Two Swedish founder <i>MSH6</i> mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome

Cederquist, Kristina; Emanuelsson, Monica; Wiklund, Fredrik; Golovleva, Irina; Palmqvist, Richard; Grönberg, Henrik

doi:10.1111/j.1399-0004.2005.00537.x

Cited by 39 publications

(23 citation statements)

References 28 publications

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“…The study also reported a small difference in the mean age of onset between the MSH2 mutation carriers (45 years; range, 37-58 years) and the MLH1 mutation carriers (51 years; range, 35-75 years) (16). By contrast, the onset of ovarian cancer is also more frequent (33%) in families with an MSH6 mutation, although the lifetime risk of this mutation has not been established (17). The majority of ovarian cancers in Lynch syndrome are well-or moderately-differentiated and at the International Federation of Gynecology and Obstetrics stage I or II at diagnosis.…”

Section: Characteristics Of Ovarian Cancer In Lynch Syndromementioning

confidence: 81%

Features of ovarian cancer in Lynch syndrome (Review)

Nakamura

Banno

Yanokura

et al. 2014

Molecular and Clinical Oncology

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Lynch syndrome is a hereditary ovarian cancer with a prevalence of 0.9-2.7%. Lynch syndrome accounts for 10-15% of hereditary ovarian cancers, while hereditary breast and ovarian cancer syndrome accounts for 65-75% of these cancers. The lifetime risk for ovarian cancer in families with Lynch syndrome is ~8%, which is lower than colorectal and endometrial cancers, and ovarian cancer is not listed in the Amsterdam Criteria II. More than half of sporadic ovarian cancers are diagnosed in stage III or IV, but ≥80% of ovarian cancers in Lynch syndrome are diagnosed in stage I or II. Ovarian cancers in Lynch syndrome mostly have non-serous histology and different properties from those of sporadic ovarian cancers. A screening method for ovarian cancers in Lynch syndrome has yet to be established and clinical studies of prophylactic administration of oral contraceptives are not available. However, molecular profiles at the genetic level indicate that ovarian cancer in Lynch syndrome has a more favorable prognosis than sporadic ovarian cancer. Inhibitors of the phosphatidylinositol 3-kinase/mammalian target of the rapamycin pathway and anti-epidermal growth factor antibodies may have efficacy for the disease. To the best of our knowledge, this is the first review focusing on ovarian cancer in Lynch syndrome.

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Section: Characteristics Of Ovarian Cancer In Lynch Syndromementioning

confidence: 81%

Features of ovarian cancer in Lynch syndrome (Review)

Nakamura

Banno

Yanokura

et al. 2014

Molecular and Clinical Oncology

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“…32,34 Unlike colorectal cancer, endometrial cancer risk is not apparently lower in MSH6 mutation carriers. 36,38 Studies have consistently reported modestly increased risks for cancers in additional sites including the stomach, ovary, urinary tract, hepatobiliary tract, brain, small intestine, and skin (sebaceous adenomas or carcinomas and keratoacanthomas) with a trend toward increased risks for pancreatic cancer. [32][33][34][35] Of these sites, gastric cancer shows marked variation in risk between different populations.…”

Section: Risk Of Cancer In Lynch Syndromementioning

confidence: 99%

Recommendations for the Care of Individuals With an Inherited Predisposition to Lynch Syndrome

Lindor¹,

Petersen²,

Hadley³

et al. 2006

JAMA

596

512

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“…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%

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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Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome

Cited by 39 publications

References 28 publications

Features of ovarian cancer in Lynch syndrome (Review)

Features of ovarian cancer in Lynch syndrome (Review)

Recommendations for the Care of Individuals With an Inherited Predisposition to Lynch Syndrome

MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

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