A review on the molecular diagnostics of Lynch syndrome: a central role for the pathology laboratory

Lier, Margot G F van; Wagner, Anja; Leerdam, Monique E. van; Biermann, Katharina; Kuipers, Ernst J.; Steyerberg, Ewout W.; Dubbink, Hendrikus J.; Dinjens, Winand N.M.

doi:10.1111/j.1582-4934.2009.00977.x

Cited by 67 publications

(84 citation statements)

References 124 publications

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“…Promoter hypermethylation or loss of LKB1 expression has been described for sporadic testicular, papillary breast, endometrial, neuroendrocrine lung and pancreatic cancer . Germ-line mutations in LKB1 predispose to the Peutz-Jeghers syndrome (PJS), (Hemminki et al, 1998;Jenne et al, 1998) which is characterized by mucocutaneous hyperpigmentation, gastrointestinal hamartomatous polyposis and a highly increased risk for developing gastrointestinal, breast, gynecological and lung cancer (Tomlinson and Houlston, 1997;McGarrity and Amos, 2006;van Lier et al, 2010) (Table 1). LKB1 is classified as a tumor suppressor gene implying that both alleles need to be inactivated to induce tumor development.…”

Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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“…However, the resistance of BRAF-mutated tumors to EGFR inhibitors is still controversial [De Stefano and Carlomagno, 2014;Benvenuti et al 2007;Haraldsdottir and Bekaii-Saab, 2013]. Moreover, BRAF mutation is often associated with sporadic MSI-H CRC and a sessile/ serrated adenoma sequence, and so it can be considered a diagnostic biomarker that can be used to distinguish hereditary from sporadic MSI-H tumors [van Lier et al 2010;Sideris and Papagrigoriadis, 2014]. The role of BRAF mutation as a prognostic biomarker depends on the combination with other genetic alterations.…”

Section: Prognostic and Predictive Molecular Biomarkersmentioning

confidence: 99%

The biological complexity of colorectal cancer: insights into biomarkers for early detection and personalized care

Rosa

Rega

Costabile

et al. 2016

Therap Adv Gastroenterol

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Colorectal cancer has been ranked the third and second most prevalent of all cancers in men and women, respectively, and it represents the fourth most common cause of cancer deaths. In 2012, there were 1.4 million estimated cases of colorectal cancer worldwide, and 700,000 estimated deaths, which implies significant impact on public health, especially in economically-developed countries. In recent years, there has been an increase in the number of tumors, although this has been accompanied by decreased mortality, due to more appropriate and available information, earlier diagnosis, and improvements in treatment. Colorectal cancers are characterized by great genotypic and phenotypic heterogeneity, including tumor microenvironment and interactions between healthy and cancer cells. All of these traits confer a unique peculiarity to each tumor, which can thus be considered as an individual disease. Well conducted molecular and clinical characterization of each colorectal cancer is essential with a view to the implementation of precision oncology, and thus personalized care. This last aims at standardization of therapeutic plans chosen according to the genetic background of each specific neoplasm, to increase overall survival and reduce treatment side effects. Thus, prognostic and predictive molecular biomarkers assume a critical role in the characterization of colorectal cancer and in the determination of the most appropriate therapy

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“…IHC was performed as primary molecular analysis to assess MMR protein expression (MLH1, MSH2, MSH6, PMS2), according to standard procedure (Matthews et al 2008;Backes et al 2009;van Lier et al 2010). An appropriate paraffin-embedded tissue was cut at 4 μm.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The MMR proteins function as heterodimers; MSH2 forms a heterodimer with MSH6 or MSH3, and MLH1 forms a heterodimer with PMS2 or PMS1 (van Lier et al 2010;Moline et al 2013). Thus, the corresponding MMR gene mutations were predicted from loss of MMR protein expression (see Table 2).…”

Section: Prediction Of Corresponding Mmr Gene Mutationsmentioning

confidence: 99%

Efficient Screening Strategy for Lynch Syndrome in Japanese Endometrial Cancer

Sugawara

Sato

Shimizu

et al. 2015

Tohoku J. Exp. Med.

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Lynch syndrome (LS) is an inherited disorder caused by a germline mutation in the DNA mismatch repair (MMR) genes and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). It is significant to identify LS in EC patients for prediction and prevention of the succeeding other associated cancers. However, useful LS screening guidelines for EC have not been established. The purpose of our study is to devise an efficient and practical screening strategy for LS in EC. We designed original criteria, named "APF criteria," with lenient terms (Age of onset < 50, or Personal or Family history of associated cancers) and applied it to unselected EC patients. We performed immunohistochemistry (IHC) and the methylation assay of MutL homolog 1 (MLH1) gene promoter using the tumors of patients who met our criteria, and thus selected "suspected LS" as the candidates for genetic analyses. Of 360 EC patients, 187 (51.9%) met the APF criteria, and the tumor specimens were available from 182 out of the 187 patients. IHC revealed that expression of at least one MMR protein was absent in cell nuclei of 54 (29.6%) tumors. Of 20 tumors lacking MLH1 protein expression, 14 cases were judged sporadic EC because of the hypermethylated MLH1 promoter. We thus selected 40 (11.1%) of 360 EC patients as "suspected LS." Our strategy that consists of clinical triage and the molecular analyses is expected to improve the screening efficiency and reduce the cost of LS identification in EC.

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A review on the molecular diagnostics of Lynch syndrome: a central role for the pathology laboratory

Cited by 67 publications

References 124 publications

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

The biological complexity of colorectal cancer: insights into biomarkers for early detection and personalized care

Efficient Screening Strategy for Lynch Syndrome in Japanese Endometrial Cancer

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