Henry Ford Hospital Medical Journal Henry Ford Hospital Medical Journal

Volume 37 Number 3 Article 6

9-1989

Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of

Three Related Syndromes Three Related Syndromes

Hagay Sobol

Steven A. Narod

Isabelle Schuffenecker

Chris Amos

R. Alan B. Ezekowitz

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Recommended Citation Recommended Citation Sobol, Hagay; Narod, Steven A.; Schuffenecker, Isabelle; Amos, Chris; Ezekowitz, R. Alan B.; and Lenoir, Gilbert M. (1989) "Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of Three Related Syndromes," Henry Ford Hospital Medical Journal : Vol. 37 : No. 3 , 109-111. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol37/iss3/6

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons.

Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of Three Related Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of Three Related Syndromes Syndromes

Authors Authors Hagay Sobol, Steven A. Narod, Isabelle Schuffenecker, Chris Amos, R. Alan B. Ezekowitz, and Gilbert M. Lenoir

This article is available in Henry Ford Hospital Medical Journal: https://scholarlycommons.henryford.com/hfhmedjournal/vol37/iss3/6

Hereditary Medullary Thyroid Carcinoma: Genetic Analysis of Three Related Syndromes

Hagay Sobol,* Steven A. Narod,* Isabelle Schuffenecker,* Chris Amos,* R. Alan B. Ezekowitz,' Gilbert M. Lenoir,* and the Groupe d'Etude des l\imeurs a Calcitonine

Hereditary medullary thyroid carcinoma (MTC) appears in three forms: 1) in as.sociation with pheochromocytomas and parathyroid hyperplasia (multiple endocrine neoplasia type 2 A [MEN 2A]); 2) with pheochromocytomas, neuromas of the mucous membranes, and a marfanoid appearance (MEN 2B): and 3) without pheochromocytoma. Despite these differences in presentation, age of onset, and clinical severity, limiled genetic studies suggest lhal the three MTC variants may be due to inherited mutations at the same gene locus. We present furlher dala in support oflhe hypothesis lhal allelic variation may underlie the diversity ofthese endocrine neoplasia syndromes. (Henry Ford Hosp MedJ 1989:37:109-11)

More than 70 families have been identified in France in which two or more members are affected with medullary

thyroid carcinoma (MTC) (I) , Pheochromocytomas are also seen in a majorfiy of these families, Howeven a substantial number of families have only the thyroid tumon Rare cases of multiple endocrine neoplasia type 2B (MEN 2B) have been doc­umented as well.

The gene for MEN 2A has been assigned by linkage to chro­mosome to (2-4). As part of a national screening effort under­taken in collaboration with the Groupe d'Etude des Tumeurs a Calcitonine (GETC), we have perfonned linkage analysis on 33 MTC families using a number of polymorphic probes flanking the centromere of chromosome 10. We present the results by MTC subgroup and discuss the issue of genetic heterogeneity in MTC families.

Methods Thirty-three families suitable for linkage have been identified

by the GETC and other collaborating physicians. Diagnosis of MTC and/or pheochromocytoma was based on pathology re­ports, hospital records, and the results of pentagastrin provoca­tion tests. Details ofthe polymorphisms used are provided else­where (5,6). For the linkage program, penetrance was entered as 10%, 30%, 50%, 80%, and 95% for age groups 0-9, 10-14, 15-19, 20-29, and 30 years and above for the MEN 2A and MTC without pheochromocytoma (MTCWP) families. For MEN 2B, penetrance was set at 50% for ages 5 to 9 and 80% for 10 years and above. The HOMOG program was used to test whether the ob.served data are consistent with a single recombination frac­tion for both the MEN 2A and the MTCWP families (7).

Results Nineteen families with MEN 2A, 13 families with MTCWR

and one family with MEN 2B were suitable for our linkage stud­

ies. Lod scores obtained with five informative probes are pre­sented in the Table (8-11).

Because no recombinafion was found between the MCK2 and IRBRH4 probes in our data (maximum lod = 15.24;9 = 0.00), we also assessed linkage between the MTC gene and the IRBRH4/MCK2 haplotype. tn the MTCWP families, a max­imum lod score of 2.61 was seen at 9 = 0.10. Although these results are supportive of a single genefic locus for the three syn­dromes, the Iod scores attained for the MTCWP and MEN 2B families are insufficient to confinn linkage to the region.

The presence of possible genetic heterogeneity among the families was tested in two ways. First, we were unable to reject the hypothesis that atl tested families were linked at a single locus. Second, when MEN 2A families were compared with the MTCWP families the recombination distances estimated with any of the five probes used did not vary significantly between the two groups (Table). For the MEN203 probe, the P-value ap­proached significance, but this should be interpreted in view of the number of comparisons evaluated.

Discussion Several large families have been reported in which MTC has

been observed in the absence of pheochromocytoma (12-14). The distinction between the MEN 2A and MTCWP subtypes has been supported statistically ( I I ) . Whether the two forms repre-

Subniittcd tor publication: September 30, 1989. Accepted for publication; October 20, 1989. '''International Agency for Research on Cancer, Lyon, France. tHarvard Medical School, Boston, MA. Address con-e.spondence to Dr Lenoir, International Agency for Research on Cancer, 150

Cours Albert-Thomas, 69372 Lyon Cedex 2, France.

Henry Ford Hosp Med J—Vol 37, Nos 3 & 4, 1989 Linkage Analysis of MEN 2 Variants—Sobol et al 109

Table Linkage Resuhs of MTC Families

F 2 0 4

Number of Informative Maximum Recombination

Probes Families _od Score Fraction

IRBPH4 (8) MEN 2A 16 11.76 O.IK)

MTCWP 7 1.06 0.13

MEN 2A versus MTCWP P-value = 0.14

MCK2 (9) MEN 2A 10 14.18 0.00

MEN 2B I 0.59 0.00

MTCWP 9 1.74 0.08

MEN 2A versus MTCWP P-value = 0.10

MEN 203'" MEN 2A 7 2.98 0.00

MEN 2B 1 0.58 0.00

MTCWP 5 0.50 0.17

MEN 2A versus MTCWP P-value = 0.06

TBI4.,34(I0) MEN 2A 4 1.89 0.00

MTCWP 4 0.88 0.01

MEN 2A versus MTCWP P-value = 0.90

4X11 ( I I ) MEN 2A 7 2.89 0.03

MTCWP 7 1.43 O.IO

MEN 2A versus MTCWP P-value = 0.53

*Y. Nakamura, pcrsonal communication. 1989 (unpublished data). Lod scores are maximal at the recombination fractions indicated. 1RBPH4 is informative with Bglll in all families except one in which it is informauve

with Mspl. The homogeneity test calculates the P-value for rejecting a single recombination frac­

tion for thc two M TC subgroups.

F 4 2 6

11

111 L i i i i'':- • i

-O

•

Fig 1—Pedigree of MTCWP family demonstrating possible re­duced penetrance in younger individuals. Solid circles (females) and solid squares (males) represent affected individuals.

sent discrete clinical entities or should be considered as part ofa spectrum of tumor liability is not yet known (11,15).

MTC tends to be less aggressive in families in which pheo­chromocytoma does not appear (13) and the penetrance of thy­roid malignancy appears to be reduced. In a family recently re­ported to the GETC, none of the 23 at-risk individuals in the third generation was found to be affected (Fig 1). Twelve ofthese family members, ranging in age from 17 to 36 years, were nega­five with pentagastrin testing and three had equivocal results. Based on penetrance figures published for MEN 2A (16), six cases of MTC (or C-cell hyperplasia) are expected. Linkage to chromosome 10 has been reported in two large MTCWP fami­lies (maximum lod = 3.27; 9 = 0.15) (17). Several factors may

AIA A D B|A

I

11 i i i i AlA D D AIA

Pif, 2—Pedigree of MEN 2B family. Letters represent marker al­leles. Upper letters = IRBP.H4, middle letters = MCK2, lower letters = MEN203. MEN2B mutation appears linked to AAB haplotype.

account for a higher recombination fraction in MTCWP families than in MEN 2A families. One is chance variation. Also, the two different susceptibility loci may be situated close to each other but not at identical sites. Altematively, if a proportion of the MTCWP families are unlinked (ie, 9 = 0.50). the recom­bination fraction for the entire subgroup witl be elevated (7). Fi­nally, if the linkage parameters, which are derived from studies of MEN 2A families, are inappropriate for the MTCWP fami­lies, the recombination fraction may be biased. In our data, when the maximum penetrance ofthe MTCWP families was re­duced to a 50% estimate, the recombination fraction for IRBPH4 became 0.03 (Iod = 1.48) in this subgroup. Pen­etrance studies among MTCWP families should be a priority if the issue of heterogeneity is to be solved.

In contrast to MTCWP, thyroid tumors appear at a very young age in MEN 2B and are often very aggressive (15,18). The me­dian age of MTC diagnosis in one series was 18 years (18). tn our family with MEN 2B (Fig 2), the mother, 1-2, had surgery for MTC at age 17 and was found to have metastatic disease at age 41. Her affected daughters had MTC diagnosed at 6 and 12 years of age. Pentagastrin test results have been negative to date in the two healthy children (11 and 8 years old). Although segregation of the marker alleles ofthe probes tested is consistent with link­age in this family, more data are required before the location of the gene for MEN 2B can be assigned with confidence. One re­port associates the MEN 2B gene to the chromosome 10 cen­tromeric region with a lod score of 2.68 (19).

These data do not suggest that different genetic loci may un­derlie the different MTC syndromes. There were more recombi­nants observed in the MTCWP families than in the MEN 2A families, but in no individual family could linkage be readily excluded. Epidemiologic studies of MTCWP families will be helpful in determining the linkage parameters with precision so

110 Henry Ford Hosp Med J —Vol 37. Nos 3 & 4. 1989 Linkage Analysis of MEN 2 Variants—Sobol et al

that the problem of heterogeneity can be addressed with confidence.

Acknowledgments We thank M. F Lavoue, C. Bonnardel, S. Pauly, and B. S.

Sylla for their helpful advice and technical assistance. This study was funded in part by the Ligue Nationale Fran-

caise contre le cancer du departement de I'Ain and by the On­tario Ministry of Health.

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