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Institute of Surgical Clinics University of Siena 53100 Siena, Italy
In a recent article Stratakis et al. (1) tested the hypotheses in two multitumoral syndromes showing genetic heterogeneity, such as Carney Complex (CC) and Peutz-Jeghers-Syndrome (PJS), that some families with CC may map to the genetic loci of these conditions (locus 2p16 and 19p13.3 or 19q13.4, respectively), and that loss of heterozygosity (LOH) for PJS and Cowden disease (PTEN gene mapped at 10q22–23) loci were involved in the molecular pathology of CC tumors. The first suggested explanation was the following. "Because the STK11/KKB1 and PTEN genes appear to function as tumor suppressor genes, it is possible that the products of these genes are members of a family of proteins that regulate the same cellular process." Stratakis et al. report as examples of clinical and genetic overlap the Muir-Torre syndrome and HNPCC or MEN2 and Hirschsprung disease. However, the two non-2p-linked CC families analyzed in the study by Stratakis et al. (not mapping at 2p16) did not map to the 19p13, 19q13.4, and 10q23 loci either, and tumors from patients with CC did not show LOH for these loci. The authors conclude that "the PJS and the PTEN genes may not play a significant role in the molecular pathogenesis of tumors associated with CC, despite the clinical and histological similarities between these disorders." Because the PJS locus was identified by screening only DNA of colonic polyps, the authors suggest that, "It is possible...that LOH for the PJS genomic region is necessary for oncogenesis in the colon but not in other organs affected by PJS or CC. According to Knudson’s hypothesis..., LOH is necessary for oncogenesis in the presence of a recessive mutant allele, whereas a dominant mutant allele is sufficient for tumorigenesis. If tissue-specific conditions were to determine the dominant or recessive function of the mutant PJS allele, a variable pattern of LOH for the PJS locus would be observed in the various tissues from patients with the syndrome."
Here, we report a similar experience with another multitumoral syndrome, namely familial adenomatous polyposis (FAP), concerning an extracolonic manifestation of endocrinologic interest, such as thyroid carcinoma. Thyroid carcinoma of the papillary histotype is a tumor integral to the FAP syndrome (2), determined by germ-line mutations of the APC gene, mapped at 5q21 (3). LOH of the APC gene is common in patients with colonic polyps or cancer, desmoids or hepatoblastomas belonging to the FAP syndrome (4). However, we found no LOH for APC in the thyroid tumoral tissue of five patients with FAP associated papillary carcinoma (5). Four of them had an APC germ-line mutation at codon 1061 (6). The last one had mutation at codon 1309. It is noteworthy that three of them belonged to the same kindred (7). Interestingly, three of the four had activation of the chimeric RET-PTC, as RET-PTC1, deriving from the fusion of the RET gene with another gene named H4 (8). This observation is consistent with the lack of mutations of the tumor suppressor gene APC in sporadic thyroid tumors (9, 10). Even if other factors are required for the expression of the tumoral phenotype in the thyroid tissue, such as sex-related factors (female to male ratio: 20:1) or environmental factors, namely radiation in the atmosphere (11), according to the hypothesis suggested by Stratakis et al. (1), our findings could simply suggest that APC gene acted as a dominant gene, and the dominant or recessive function of the mutant allele of a tumor suppressor gene, such as APC, could be determined by tissue specific conditions, varying from one tissue to another in the same patient. For instance, in our patients, the germ-line APC mutation cooperated with the ki-ras oncogene, according to the Vogelstein and Fearon model of tumorigenesis (12) to determine colonic polyps and cancer, and with ret-PTC, which is mutually exclusive with ki-ras in thyroid tumorigenesis, to determine papillary thyroid carcinoma (13).
Footnotes
Address correspondence to: Francesco Cetta, Institute of Surgical Clinics, University of Siena, Nuovo Policlinico, Viale Bracci, 53100 Siena, Italy.
Received December 16, 1998.
References
This article has been cited by other articles:
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  F. Cetta, G. Montalto, M. Gori, M. C. Curia, A. Cama, and S. Olschwang Germline Mutations of the APC Gene in Patients with Familial Adenomatous Polyposis-Associated Thyroid Carcinoma: Results from a European Cooperative Study J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 286 - 292. [Abstract] [Full Text]
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