTC patients is additionally Discussion presented in a nationwide cohort study. Cumulative risk The unique resource of the Swedish FCD enabled us is an absolute risk measure, tangible to clinicians and to study the familial risk of MTC as part of MEN2 patients and their family members. The CRTC in women syndromes (type A and B) or MTC alone and to provide with one FDR affected with early-onset MEN2B was

already about 30% by age 25 years (men 28%; lifetime risk: favor of unbiased estimates, although one should also about 55% in women and 42% in men, much higher than consider the CIs when it comes to the application of that in the general population (LCRTC !0.5%)). When results in clinical practice. MEN2B was diagnosed at older ages, the LCRTC (17–24%), In conclusion, simply available data on the number of especially CRTC (6–7%) at 0–24 years, was substantially FDRs and even SDRs affected with MTC and their age at lower than that of early-onset MEN2B. The same pattern diagnosis were quite informative for the estimation of the (high risk of developing early-onset cancer when relatives risk of thyroid cancer in probands. The relatives of patients had early-onset MTC and relatively lower risk of early- with early-onset MTC exhibited a high tendency to onset cancer in relatives of late-onset MTC patients, develop early-onset thyroid cancer. This may suggest although still higher than the risk in the general that age at diagnosis of thyroid cancer in individuals is population) could be observed in one FDR with MTC to some extent predetermined by age at diagnosis of MTC alone too. On the one hand, these may suggest that the in their relatives. In settings where genetic testing is not age at diagnosis of thyroid cancer in individuals may be to available or affordable for all, evidence-based cumulative some extent predetermined by the age at diagnosis of MTC risks in this nationwide study may help physicians to in their relatives. On the other hand, the tendency for identify very high-risk individuals. concordant age at diagnosis might partly be due to the difference in average age at diagnosis between different

subtypes of MTC (MTC alone at older ages and MEN2B and Supplementary data MEN2A at younger ages) and concordant familial associ- This is linked to the online version of the paper at http://dx.doi.org/10.1530/ ation of these MTC subtypes, although the role of more ERC-13-0021. intensive earlier surveillance among relatives of early- onset MTC patients could not be ruled out. Although SIRs (risk ratios) for men were usually higher Declaration of interest The authors declare that there is no conflict of interest that could be than those for women, the LCRTC generally remained perceived as prejudicing the impartiality of the research reported. higher in women than in men with MEN2/MTC-alone patients in their family (Fig. 1). This is in line with the higher risk of thyroid cancer in women (0–74 years Funding cumulative riskZ0.47%) in the general population than This work was supported by the Swedish Council for Working Life and Endocrine-Related Cancer Social Research and the German Cancer Aid. The funding sources had no in men (0.15%) (Ferlay et al. 2010). role in any stage of this study. The present study, which is the largest yet published, benefited from the nationwide cohort with unbiased data on family history of cancers. However, the histological Author contribution statement type used in older periods of time (less specific codes) in K Hemminki and M Fallah were responsible for study concept and design; such a long follow-up study may not be as accurate as that K Sundquist was responsible for study material provision; M Fallah carried out data analysis; M Fallah and K Hemminki were involved in study result used in recent years (e.g. MTC could have been coded as interpretation and manuscript writing; and all authors commented on the unspecified thyroid cancer before 1985). This in turn could manuscript and gave final approval for the manuscript. be the source of a potential bias toward the under- estimation of SIRs only for concordant histological types. We tried to rectify this potential bias by reporting the risk References of thyroid cancer (medullary, non-medullary, and unspe- Amundadottir LT, Thorvaldsson S, Gudbjartsson DF, Sulem P, cified together) in relatives of known medullary cases. We Kristjansson K, Arnason S, Gulcher JR, Bjornsson J, Kong A, counted individuals with unspecified thyroid cancers as Thorsteinsdottir U et al. 2004 Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. MEN2A if they had a personal or family history of both PLoS Medicine 1 e65. (doi:10.1371/journal.pmed.0010065) parathyroid and adrenal tumors because these few highly Boyle PL & Levin B 2008 World Cancer Report 2008. Lyon, France: IARC likely MEN2A cases exhibited a familial risk that was very Press. DeLellis RA, Lloyd RV, Heitz PU & Eng C 2004 In World Health Organization similar to that exhibited by those with well-defined Classification of Tumours: Pathology and Genetics of Tumors of Endocrine MEN2A (MTC and parathyroid and adrenal tumors). Organs. Lyon, France: IARC Press. Statistically significant sex- and age-specific SIRs, however, Ferlay J, Shin HR, Bray F, Forman D, Mathers C & Parkin DM 2010 GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: consistently showed a high familial risk in line with the IARC CancerBase no. 10 (Internet). Lyon, France: International pattern of overall results (internally validated), which is in Agency for Research on Cancer. (available at: http://globocan.iarc.fr)

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Received in ﬁnal form 23 July 2013 Accepted 7 August 2013 Made available online as an Accepted Preprint 8 August 2013 Endocrine-Related Cancer