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© 2001 American Society for Clinical Oncology Estimation of Risk of Inherited Medullary Thyroid Carcinoma in Apparent Sporadic PatientsFrom the Departments of Nuclear Medicine and Endocrine Oncology, Tumor Biology, Clinic of Oncological Surgery, and the Department of Pathology, Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Gliwice; and the Department of Endocrinology, Medical Center of Postgraduate Education, Warsaw, Poland. Address reprint requests to Barbara Jarzab, MD, Department of Nuclear Medicine and Endocrine Oncology, Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Wybrzeze AK 15, 44-101 Gliwice, Poland; email: bjarzab{at}io.gliwice.pl
PURPOSE: The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. PATIENTS AND METHODS: One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing. RESULTS: Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P < .05). CONCLUSION: The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.
MEDULLARY THYROID carcinoma (MTC) is a tumor that develops from thyroid C cells. MTC may occur sporadically or as a part of the inherited cancer syndrome known as multiple endocrine neoplasia type 2 (MEN 2) (for a review see1-3). MEN 2A is characterized by a concomitant predisposition to adrenal tumors (pheochromocytomas) and to parathyroid hyperplasia. In MEN 2B syndrome, MTC is associated with pheochromocytomas and a variety of developmental abnormalities including marfanoid habitus, mucosal neuromas, and hindgut hyperganglionosis. In familial medullary thyroid carcinoma (FMTC), an inherited predisposition to MTC is the only feature of the disease. Inherited MTCs are caused by germline mutations of the RET gene.2-4 Missense mutations are observed in cysteine codons in exons 10 (codons 609, 611, 618, and 620) and 11 (codon 634) in MEN 2A and FMTC5-7 or in exons coding for the intracellular tyrosine kinase domain (exons 13 to 16) in all MEN 2B cases (mainly codon 918, seldom codon 883)8,9 and rare cases of FMTC.10-12 Rare point mutations in codon 630 as well as 9– and 12–base pair duplications that create additional cysteine residues have been described in exon 11 in some MEN 2A/FMTC families.13-15 Many prospective data have been obtained since the discovery of RET mutations, but the true frequency of inherited disease among apparent sporadic MTC cases and the frequency of de novo germline mutations of the RET proto-oncogene remain a matter of discussion.3,16,17 The extent of genetic analysis needed for exclusion of inherited disease is also not well defined.3 Although extremely rare mutations do not need to be included in routine diagnosis, there have only been a few attempts to define the risk of inherited disease in relation to the range of genetic investigations. Published data indicate differences among the frequencies of exon 13 and 14 mutations in analyzed populations.7,11,12,18,19 Our goal was to estimate the risk of germline mutations in apparent sporadic MTC patients in the Polish population and decide whether the analysis of the most frequent mutations in exons 10 and 11 is sufficient for routine screening or should be extended.
Patients and Their Family Members Among 176 patients diagnosed with MTC in our Institute in the years 1990 to 1999, there were 39 patients with a positive familial history of MTC, and 137 patients were apparent sporadic cases. Germline DNA was available for 116 of the apparent sporadic cases. Of these patients, there were 28 males and 88 females, and their mean age at diagnosis was 47 ± 13.4 years. Fourteen patients (12%) were diagnosed before the age of 30 years, 35 patients (30%) were diagnosed between 31 and 45 years of age, and 67 patients (58%) were older than 45 years of age when diagnosed. Twenty healthy relatives from the families of the newly detected germline mutation carriers were also investigated. The study was approved by the local ethics committee and all patients gave informed consent for the investigation.
Diagnostic Procedures
Genetic Analysis of Exons 10, 11, 13, 14, and 16 of the RET Proto-Oncogene
PCR products of exon 11 were subjected to restriction analysis with a panel of five restriction enzymes (Cfo I, Rsa I, Dde I, Hae III, and Fnu4HI) with the use of the buffers and conditions recommended by the manufacturer (Boehringer Mannheim GmbH; New England Biolabs Inc, Frankfurt am Main, Germany). Endonuclease digestion products were subjected to electrophoresis in 3% agarose gels (Cfo I, Rsa I, Dde I, Hae III) or 5% polyacrylamide gels (Fnu4HI) stained with ethidium bromide. PCR products of exons 10, 13, 14, and 16 were purified using exonuclease I and shrimp alkaline phosphatase (Amersham Life Science, Cleveland, OH) to remove the excess of primers and deoxyribonucleotides. Both strands were sequenced, using the same primers as for PCR amplification, by the fluorometric method (ABI PRISM Big Dye Terminator Cycle Sequencing Ready Reaction Kit With AmpliTaq Polymerase, FS, PE Applied Biosystem, Warrington, United Kingdom) and 377 DNA Sequencer (Perkin Elmer Biosystem). For all MTC patients, the restriction analysis of codon 634 was performed as the first step of analysis. When this analysis was negative, exon 10 was sequenced. Extended analysis, comprising the sequencing of exons 13, 14, and 11, was performed in cases where a young age at diagnosis (< 45 years) increased the probability of inherited disease. We also considered the presence of bilateral MTC, simultaneous presence of adrenal incidentaloma, or equivocal results of biochemical testing in the relatives as risk factors when the age at MTC diagnosis was later than 45 years. For patients younger than 30 years at diagnosis, we also sequenced exon 16. When these analyses were negative, they were completed by the sequencing of exon 11 in all patients younger than 45 years of age.
Among 116 apparent sporadic MTC cases, we found seven patients (6%) with germline mutations in exons 10 and 11 of the RET proto-oncogene. The average age at diagnosis of MTC was 40 ± 12 years (range, 26 to 57 years). Five individuals carried mutations in exon 11, codon 634 and two individuals had a mutation in exon 10, codon 611, and codon 618. The changes in nucleotides and amino acids are listed in Table 2.
We examined exons 13, 14, and 16 of the RET gene in a stepwise manner for the remaining apparent sporadic MTC patients (in whom the analysis of exons 10 and 11 gave negative results). First, we examined 12 patients with diagnosis of MTC before 30 years of age (range, 14 to 29 years) by sequencing exons 13, 14, and 16. Next, exons 13 and 14 were sequenced in 32 other patients diagnosed between 30 and 45 years of age and in 14 older patients. We found two germline mutations in codon 804 in exon 14 in patients aged 29 and 50, and one mutation in codon 768 in exon 13 in a 41-year-old patient (Table 2). Although we did not observe any deletion or insertion variants in the exon 11 post-PCR electrophoresis, the presence of rare mutations was still possible in codon 630.14 The last step was to sequence exon 11 of the RET gene. We did not find any mutation in this codon, but in a 44-year-old woman we identified a mutation in codon 649 (TCG to TTG) that led to a substitution of Ser by Leu ( Fig 1). The same nucleotide change was found in one of her two children (a 22-year-old male, asymptomatic by thyroid sonography and pentagastrin-stimulated calcitonin estimation).
In the families identified as carrying a mutated RET gene, we analyzed 18 additional at-risk relatives who were unaffected at that time. We found seven mutation carriers. One mutation carrier was found who had not discovered the evident cancer until the time of the examination, and two other mutation carriers had increased basal calcitonin levels at the time of genetic diagnosis, thus clinically evident MTC was diagnosed and formed an indication for surgery. Three children received prophylactic thyroidectomies. C-cell hyperplasia was found in all three despite normal basal and stimulated calcitonin levels. An additional child has not been operated on yet because of his young age (a 2-year-old with a TGC>TAC mutation in codon 634). The age-dependent frequency of RET germline mutations in apparent sporadic MTC patients and its relation to the extent of genetic diagnosis are presented in Table 3.
The sequencing of exons 10, 11, 13, 14, and 16 revealed rare polymorphic variants in codons 769 and 836 in the group of sporadic MTC patients younger than 45 years at diagnosis. They were found with the following frequencies: 36% for L769L (CTT/CTG) and 4.5% for S836S (AGC/AGT) in patients younger than 30 years, and 15% and 0%, respectively, in patients aged 31 to 45 years ( Table 4). The difference in allelic frequency of L769L was statistically significant by Fisher’s exact test (P < .05). In one case, we also found a previously not described germline nucleotide change in codon 845 (GCC to GCT) that does not predict an amino acid substitution (Ala to Ala). No other polymorphic variants were observed in the analyzed exons.
The diagnosis of inherited MTC solely on a clinical basis is easy in a patient with fully developed MEN 2 syndrome or in the presence of a positive familial history. When only MTC is present and a patient has a negative familial history, a differential diagnosis based on clinical data is uncertain. First, MEN 2 syndrome may be due to de novo mutations.16,17 Second, the family history often is not well known to the patient or not adequately asked by the physician and third, MTC precedes other symptoms of MEN 2, sometimes by many years.18,23,24 This implies that only the negative result of germline RET mutations analysis allows a definite diagnosis of sporadic MTC. Before this analysis is finished, the patient should be regarded as an apparent sporadic case only.7 However, the true risk of inherited disease in those patients is only roughly estimated, and prospective studies are lacking. Our results may be regarded as a primary approach for the genetic diagnosis of inherited MTC in an unpreselected population of apparent sporadic patients. The vast majority of them (112 patients) had not received previous familial screening by biochemical methods. The entire group of 176 patients diagnosed with MTC at our center constitutes 4.4% of thyroid cancer patients treated by us in the 1990s, coming from all over Poland. This figure is close to the known 3% to 5% of MTC prevalence among all thyroid cancers and does not indicate the risk of a preselection and an artificial increase of inherited cases.25 It has been reported that 90% to 95% of all MEN 2/FMTC cases are caused by mutations in codon 634 of exon 11 or mutations in exon 10 (in codons 609, 611, 618, or 620).3,7 In our material, analysis of these five codons gave a 6.0% probability of finding an inherited case among apparent sporadic MTC patients. Although this value is similar to data on American17 and Italian26 populations, it is two times lower than the risk estimated in the German studies27 (Table 5). We regarded the extension of the analysis to exons 13 and 14 as essential. However, the risk of a mutation in exons 13 and 14 (E768D, L790F, Y791F, V804L, V804M)10,11,19 in hereditary carcinoma has been estimated at 1%.19 Because of this low overall risk, we analyzed exons 13 and 14 only in those patients in whom clinical data increased the probability of inherited disease, mainly, patients younger than 45 years at diagnosis.32 The same considerations applied to sequencing exon 11, as only a few cases have been reported with a mutation in exon 11 outside codon 634.13-15 These additional analyses resulted in a clear increase of the detection of inherited disease, with a final estimation of 9.5% in the whole population of apparent sporadic MTC patients and 16.3% in the subgroup of patients younger than 45 years at diagnosis (Table 3). The frequencies observed in other reports of apparent sporadic MTC cases range from as low as 0%29 to the highest risk of 14% to 15%27,30 ( Table 5).31 The differences in the results obtained might be explained by the former preselection of patients. An earlier extensive search for inherited MTC by biochemical testing would lower the number of cases found subsequently by genetic analysis.28 However, the prevalence of inherited cancers may be increased in centers to which only preselected cases with an increased risk for genetic background are referred for molecular investigations. True differences in the prevalence of inherited MTC between populations may also be expected. It is possible that mutations in codons 790 and 791 exhibit such differences. They have been found to create a new hot spot in the German population19 but they were not found in our study nor in other analyses.3 However, the penetration of this mutation may be shifted to older ages and could be missed by not sequencing exon 13 in all patients older than 45 years.
In previous reports, no final conclusions were drawn regarding how extensively genetic analysis should be performed in clinical practice in apparent sporadic MTC cases. The screening of all known mutation loci is recommended3,11,19; however, evidence for the validity of this view is incomplete. These questions are important when the costs of a full analysis are taken into consideration. A distinct increase of the costs, connected with the sequencing of additional exons, may make the genetic diagnostics unacceptable to be covered by the health service system. This may lead to the limiting of the routine analysis only to the most frequent mutations in exons 10 or 11. We present an intermediary approach and propose to evaluate the risk of inherited MTC with relation to the age at diagnosis (Table 3). We chose the limit of 45 years on the basis of the known relation of inherited MTC occurrence with younger age.32 An additional argument for this age criterion is that it is the same age limit used in tumor-node-metastasis staging of differentiated thyroid carcinoma.33 As it may be concluded from Tables 3 and 5, the extension of genetic analysis to all known loci in patients older than 45 years at diagnosis probably will not lead to discovering many new cases. When the newly detected inherited MTC patients are combined with the previously known 39 familial cases, the frequency of heritable MTC is estimated in our material at 32.3% (50 of 155). This high percentage strengthens the conclusion that most cases of inherited MTC were found by the applied stepwise protocol. However, recent reports shift the upper limit of the presentation of clinical symptoms in familial MTC to the fourth or even the fifth decade of life, particularly with the rarer mutations in codons 13 and 14.3,11 A posthoc survey revealed three patients with inherited MTC who were diagnosed when they were older than 45 years of age. Additionally, the genetic screening of the families of newly detected patients with inherited disease resulted in the identification of a family member above this age limit who had not realized that he had cancer (Poland lies in the area of light to moderate endemic goiter, and nodular goiter is a frequent finding). Thus the ultimate gain of the genetic analysis in older patients at diagnosis has to be carefully estimated. Although the risk of inherited MTC in the apparent sporadic disease was the highest in the subgroup of patients younger than 30 years at diagnosis of MTC, as expected from previous analyses,2,32 only every fifth patient younger than 30 years at diagnosis of MTC exhibited a germline RET mutation. It has been proposed that the families of these patients should be screened by pentagastrin tests when the RET analysis is negative.7 Along with known germline RET mutations, other factors probably contribute to the early clinical presentation of MTC. In this context, more attention is paid to polymorphic sequences of the gene. We observed an overrepresentation of a sequence variant L769L (CTT/CTG) in exon 13 in the youngest patients. We found this rarer polymorphic variant in both alleles of two index patients (aged 24 and 21 years). In the whole group of patients younger than 30 years, the frequency of this polymorphic variant was 36%, whereas in the group of patients aged 31 to 45 years it was distinctly lower, at 15% (Table 4). We cannot suggest any role of this polymorphism in Polish patients until its frequency in healthy subjects is estimated, but possible contribution of L769L polymorphism to the genetic predisposition for MTC should be carefully tested. The reported frequency of this variant in normal populations varies between 26% and 14% (Table 4).21,22,34 Notably, Borrego et al22 reported the polymorphism at 769 to be associated with sporadic Hirschsprung’s disease. Gimm et al21 found an overrepresentation of a rare sequence variant, S836S (AGC/AGT) (exon 14), in the germline DNA of patients with sporadic MTC. They reported 9% of the T allele frequency in their cohort, significantly higher than the 3.6% frequency in controls without MTC.21 Further, they identified somatic M918T mutations in tumor samples in eight of nine cases with the rare sequence variant. This was also more frequent than in patients with the more common S836S variant (AGC/AGC). They suggested a promoting role of AGC/AGT sequence variant of codon 836 in the genesis of sporadic MTC. In the present study, we found a 1.2% frequency of the rare variant in all analyzed cases and a 4.5% frequency in the group of patients with sporadic MTC who were younger than 30 years at diagnosis (Table 5). This variant was not found in the group of patients who were between 31 and 45 years of age at diagnosis. Our present results are not sufficient to support the role of this polymorphism in sporadic MTC. In regard to other polymorphic variants, in one case we noted an unreported change in codon 845 (GCC>GCT, Ala>Ala) that does not lead to an amino acid substitution. This might be a rare polymorphic allele, similar to that described in codon 841 (Pro) by Kitamura et al.14 In our group, sequence analysis of exon 11 disclosed one case of an unreported germline mutation in codon 649 (TCG>TTG, Ser>Leu). It was found in a 44-year-old woman and her 22-year-old asymptomatic son. We found only one report of a silent mutation in RET codon 649, present in Hirschsprung disease, and suggested to be a variant splicing mutation.35 The mutation found in our patient constitutes the first noncysteine codon affected in the extracellular and transmembrane domain in the germline of an MTC patient. Recently, Tessitore et al36 reported a change in codon 640 (Ala to Gly), but it accompanied the typical mutation in codon 634 (Cys to Arg). In the case presented in this study, the mutation in codon 649 is the only mutation found, despite the sequencing of exons 10, 13, and 14. The replacement of serine, which forms hydrogen bonds, with hydrophobic leucine may cause a destabilization of the protein structure and affect the activity of the receptor. However, a biologic effect should be confirmed by in vitro experiments, and we do not propose any therapeutic procedures for the proband’s son, who exhibits the same mutation but is asymptomatic by thyroid sonography and pentagastrin test. We identified another seven mutation carriers through familial screening of MTC patients investigated as apparently sporadic cases and confirmed as inherited cases. This is a small number; however, we should stress that those patients came from small families. The lack of relatives (potential carriers of the disease allele) might justify the lack of a previous clinical diagnosis of familial cancer. In total, with our algorithm of examination of apparent sporadic patients, we performed 39 sequencing analyses and 13 full genetic tests per one new mutation carrier found, a fairly low number compared with other inherited diseases.27,37 Goretzki et al27 estimated that finding a mutation carrier among an identified family costs $355. This clearly indicates that genetic analysis of apparent sporadic MTC patients to identify unknown germline mutation carriers and to detect new cancers among their families is a cost-effective procedure. This is stressed by the fact that diagnosis of the inherited predisposition gives a clear indication for further therapeutic decisions in MTC.3,38 In conclusion, by stepwise analysis, we estimate the risk of inherited MTC among apparent sporadic patients to be 9.5%. We also see the need to analyze the impact of rarer mutations in patients older than 45 years at diagnosis of MTC.
Supported by the State Committee for Scientific Research (KBN, Poland) grant no. 4P05B 088 12 (B.J.) We appreciate the help of Prof M. Chorazy at the introduction of genetic RET analysis. We acknowledge the gifts of positive DNA samples from Dr C.E. Jackson (University of Chicago) and Prof G. Brabant (University School of Medicine, Hannover, Germany). We thank Malgorzata Oczko for her excellent technical assistance and Heather Chaulk for the correction of the English manuscript. We are also grateful for the cooperation of patients.
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Donis-Keller H, Dou S, Chi D, et al: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2: 851-856, 1993 7. Eng C, Clayton D, Schuffenecker I, et al: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. JAMA 276: 1575-1579, 1996[Abstract]
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Gimm O, Marsh DJ, Andrew SD, et al: Germline dinucleotide mutation in codon 883 of the RET protooncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 82: 3902-3904, 1997 10. Eng C, Smith DP, Mulligan L, et al: A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in family with FMTC. Oncogene 10: 509-513, 1995[Medline] 11. Bolino A, Schuffenecker I, Luo Y, et al: RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10: 2415-2419, 1995[Medline]
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Hofstra R, Fattoruso O, Quadro L, et al: A novel mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 82: 4176-4178, 1997
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Höppner W, Ritter MM: A duplication of 12bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet 6: 587-590, 1997 14. Kitamura Y, Goodfellow PJ, Shimizu K, et al: Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): Mutation analysis in Japanese patients with MTC. Oncogene 14: 3101-3106, 1997 15. Höppner W, Dralle H, Brabant G, et al: Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mut 1: S128-S130, 1998 (suppl 1)
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Zedenius J, Wallin G, Hamberger B, et al: Somatic and MEN 2A de novo mutations identified in the RET protooncogene by screening of sporadic MTCs. Hum Mol Genet 3: 1259-1262, 1994 17. Wohllk N, Cote GJ, Bugalho MMJ, et al: Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 81: 3740-3745, 1996[Abstract] 18. Calender A: Genetic testing in multiple endocrine neoplasia and related syndromes. Forum 8: 146-159, 1998[Medline]
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Berndt I, Reuter M, Saller B, et al: A new hot spot for mutations in the RET proto-oncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 83: 770-774, 1998 20. Kambouris M, Jackson CE, Feldman GL: Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat 8: 64-70, 1996[Medline] 21. Gimm O, Neuberg DS, Marsh DJ, et al: Over-representation of germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene 18: 1369-1373, 1999[Medline]
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Borrego S, Saez ME, Ruiz A, et al: Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. J Med Genet 36: 771-774, 1999 23. Conte-Devolx B, Schuffenecker I, Niccoli P, et al: Multiple endocrine neoplasia type 2: Management of patients and subjects at-risk. Horm Res 47: 221-226, 1997[Medline]
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Schuffenecker I, Virally-Monod M, Brohet R, et al: Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations in codon 634 of the RET proto-oncogene. J Clin Endocrinol Metab 83: 487-491, 1998 25. Ball DW, Baylin SB, de Bustros AC: Medullary thyroid carcinoma, in Braverman LE, Utiger RD (eds): The Thyroid: A Fundamental and Clinical Text. Philadelphia PA, Lippincott-Raven Publishers, 1996, pp 946-960 26. Bottici V, Elisei R, Molinaro E, et al: Genetic screening of RET proto-oncogene mutations in medullary thyroid carcinoma (MTC): A 6-year experience. J Endocrinol Invest 6:S54, 1999 (suppl 22) (abstr) 27. Goretzki PE, Hoppner W, Dotzenrath C, et al: Genetic and biochemical screening for endocrine disease. World J Surg 22: 1202-1207, 1998[Medline] 28. Eng C, Mulligan LM, Smith DP, et al: Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 43: 123-127, 1995[Medline] 29. Fink M, Wein-Hausel A, Niederle B, et al: Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. Int J Cancer 69: 312-316, 1996[Medline] 30. Uchino S, Noguchi S, Adachi M, et al: Novel point mutations and allele loss at the RET locus in sporadic medullary thyroid carcinomas. Jpn J Cancer Res 89: 411-418, 1998[Medline] 31. Scurini C, Quadro L, Fattoruso O, et al: Germline and somatic mutations of the RET proto-oncogene in apparently sporadic medullary thyroid carcinomas. Mol Cell Endocrinol 137: 51-57, 1998[Medline] 32. Ponder BAJ, Ponder MA, Coffey R, et al: Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet 1: 397-400, 1988[Medline] 33. American Joint Committee on Cancer: Head and neck tumors: Thyroid gland, in Beahrs OH, Henson DE, Huttler RVP, et al (eds): Manual for Staging of Cancer. Philadelphia PA, JB Lippincott, 1992, pp 53-54 34. Rodien P, Jeunemaitre X, Dumont C, et al: Genetic alterations of the RET proto-oncogene in familial and sporadic pheochromocytomas. Horm Res 47: 263-268, 1997[Medline]
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Tessitore A, Sinisi AA, Pasquali D, et al: A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET protooncogene. J Clin Endocrinol Metab 84: 3522-3527, 1999 37. Petersen GM, Brensinger JD, Johanson KA, et al: Genetic testing and counselling for hereditary forms of colorectal cancer. Cancer 86: 2540-2550, 1999[Medline]
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Offit K, Biesecker BB, Burt RW, et al: Statement of the American Society of Clinical Oncology: Genetic testing for cancer susceptibility. J Clin Oncol 14: 1730-1736, 1996 Submitted April 24, 2000; accepted November 14, 2000. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
