Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications
TLDR
Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential, and subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC.Abstract:
More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (~30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC’s proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir-Torre variant). LS explains only 10–25% of familial CRC.read more
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Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts
Hans F. A. Vasen,Ignacio Blanco,Katja Aktan-Collan,Jessica P. Gopie,Angel Alonso,Stefan Aretz,Inge Bernstein,Lucio Bertario,John Burn,Gabriel Capellá,Chrystelle Colas,Christoph Engel,Ian M. Frayling,Maurizio Genuardi,Karl Heinimann,Frederik J. Hes,Shirley Hodgson,John A. Karagiannis,Fiona Lalloo,Annika Lindblom,Jukka-Pekka Mecklin,Pål Møller,Torben Myrhøj,Fokko M. Nagengast,Yann Parc,Maurizio Ponz de Leon,Laura Renkonen-Sinisalo,Julian R. Sampson,Astrid Stormorken,Rolf H. Sijmons,Sabine Tejpar,Huw Thomas,Nils Rahner,Juul T. Wijnen,Heikki Järvinen,Gabriela Möslein +35 more
TL;DR: The guidelines described in this paper may be helpful for the appropriate management of families with LS and Prospective controlled studies should be undertaken to improve further the care of these families.
Journal ArticleDOI
Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors
Thomas Duhen,Rebekka Duhen,Ryan Montler,Jake Moses,Tarsem Moudgil,Noel F C C de Miranda,Cheri P. Goodall,Tiffany C. Blair,Bernard A. Fox,Jason E. McDermott,Shu Ching Chang,Gary L. Grunkemeier,Rom Leidner,R.B. Bell,Andrew D. Weinberg +14 more
TL;DR: The authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells, which may lead to future adoptive T-cell cancer therapies.
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The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Peter Bouwman,Jos Jonkers +1 more
TL;DR: Tumours with specific DNA repair defects can be completely dependent on back-up DNA repair pathways for their survival and may acquire resistance by invoking biochemical mechanisms that reduce drug action or by acquiring additional alterations in DNA damage response pathways.
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MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18
Rosalba Salcedo,Andrea Worschech,Marco Cardone,Yava Jones,Zsofia Gyulai,Ren-Ming Dai,Ren-Ming Dai,Ena Wang,Winnie Ma,Diana C. Haines,Colm O'hUigin,Colm O'hUigin,Francesco M. Marincola,Giorgio Trinchieri +13 more
TL;DR: A previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis is revealed.
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Cancer Epigenetics
References
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A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of International Criteria for the Determination of Microsatellite Instability in Colorectal Cancer
C. Richard Boland,Stephen N. Thibodeau,Stanley R. Hamilton,David Sidransky,James R. Eshleman,Randall W. Burt,Stephen J. Meltzer,Miguel A. Rodriguez-Bigas,Riccardo Fodde,G. Nadia Ranzani,Sudhir Srivastava +10 more
TL;DR: The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms.
Journal ArticleDOI
Microsatellite instability in cancer of the proximal colon
TL;DR: Colorectal tumor DNA was examined for somatic instability at (CA)n repeats on human chromosomes 5q, 15q, 17p, and 18q, and this instability was significantly correlated with the tumor's location in the proximal colon and with increased patient survival and loss of heterozygosity.
Journal ArticleDOI
Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability
Asad Umar,C. Richard Boland,Jonathan P. Terdiman,Sapna Syngal,Albert de la Chapelle,Josef Rüschoff,Richard Fishel,Noralane M. Lindor,Lawrence J. Burgart,Richard Hamelin,Stanley R. Hamilton,Robert A. Hiatt,Jeremy R. Jass,Annika Lindblom,Henry T. Lynch,Päivi Peltomäki,Scott D. Ramsey,Miguel A. Rodriguez-Bigas,Hans F. A. Vasen,Ernest T. Hawk,J. Carl Barrett,Andrew N. Freedman,Sudhir Srivastava +22 more
TL;DR: This commentary summarizes the Workshop presentations on HNPCC and MSI testing; presents the issues relating to the performance, specificity, and specificity of the Bethesda Guidelines; outlines the revised Bethesda Guidelines for identifying individuals at risk for H NPCC; and recommend criteria for MSI testing.
Journal ArticleDOI
The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
Richard Fishel,Mary Kay Lescoe,M.R.S. Rao,Neal G. Copeland,Nancy A. Jenkins,Judy Garber,Michael F. Kane,Richard D. Kolodner +7 more
TL;DR: Data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with H NPCC suggest that hMSH2 is the HNPCC gene.
Journal ArticleDOI
Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis
TL;DR: It is shown that 12 per cent of colorectal carcinomas carry somatic deletions in poly(dA . dT) sequences and other simple repeats, and it is concluded that these mutations reflect a previously undescribed form of carcinogenesis in the colon mediated by a mutation in a DNA replication factor resulting in reduced fidelity for replication or repair (a 'mutator mutation').
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