New founding mutation in MSH2 associated with hereditary nonpolyposis colorectal cancer syndrome on the Island of Tenerife

Medina-Arana, Vicente; Barrios, Ysamar; Fernández-Peralta, Antonia M.; Herrera, Mercedes; Chinea, Nancy; Lorenzo, Nieves María Concepción; Jiménez, Alejandro; Martín-López, Juana V.; Gonzalez-Hermoso, Fernando; Salido, Eduardo; González-Aguilera, Juan J.

doi:10.1016/j.canlet.2005.12.033

Cited by 19 publications

(29 citation statements)

References 18 publications

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“…Before our report, two founder mutations in the MSH2 gene had been identified in Spanish Lynch syndrome families, although their frequencies were low in our population (11,12). In the cohort of Lynch syndrome families from ICO, the identified c.306 +5G>A and c.1865T>A mutations account for 28.8% of the 45 families carrying MLH1 alterations (13 founders and 32 nonfounders) and represent 17.6% (13 of 74) of all families with mutations in MMR genes.…”

Section: Discussionmentioning

confidence: 60%

“…In MLH1, founder mutations were identified in several populations (6)(7)(8), where they can explain a substantial fraction of Lynch syndrome occurrences (9,10), facilitating genetic diagnosis. In Spain, founder mutations in MMR genes have only been identified in the MSH2 gene (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Most of them encode truncated proteins and are readily categorized as pathogenic mutations. However, founder MMR variants with uncertain pathogenicity have also been identified (11,13,14). To investigate the functional effect of MMR variants, numerous assays at the RNA and protein level have been developed (15,16).…”

Section: Introductionmentioning

confidence: 99%

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MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

et al. 2010

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The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome. Cancer Res; 70(19); 7379-91. ©2010 AACR.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

et al. 2010

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“…We knew previously that the patient carried a germinal mutation c.2063T[G (M688R) in the MSH2 gene [11], and the adrenal tumor also presented the mutation (Fig. 2).…”

Section: Resultsmentioning

confidence: 96%

“…On the island of Tenerife (Spain) we found a founder mutation in exon 13 of the MSH2 gene (c.2063T[G) that affects to ten families, resulting in a nonconservative aminoacid change, M688R, at the ATPase domain of the Msh2 protein [11]. In the analysis of a family who had this mutation and met the Amsterdam criteria, we found a patient who developed adrenal cortical carcinoma whose molecular study shows a relationship to the syndrome that would broaden the spectrum of tumors appearing in the Lynch syndrome.…”

Section: Introductionmentioning

confidence: 99%

Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome

et al. 2011

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Lynch syndrome (LS) is an autosomal dominant condition that predisposes to colorectal cancer and specific other tumors. Extracolonic tumors occur mainly in the endometrium, stomach, ovary, small intestine and urinary tract. The presence of rare tumors in patients belonging to families who have Lynch syndrome is always interesting, because the question arises whether these tumors should be considered as a coincidence or are related with the syndrome. In this last case, they are also the result of the defect in the mismatch repair system, opening the possibility of extending the tumor spectrum associated with the syndrome. Here we describe a patient from a Lynch syndrome family with a germline mutation c.2063T>G (p.M688R) in the MSH2 gene, who developed an adrenal cortical carcinoma, a tumor not usually associated with LS. We analyzed the adrenocortical tumour for microsatellite instability (MSI), LOH and the presence of the germline c.2063T>G (M688R) mutation. The adrenal cortical carcinoma showed the MSH2 mutation, loss of heterozygosity of the normal allele in the MSH2 gene and loss of immunohistochemical expression for MSH2 protein, but no microsatellite instability. Additionally, the adrenal cortical carcinoma did not harbour a TP53 mutation. The molecular study indicates that this adrenal cortical cancer is probably due to the mismatch repair defect.

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Impact of the MTHFR C677T polymorphism on colorectal cancer in a population with low genetic variability

Delgado‐Plasencia

Medina-Arana

Bravo‐Gutiérrez

et al. 2013

Int J Colorectal Dis

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New founding mutation in MSH2 associated with hereditary nonpolyposis colorectal cancer syndrome on the Island of Tenerife

Cited by 19 publications

References 18 publications

MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome

Impact of the MTHFR C677T polymorphism on colorectal cancer in a population with low genetic variability

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