Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC

Laken, Steven J.; Petersen, Gloria M.; Gruber, Stephen B.; Oddoux, Carole; Ostrer, Harry; Giardiello, Francis M.; Hamilton, Stanley R.; Hampel, Heather; Markowitz, Arnold J.; Klimstra, David S.; Jhanwar, Suresh C.; Winawer, Sidney J.; Offit, Kenneth; Luce, Michael C.; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1038/ng0997-79

Cited by 607 publications

(432 citation statements)

References 21 publications

Supporting

Mentioning

397

Contrasting

Unclassified

Order By: Relevance

“…Theoretically, polymorphisms represent sequence variations, which are present in the general population and confer no obvious or important deleterious effects. However, it becomes clear that some polymorphisms like the APC gene in colorectal cancer in the Ashkenazim (Laken et al, 1997) and the paraoxonase gene in coronary heart disease in type 2 diabetes (Ruiz et al, 1995) are not entirely harmless. These observations taken together with our present data argue in favour that RET G691S variant can constitute a factor contributing to the development of CCH in the peritumoural tissues of irradiated thyroid glands.…”

Section: Genetics and Genomicsmentioning

confidence: 99%

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

et al. 2002

View full text Add to dashboard Cite

The RET proto-oncogene encodes a protein structurally related to transmembrane receptors with an intracellular tyrosine kinase domain. In human thyroid gland, the RET proto-oncogene is normally expressed in parafollicular C-cells. Thyroid C-cell hyperplasia is associated with inherited medullary thyroid carcinomas and is considered as a pre-neoplastic stage of C-cells disease. It has also been observed in thyroid tissues adjacent to follicular and papillary carcinomas. In order to study the relationship between a misfunctioning of the RET proto-oncogene and the presence of C-cell hyperplasia, we compared a series of thyroid glands presenting sporadic or radiation-associated tumours, as well as samples of unrelated normal thyroid tissues, for alteration in exons 10 and 11 of the gene and for the presence or absence of C-cell hyperplasia. Here we report a significantly higher frequency of C-cell hyperplasia present in peritumoural thyroid tissues of radiation-induced epithelial thyroid tumours, than in peritumoural of sporadic thyroid tumours or in control normal thyroid tissues (P=0.001). A G691S RET polymorphism was present with a higher frequency in radiation-induced epithelial thyroid tumours (55%) than in sporadic tumours (20%) and in control normal thyroid tissues (15%). Interestingly, this polymorphism was associated in the majority (88%) of radiation-induced tumours with a C-cell hyperplasia in the peritumoural tissues. Several explanations for this association are discussed.

show abstract

Section: Genetics and Genomicsmentioning

confidence: 99%

Association of RET codon 691 polymorphism in radiation-induced human thyroid tumours with C-cell hyperplasia in peritumoural tissue

et al. 2002

View full text Add to dashboard Cite

show abstract

“…In this situation, the c.2439T variant may create an unstable sequence downstream at codon 918, resulting in the somatic M918T mutation instead of directly participating in the tumourigenic process. Such a mechanism has been observed in the APC gene in a fraction (28%) of Ashkenazim with familial colorectal cancer where additional somatic mutations were more often found on that allele carrying a seemingly innocuous germline missense mutation predicted to result in a conservative amino acid change (I1307K) (Laken et al, 1997). Although a plausible explanation when the c.2439T and M918T variants are on the same allele, this mechanism cannot explain the origin of the somatic M918T mutation in trans with the c.2439T variant in the remaining two patients.…”

mentioning

confidence: 97%

Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation

et al. 1999

View full text Add to dashboard Cite

The aetiology of sporadic medullary thyroid carcinoma is unknown. About 50% harbour a somatic mutation at codon 918 of RET (M918T). To investigate whether other RET sequence variants may be associated with or predispose to the development of sporadic medullary thyroid carcinoma, we analysed genomic DNA from the germline and corresponding tumour from 50 patients to identify RET sequence variants. In one patient, tumour DNA showed a novel somatic 12 bp in-frame deletion in exon 15. More interestingly, we found that the rare polymorphism at codon 836 (c.2439C4T; S836S) occurred at a signi®cantly higher frequency than that in control individuals without sporadic medullary thyroid carcinoma (Fisher's exact test, P=0.03). Further, among the nine evaluable cases with germline c.2439C/T, eight also had the somatic M918T mutation in MTC DNA which was more frequent than in patients with the more common c.2439C/C (89% vs 40%, respectively; Fisher's exact test, P=0.01). These ®ndings suggest that the rare sequence variant at codon 836 may somehow play a role in the genesis of sporadic medullary thyroid carcinoma.Keywords: tyrosine kinase; polymorphism; germline mutation; somatic mutation; medullary thyroid cancer Medullary thyroid carcinoma (MTC) comprises approximately 5 ± 10% of all thyroid malignancies (Bergholm et al., 1990). About 75% of all MTCs are believed to be sporadic (Bergholm et al., 1990;Raue et al., 1993), and the remaining 25% comprise the autosomal dominant multiple endocrine neoplasia type 2 (MEN 2) syndromes, MEN 2A, MEN 2B and familial MTC (Farndon et al., 1986;Schimke, 1984). Germline mutations of the RET protooncogene a ecting exons 10, 11, 13, 14, 15 and 16 have been found to be associated with MEN 2 (Bolino et al., 1995;Carlson et al., 1994;Donis-Keller et al., 1993;Eng et al., 1994Eng et al., , 1995Farndon et al., 1986;Gimm et al., 1997;Hofstra et al., 1994;Mulligan et al., 1993;Schimke, 1984; Smith et al., 1997). Speci®cally, germline mutation at codon 918 (M918T) in exon 16 is associated with 495% of MEN 2B , which is characterized by a more severe form of MTC and phaeochromocytoma occurring at a young age and classic stigmata such as ganglioneuromatosis and a marfanoid habitus. Functional, biochemical and limited animal modelling studies have demonstrated that the RET mutations which characterize MEN 2 are capable of activation, sometimes in a constitutive manner, of the RET signalling pathway (Borrello et al., 1995;Ceccherini et al., 1997;Michiels et al., 1997;Pasini et al., 1997;Santoro et al., 1995). The MEN 2B-type mutation, M918T, has been shown to alter substrate speci®city (Borrello et al., 1995;Santoro et al., 1995;Songyang et al., 1995). Interestingly, a median of 50% of sporadic MTC harbour somatic M918T mutations (Eng and Mulligan, 1997). Despite our rapidly accumulating knowledge of the genetics and biochemistry of RET, it is not really known how M918T occurs. Further, while a number of the MEN 2-and MTC-associated RET mutations have been shown to be functionally signi®cant, it is no...

show abstract

“…The missense variant APC I1307K acts as an unusual tumour predisposition allele, because it acts as a 'premutation' (Laken et al, 1997). The change, which is largely present in those of Ashkenazi Jewish origin, creates a hypermutable A 8 tract.…”

Section: Low-penetrance Apc Variantsmentioning

confidence: 99%