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Genetics and Clinicopathological Findings in Thyroid Carcinomas Associated with Familial Adenomatous Polyposis

      The recent paper by Soravia et al
      • Soravia C
      • Sugg SL
      • Berk T
      • Mitri A
      • Cheng H
      • Gallinger S
      • Cohen Z
      • Asa SL
      • Bapat BV
      Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.
      describes two kindreds with thyroid carcinoma associated with familial adenomatous polyposis (FAP). The former included three and the latter two FAP siblings with papillary thyroid carcinoma (PTC). The patients had a germline mutation of APC, the tumor suppressor gene responsible for FAP,
      • Kinzler KW
      • Vogelstein B
      Lessons from hereditary colorectal cancer.
      at codons 698 and 313, respectively, and activation of ret/PTC, a chimeric gene that is restricted to the papillary histotype,
      • Santoro M
      • Carlomagno F
      • Hay ID
      • Herrmann MA
      • Grieco M
      • Melillo R
      • Pierotti MA
      • Bongarzone I
      • Della Porta G
      • Berger N
      • et al.
      Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype.
      in the thyroid tumoral tissue of three out of three subjects. Interestingly, ret/PTC was always found as its most frequent isoform, ret/PTC1.
      • Santoro M
      • Carlomagno F
      • Hay ID
      • Herrmann MA
      • Grieco M
      • Melillo R
      • Pierotti MA
      • Bongarzone I
      • Della Porta G
      • Berger N
      • et al.
      Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype.
      This commentary discusses the issues of PTC as an extracolonic manifestation that is integral to FAP, genotype-phenotype correlations, the presence or absence of somatic mutations of the APC gene in the thyroid tumoral tissue, ret/PTC activation, possible cooperation among genes, histological significance of molecular alterations, and the natural history of these particular tumors.

      FAP PTC Is an Extracolonic Manifestation Integral to FAP

      Thyroid carcinoma has been considered a possible extracolonic manifestation of FAP since 1949.
      • Harach HR
      • Williams GT
      • Williams ED
      Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.
      However, it is a rare manifestation, reported in only 1–2% of patients included in the largest FAP registries. The Leeds Castle Polyposis Group has recently reported an incidence of 1.2% of thyroid carcinoma.
      • Bulow C
      • Bulow S
      Is screening for thyroid carcinoma indicated in familial adenomatous polyposis? The Leeds Castle Polyposis Group.
      Is this the actual incidence, or would intensive screening for this tumor detect a greater number of affected patients, as suggested by some authors?
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.
      In a recent review of the literature we have identified 110 patients with FAP-associated thyroid carcinoma.

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      The mean age was 27.65 years (range 15–62); the female-to-male ratio among patients with at least two siblings in the same kindred was 17:1. Papillary histotype was quite constant, even if an unusual subtype, the so-called cribriform histotype, was very frequent.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      This finding suggests that the follicular histotype, which has been described in some case reports, deserves careful re-evaluation, including analysis of ret/PTC, to confirm or exclude that these patients had a papillary tumor, even if it had prominent follicular areas. The APC gene has rarely been involved in the development of sporadic thyroid tumors (1/121) and a two-hit inactivation of the APC gene has not been observed, even in patients with APC germline mutations.

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      These observations raised questions as to whether thyroid carcinoma was integral to FAP syndrome. However, familial aggregation is indisputable. In particular, the observation of two kindreds (one from Soravia,
      • Soravia C
      • Sugg SL
      • Berk T
      • Mitri A
      • Cheng H
      • Gallinger S
      • Cohen Z
      • Asa SL
      • Bapat BV
      Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.
      one from ourselves) with three siblings,
      • Cetta F
      • Toti P
      • Petracci M
      • Montalto G
      • Disanto A
      • Lore F
      • Fusco A
      Thyroid carcinoma associated with familial adenomatous polyposis.
      in addition to the six pairs of siblings with FAP-associated thyroid carcinoma already reported, confirms that thyroid carcinoma is undoubtedly an aspect of the FAP syndrome. This view is given further support by our recent observation of three FAP kindreds with thyroid carcinoma in association with hepatoblastoma,
      • Cetta F
      • Montalto G
      • Petracci M
      Hepatoblastoma and APC gene mutation in familial adenomatous polyposis.
      a childhood tumor that is very rare but extremely frequent in FAP (estimated greater risk >1000:1).

      Genotype-Phenotype Correlation

      Many reports suggest a close relationship between the site of APC mutation in a family and the occurrence of some extracolonic manifestations. In particular, it has been reported that patients with mutations in codons 463-1387 regularly develop congenital hypertrophy of the retinal pigment epithelium,
      • Olschwang S
      • Tiret A
      • Laurent-Puig P
      • Muleris M
      • Parc R
      • Thomas G
      Restriction of ocular fundus lesions to a specific subgroup of APC mutations in adenomatous polyposis coli patients.
      whereas those with mutations in codons 1445–1578 develop desmoid tumors but lack retinal lesions.
      • Caspari R
      • Olschwang S
      • Friedl W
      • Mandl M
      • Boisson C
      • Boker T
      • Augustin A
      • Kadmon M
      • Moslein G
      • Thomas G
      • et al.
      Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444.
      Soravia et al detected in their two kindreds the specific APC germline mutations at codons 313 and 698, respectively, and therefore not in the mutation cluster region (MCR) at codons 1286–1513, where more than 60% of somatic mutations have been found.
      • Miyoshi Y
      • Ando H
      • Nagase H
      • Nishisho I
      • Horii A
      • Miki Y
      • Mori T
      • Utsunomiya J
      • Baba S
      • Petersen G
      • et al.
      Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients.
      Interestingly, as a result of international cooperation, we have recently shown that 22 of 24 germline mutations in patients with FAP PTC were in the 5′ portion of the APC gene, outside the MCR.

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      Only two patients had mutations at codon 1309. None had mutations in the desmoid-associated area at codons 1445–1578.

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      Somatic APC Mutations

      Soravia et al screened only the MCR, where most somatic mutations have been located, for somatic mutations. The analysis of 9 different tumor sections from 4 thyroid tumors showed a deletion of 205 bp and a concomitant insertion of 160 bp between APC nucleotides 4366 and 4571 (codons 1455–1523) in the unusual patient with an aggressive tumor, which also had a p53 mutation. On the contrary, they did not find any somatic APC mutation in the other tumors. These data are in agreement with our previous findings, showing the absence of somatic APC mutations in six patients with FAP-associated thyroid carcinoma not only in the MCR, but also in the 5′ genomic area, where most of the germline mutations have been found in patients with FAP PTC.
      • Cetta F
      • Montalto G
      • Petracci M
      • Gori M
      • Baldi C
      • Curia MC
      • Battista P
      • Cama A
      • Mariani-Constantini R
      The wild type APC allele is not lost in FAP associated thyroid tumors, showing activation of the chimeric oncogene ret-PTC.
      This also accords with the infrequent finding of APC somatic mutations in sporadic thyroid carcinoma

      Cetta F, Montalto G, Baldi C, Raffaelli N, Gori M, Curia MC, Cama A, Olschwang S: Germ-line mutations of the APC gene in patients with FAP associated thyroid carcinoma. Results from an European cooperative study. J Clin Endocrinol Metab 1999, in press

      and suggests an unusual behavior of PTC in comparison with other phenotypic manifestations of multitumoral inherited diseases, usually showing loss of heterozygosity of the basic tumor suppressor gene in the tumoral tissue. This could suggest (i) a dominant positive function, varying from tissue to tissue, analogously to what occurs in other multitumoral syndromes,
      • Stratakis CA
      • Kirschner LS
      • Taymans SE
      • Tomlinson IP
      • Marsh DJ
      • Torpy DJ
      • Giatzakis C
      • Eccles DM
      • Theaker J
      • Houlston RS
      • Blouin JL
      • Antonarakis SE
      • Basson CT
      • Eng C
      • Carney JA
      Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan- Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.
      and/or (ii) that the APC tumor suppressor gene plays a basic role only in FAP PTC, not in sporadic PTC. In particular, in the former it could give simply a generic susceptibility to PTC that will require other cofactors for full phenotypic expression, namely modifier genes, sex-related genes (as suggested by the female-to-male ratio of 17:1), or environmental factors such as radiation.
      • Cetta F
      • Montalto G
      • Petracci M
      • Fusco A
      Thyroid cancer and the Chernobyl accident. Are long-term and long distance side effects of fall-out radiation greater than estimated?.

      ret/PTC Activation

      Soravia et al found ret/PTC activation in 3 out of 3 (of 5. patients with FAP PTC (100%). We have previously documented ret/PTC activation (always as ret/PTC1 isoform) in 4 out of 5 patients with FAP PTC.
      • Cetta F
      • Chiappetta G
      • Melillo RM
      • Petracci M
      • Montalto G
      • Santoro M
      • Fusco A
      The RET/PTC1 oncogene is activated in familial adenomatous polyposis- associated thyroid papillary carcinomas.
      This is the highest ratio of ret/PTC activation in any well defined subset of patients with PTC, even higher than that reported in children from Belarus after the Chernobyl nuclear accident (67–87%).
      • Nikiforov YE
      • Rowland JM
      • Bove KE
      • Monforte-Munoz H
      • Fagin JA
      Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.
      Interestingly, the data from Soravia et al confirm that, in contrast to Belorussian children, who usually showed the ret/PTC3 isoform,
      • Nikiforov YE
      • Rowland JM
      • Bove KE
      • Monforte-Munoz H
      • Fagin JA
      Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children.
      ret/PTC1 was the constant isoform in FAP, detected in seven of seven patients (three by Soravia and four by ourselves). The only patient who, in addition to ret/PTC1 positivity, also had focal positivity for ret/PTC3, was patient III 11, kindred no. 1, who also had nuclear positivity for p53 and thyroid cancer recurrence 17 years after the initial removal of the thyroid tumor.
      • Soravia C
      • Sugg SL
      • Berk T
      • Mitri A
      • Cheng H
      • Gallinger S
      • Cohen Z
      • Asa SL
      • Bapat BV
      Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.
      (Soravia et al report that neither of the patients with a recurrence had a total thyroidectomy as the initial operation.)

      Cooperation Among Genes

      We have suggested that there may be interaction between germline APC mutation and ret/PTC activation in the development of thyroid cancer in FAP patients.
      • Cetta F
      • Chiappetta G
      • Melillo RM
      • Petracci M
      • Montalto G
      • Santoro M
      • Fusco A
      The RET/PTC1 oncogene is activated in familial adenomatous polyposis- associated thyroid papillary carcinomas.
      • Cetta F
      • Montalto G
      • Petracci M
      • Pacchiarotti MC
      • Toti P
      • Lore F
      • Mariani Costantini R
      • Cama A
      • Fusco A
      A new type of oncogene cooperation in patients with thyroid carcinoma associated with adenomatous polyposis: APC, a tumor suppressor gene cooperates with ret-PTC.
      We were cautious in our statement that loss of function of APC cooperates with ret/PTC in thyroid tumorigenesis, because the coexistence of alterations of these two genes in the same individual does not necessarily mean that they cooperate in the multistep process of carcinogenesis.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.
      • Cetta F
      • Chiappetta G
      • Melillo RM
      • Petracci M
      • Montalto G
      • Santoro M
      • Fusco A
      The RET/PTC1 oncogene is activated in familial adenomatous polyposis- associated thyroid papillary carcinomas.
      Soravia et al confirm the hypothesis that “genetic alterations in FAP-associated thyroid cancer involve loss of function of APC along with the gain of function of ret/PTC,” also confirming that “alterations of p53 do not appear to be an early event in thyroid tumorigenesis.”
      • Soravia C
      • Sugg SL
      • Berk T
      • Mitri A
      • Cheng H
      • Gallinger S
      • Cohen Z
      • Asa SL
      • Bapat BV
      Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.
      However, Soravia et al raise a number of questions in their paper that are very important not only for the specific topic of thyroid carcinogenesis in patients with adenomatous polyposis, but also for mutual relationships and cooperation among genes and/or environmental factors, including tissue-specific cooperation of a tumor suppressor gene with different genes, sometimes mutually exclusive of each other, in different tissues of the same individual. It seems that, in the same kindred, a given germline APC mutation influences the occurrence of the tumoral phenotype in a way that differs according to the tissue of origin of the tumor. For instance, APC cooperates with ras and p53 for colonic polyps and cancer, and with p53 (but not with ras) for the occurrence of liver adenomas and carcinomas. In particular, ras activation and ret/PTC activation seem to be mutually exclusive in the progression of tumorigenesis in the thyroid tissue, the former restricted to the follicular histotype, the latter specific for the papillary one. The accumulated data strongly suggest that in the same individual, germline APC mutations cooperate with ras for the progression of colonic polyps to carcinoma, whereas they cooperate with ret/PTC, but not with ras, for the occurrence of thyroid carcinoma.

      Cetta F, Gori M, Raffaelli N, Baldi C, Montalto G: Clinical and prognostic relevance of Ret-PTC activation in patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 1999, in press

      Therefore, the mutagenic stimulus for neoplastic proliferation varies from one tissue to another in the same patient, leading to the activation of oncogenes that are both tissue-specific and stimulus-related.
      • Kinzler KW
      • Vogelstein B
      Lessons from hereditary colorectal cancer.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.

      Natural History of FAP-Associated Thyroid Carcinoma

      On the basis of the cumulative findings in the literature, FAP PTC seems to be characterized by an unusual female preponderance, age at tumor diagnosis <30 years, and papillary differentiation (>95%). Despite frequent multicentricity and early lymph nodal involvement, FAP PTCs seem to be relatively indolent tumors.
      • Kinzler KW
      • Vogelstein B
      Lessons from hereditary colorectal cancer.
      All thyroid tumors associated with ret/PTC1 activation had a good prognosis.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.
      Most of the 110 patients with FAP-associated tumors reported in the literature did not produce distant metastases, and the patients had a mean survival of >15 years without recurrence.
      • Cetta F
      • Olschwang S
      • Petracci M
      • Montalto G
      • Baldi C
      • Zuckermann M
      • Mariani-Costantini R
      • Fusco A
      Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection.

      Cetta F, Gori M, Raffaelli N, Baldi C, Montalto G: Clinical and prognostic relevance of Ret-PTC activation in patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 1999, in press

      The paper by Soravia et al is the first to give long-term information on follow-up of FAP PTCs, which included detection of both germline mutation of the APC gene and ret/PTC activation. On the basis of these observations, it seems important to screen for focal activation of ret/PTC3 in patients with tumor recurrence. These data suggest possible late recurrence, namely in patients with both ret/PTC1 and ret/PTC3 activation and concomitant p53 mutation. A different biological behavior has been proposed for ret/PTC1 and ret/PTC3.

      Cetta F, Gori M, Raffaelli N, Baldi C, Montalto G: Clinical and prognostic relevance of Ret-PTC activation in patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 1999, in press

      • Powell Jr, DJ
      • Russell J
      • Nibu K
      • Li G
      • Rhee E
      • Liao M
      • Goldstein M
      • Keane WM
      • Santoro M
      • Fusco A
      • Rothstein JL
      The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.
      If further confirmed, it may suggest that constitutive activation of ret in FAP PTCs determines a different carcinogenetic pathway, according to the different fused gene, with ret/PTC1 possibly having the better and ret/PTC3 the worse prognosis.

      Cetta F, Gori M, Raffaelli N, Baldi C, Montalto G: Clinical and prognostic relevance of Ret-PTC activation in patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 1999, in press

      • Powell Jr, DJ
      • Russell J
      • Nibu K
      • Li G
      • Rhee E
      • Liao M
      • Goldstein M
      • Keane WM
      • Santoro M
      • Fusco A
      • Rothstein JL
      The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.

      Conclusion

      FAP-associated PTC seems to be a specific type of thyroid carcinoma with a peculiar histological aspect that probably reflects cooperation among carcinogenetic genes different from that occurring in sporadic tumors. Recent findings have contributed to highlighting some aspects, but several questions still remain unanswered. However, due to the rarity of this extracolonic manifestation of FAP, only international multicenter cooperation, analyzing in detail the same genetic alterations in a sufficiently large number of patients, will give a better insight into FAP-associated thyroid carcinoma.

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        Familial adenomatous polyposis-associated thyroid cancer: a clinical, pathological, and molecular genetics study.
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        • Li G
        • Rhee E
        • Liao M
        • Goldstein M
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