The Tumor Spectrum in the Lynch Syndrome
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, Nebraska 68131, USA. Familial Cancer
(Impact Factor: 1.98).
02/2005; 4(3):245-8. DOI: 10.1007/s10689-004-7994-z
Colorectal and endometrial cancer are the characteristic tumors of the Lynch syndrome. We reviewed the available evidence on the occurrence of other types of cancer in the syndrome, aiming to identify those types that can be included in the tumor spectrum, based on this evidence. We chose to define the tumor spectrum as comprising the cancers for which Lynch syndrome patients are at elevated risk. We found sufficiently strong and consistent evidence to include gastric cancer, small bowel cancer, hepatobiliary tract cancer, upper urologic tract cancer, ovarian cancer, and brain tumors in this spectrum, in addition to colorectal and endometrial cancer. We predict that the spectrum will expand as additional studies are reported, especially as prospective studies of mutation carriers are completed.
Available from: Ignacio Blanco
- ". Clinically, Lynch syndrome is characterized by early-onset CRC and an increased risk of other associated tumors [Lynch et al., 2008; Watson and Riley, 2005]. Tumors of Lynch syndrome spectrum are associated with microsatellite instability (MSI) and loss of MMR proteins expression [Lynch et al., 2008]. "
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ABSTRACT: Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244G>A (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families. Hum Mutat 33:1576-1588, 2012. © 2012 Wiley Periodicals, Inc.
Human Mutation 01/2013; 33(11):1576-88. DOI:10.1002/humu.22142 · 5.14 Impact Factor
Available from: onlinelibrary.wiley.com
- "In fact, the lifetime risk for endometrial (Watson et al., 1994; Aarnio et al., 1995; Aarnio et al., 1999) and ovarian cancers (Watson et al., 2001) is estimated at 30–60% and 12%, respectively, compared with 3 and 2%, respectively , in the general population. An elevated risk for breast cancer in Lynch syndrome has been suggested in several studies, but the issue remains controversial (Risinger et al., 1996; Scott et al., 2001; Vasen et al., 2001; Muller et al., 2002; de Leeuw et al., 2003; Oliveira Ferreira et al., 2004; Watson and Riley, 2005; Westenend et al., 2005; Blokhuis et al., 2008; Shanley et al., 2009). "
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ABSTRACT: Lynch syndrome, an autosomal dominant cancer predisposition caused by mutations in DNA mismatch repair (MMR) genes, mainly mainly mutL homolog 1, OMIM 120436 (MLH1) and mutS homolog 2, OMIM 609309 (MSH2), encompasses a tumor spectrum including primarily gastrointestinal, endometrial, and ovarian cancer. This study aimed at clarifying the heavily debated issue of breast cancer being part of Lynch syndrome. Detailed clinical data on cancer occurrence in Swiss female MLH1/MSH2 mutation carriers were gathered, all available breast cancer specimens assessed for molecular evidence for MMR deficiency (i.e., microsatellite instability (MSI), MMR protein expression, and somatic (epi)genetic MMR gene alterations) and compiled with the scarce molecular data available from the literature. Seventy unrelated Swiss Lynch syndrome families were investigated comprising 632 female family members at risk of which 92 were genetically verified mutation carriers (52 MLH1 and 40 MSH2). On contrast to endometrial and ovarian cancer, which occurred significantly more often and at younger age in MLH1/MSH2 mutation carriers (median 50.5 and 49.0 years; P < 0.00001), overall cumulative breast cancer incidence closely mirrored the one in the Swiss population (56.5 years). Six (85.7%) of seven breast cancer specimens available for molecular investigations displayed the hallmarks of MMR deficiency. Combined with data from the literature, MSI was present in 26 (70.3%) of 37 and altered MMR protein expression in 16 (72.7%) of 22 breast cancer specimens from MLH1/MSH2 mutation carriers. These findings, thus, provide strong molecular evidence for a pivotal role of MMR deficiency in breast cancer development in Lynch syndrome.
Genes Chromosomes and Cancer 01/2012; 51(1):83-91. DOI:10.1002/gcc.20935 · 4.04 Impact Factor
Available from: ncbi.nlm.nih.gov
- "Individuals with HNPCC have an 80% probability of developing CRC by the age of 65 years. They are also at an increased risk of developing a second primary CRC, although the stage at diagnosis is reported to be lower in HNPCC families than in the general population (Watson and Riley, 2005). In addition , affected individuals are at increased risk of a number of extra-colonic malignancies, with women having a 50%~60% risk of endometrial cancer. "
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ABSTRACT: A small proportion of many cancers are due to inherited mutations in genes, which result in a high risk to the individual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes, oncogenes, genes encoding proteins involved in DNA repair and cell cycle control, and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.
Journal of Zhejiang University SCIENCE B 02/2008; 9(1):1-4. DOI:10.1631/jzus.B073001 · 1.28 Impact Factor
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