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MSH6 IHC deficient colon cancer

Tao Wang, Zsofia K Stadler, Liying Zhang, Martin R Weiser, Olca Basturk, Jaclyn F Hechtman, Efsevia Vakiani, Lenard B Saltz, David S Klimstra, Jinru Shia
Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2)...
August 17, 2017: Familial Cancer
Ju-Xiang Ye, Yan Liu, Yun Qin, Hao-Hao Zhong, Wei-Ning Yi, Xue-Ying Shi
AIM: To investigate gene mutations and DNA mismatch repair (MMR) protein abnormality in Chinese colorectal carcinoma (CRC) patients and their correlations with clinicopathologic features. METHODS: Clinical and pathological information for 535 patients including 538 tumors was reviewed and recorded. Mutation analyses for exon 2 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing except that in 9 tumors amplification refractory mutation system PCR was used...
February 7, 2015: World Journal of Gastroenterology: WJG
Sigurdis Haraldsdottir, Heather Hampel, Jerneja Tomsic, Wendy L Frankel, Rachel Pearlman, Albert de la Chapelle, Colin C Pritchard
BACKGROUND & AIMS: Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing...
December 2014: Gastroenterology
Christophe Rosty, Michael D Walsh, Noralane M Lindor, Stephen N Thibodeau, Erin Mundt, Steven Gallinger, Melyssa Aronson, Aaron Pollett, John A Baron, Sally Pearson, Mark Clendenning, Rhiannon J Walters, Belinda N Nagler, William J Crawford, Joanne P Young, Ingrid Winship, Aung Ko Win, John L Hopper, Mark A Jenkins, Daniel D Buchanan
The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved. We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers. Prostate cancers (mean age at diagnosis = 62 ± SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H)...
December 2014: Familial Cancer
Sean C Skeldon, Kara Semotiuk, Melyssa Aronson, Spring Holter, Steven Gallinger, Aaron Pollett, Cynthia Kuk, Bas van Rhijn, Peter Bostrom, Zane Cohen, Neil E Fleshner, Michael A Jewett, Sally Hanna, Shahrokh F Shariat, Theodorus H Van Der Kwast, Andrew Evans, Jim Catto, Bharati Bapat, Alexandre R Zlotta
BACKGROUND: Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse. OBJECTIVE: To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations. DESIGN, SETTING, AND PARTICIPANTS: Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E...
February 2013: European Urology
Michael D Walsh, Daniel D Buchanan, Sally-Ann Pearson, Mark Clendenning, Mark A Jenkins, Aung Ko Win, Rhiannon J Walters, Kevin J Spring, Belinda Nagler, Erika Pavluk, Sven T Arnold, Jack Goldblatt, Jill George, Graeme K Suthers, Kerry Phillips, John L Hopper, Jeremy R Jass, John A Baron, Dennis J Ahnen, Stephen N Thibodeau, Noralane Lindor, Susan Parry, Neal I Walker, Christophe Rosty, Joanne P Young
Debate continues as to the usefulness of assessing adenomas for loss of mismatch repair protein expression to identify individuals with suspected Lynch syndrome. We tested 109 polyps from 69 proven mutation carriers (35 females and 34 males) belonging to 49 Lynch syndrome families. All polyps were tested by immunohistochemistry for four mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. Detailed pathology review was performed by specialist gastrointestinal pathologists. The majority of polyps (86%) were conventional adenomas (n=94), with 65 tubular and 28 tubulovillous adenomas and a single villous adenoma...
May 2012: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Clare D'Arcy, Yong H Wen, Zsofia K Stadler, Edi Brogi, Jinru Shia
The increasingly widespread use of immunohistochemistry in the detection of DNA mismatch repair proteins has led to the observation of various unusual tumor types that occur in Lynch syndrome and exhibit mismatch repair protein deficiency. Understanding the clinical significance of such unusual tumors has become increasingly desirable. Here, we report a case of 2 synchronous breast cancers occurring in a 74-year-old woman who carried a deleterious germline mutation in MSH2 and who survived an endometrial and a colonic carcinoma...
November 2011: American Journal of Surgical Pathology
Ajay Goel, Takeshi Nagasaka, Jennifer Spiegel, Richard Meyer, Warren E Lichliter, C Richard Boland
BACKGROUND & AIMS: Colorectal cancer (CRC) is uncommon in individuals <50 years old. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes and associated with early-onset CRC, but little is known about the proportion of young patients with apparently sporadic CRC who actually have Lynch syndrome. We examined patterns of microsatellite instability (MSI) and MMR genes among patients <50 years old with non-familial CRC (patients with not more than 1 family member with CRC)...
November 2010: Clinical Gastroenterology and Hepatology
Silvia Liliana Cossio, Patricia Koehler-Santos, Suzana Arenhart Pessini, Heleuza Mónego, Maria Isabel Edelweiss, Luise Meurer, Abdellatif Errami, Jordy Coffa, Hugo Bock, Maria Luiza Saraiva-Pereira, Patricia Ashton-Prolla, João Carlos Prolla
Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 and PMS2. Clinically, Lynch syndrome is characterized by early onset (45 years) of colorectal cancer (CRC), as well as extra-colonic cancer. Male and female carriers of Lynch syndrome-associated mutations have different lifetime risks for CRC and in women endometrial cancer (EC) may be the most common tumor. Whenever Amsterdam criteria are not fulfilled, the currently recommended laboratory screening strategies involve microsatellite instability testing and immunohistochemistry staining of the tumor for the major MMR proteins...
June 2010: Familial Cancer
Maria Simona Pino, Mari Mino-Kenudson, Bernadette Mandes Wildemore, Aniruddha Ganguly, Julie Batten, Isabella Sperduti, Anthony John Iafrate, Daniel C Chung
Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen subjects with a germline MMR gene mutation who had 44 adenomas removed during surveillance colonoscopy were identified. MSI testing and IHC for MLH1, MSH2, and MSH6 were performed...
May 2009: Journal of Molecular Diagnostics: JMD
Petra Ruemmele, Wolfgang Dietmaier, Luigi Terracciano, Luigi Tornillo, Frauke Bataille, Annette Kaiser, Peter-Heinz Wuensch, Ernst Heinmoeller, Kia Homayounfar, Jutta Luettges, Guenter Kloeppel, Fausto Sessa, Tina Bocker Edmonston, Regine Schneider-Stock, Monika Klinkhammer-Schalke, Armin Pauer, Stefan Schick, Ferdinand Hofstaedter, Daniel Baumhoer, Arndt Hartmann
The prevalence and development of microsatellite instability (MSI) and underlying mismatch repair (MMR) deficiency in the carcinogenesis of adenocarcinomas of the papilla of Vater and their precursor lesions are not well established. We analyzed 120 ampullary adenomas (31 pure adenomas and 89 carcinoma-associated adenomas) and 170 pure adenocarcinomas for MSI, immunohistochemical expression of MMR proteins and specific histopathologic features. The most common histologic subtype was intestinal (46.5%), followed by pancreatobiliary (23...
May 2009: American Journal of Surgical Pathology
L H Jensen, J Lindebjerg, L Byriel, S Kolvraa, D G Crüger
OBJECTIVE: Deficiency of DNA mismatch repair (MMR) causes microsatellite instability (MSI) in a subset of colorectal cancers. Patients with these tumours have a better prognosis and may have an altered response to chemotherapy. Some of the tumours are caused by hereditary mutations (hereditary nonpolyposis colon cancer or Lynch syndrome), but most are epigenetic changes of sporadic origin. The aim of this study was to define a robust and inexpensive strategy for such classification in clinical practice...
June 2008: Colorectal Disease: the Official Journal of the Association of Coloproctology of Great Britain and Ireland
Annegret Müller, Carmen Beckmann, Gabriela Westphal, Tina Bocker Edmonston, Nicolaus Friedrichs, Wolfgang Dietmaier, Frank E Brasch, Matthias Kloor, Christoph Poremba, Gisela Keller, Daniela E Aust, Jürgen Fass, Reinhard Büttner, Heinz Becker, Josef Rüschoff
In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, more than 90% of the carcinomas show microsatellite instability (MSI) due to a loss of mismatch repair (MMR) function. Although adenomas are very common in HNPCC and demonstrate an accelerated adenoma-carcinoma sequence, data about the prevalence and development of MSI in these early neoplastic lesions are lacking. To determine whether MSI and loss of MMR-protein expression are already present in early stages of tumorigenesis and could therefore be used as a screening tool to identify HNPCC patients before they develop an invasive carcinoma, we analyzed 71 adenomas of 36 HNPCC patients during a 5-year follow-up study...
October 2006: International Journal of Colorectal Disease
Miina Ollikainen, Wael M Abdel-Rahman, Anu-Liisa Moisio, Annette Lindroos, Reetta Kariola, Irma Järvelä, Minna Pöyhönen, Ralf Butzow, Päivi Peltomäki
PURPOSE: Familial clustering of endometrial carcinoma (EC) may occur as part of hereditary nonpolyposis colorectal cancer (HNPCC), a multiorgan cancer syndrome with mismatch repair (MMR) deficiency. Clustering of EC alone, termed as familial site-specific EC, may constitute a separate entity. Because its genetic basis is unknown, our purpose was to characterize such families molecularly. MATERIALS AND METHODS: Twenty-three families with site-specific EC were identified among 519 consecutive patients diagnosed with EC during 1986 to 1997...
July 20, 2005: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Marcia R Campbell, Patrick N Nation, Susan E Andrew
Inheritance of a germline mutation in one of the DNA mismatch repair genes predisposes human individuals to hereditary nonpolyposis colorectal cancer, characterized by development of tumors predominantly in the colon, endometrium, and gastrointestinal tract. Mice heterozygous for a mismatch repair-null mutation generally do not have an increased risk of neoplasia. However, mice constitutively lacking mismatch repair are prone to tumor development from an early age, particularly thymic lymphomas. Mismatch repair-deficient mice crossed to Apc(+/-) mice develop an increased spontaneous intestinal tumor incidence, demonstrating that the tumor spectrum can be genetically influenced...
April 1, 2005: Cancer Research
Steven Gallinger, Melyssa Aronson, Katayoon Shayan, Elyanne M Ratcliffe, Justin T Gerstle, Patricia C Parkin, Heidi Rothenmund, Marina Croitoru, Ewa Baumann, Peter R Durie, Rosanna Weksberg, Aaron Pollett, Robert H Riddell, Bo Y Ngan, Ernest Cutz, Alain E Lagarde, Helen S L Chan
Heterozygous germline DNA mismatch repair gene mutations are typically associated with hereditary nonpolyposis colorectal cancer. The molecular hallmark of this syndrome is high-frequency microsatellite instability in the tumors. Rare childhood cases with homozygous or compound heterozygous DNA mismatch repair gene mutations have a described predisposition to leukemia, lymphoma, and brain tumors but not to gastrointestinal cancer. We have now characterized a family in which 2 children with a homozygous germline DNA mismatch repair gene mutation developed early-onset gastrointestinal cancers...
February 2004: Gastroenterology
Yvonne Hendriks, Patrick Franken, Jan Willem Dierssen, Wiljo De Leeuw, Juul Wijnen, Enno Dreef, Carli Tops, Martijn Breuning, Annette Bröcker-Vriends, Hans Vasen, Riccardo Fodde, Hans Morreau
Immunohistochemistry (IHC) of mismatch repair (MMR) proteins in colorectal tumors together with microsatellite analysis (MSI) can be helpful in identifying families eligible for mutation analysis. The aims were to determine sensitivity of IHC for MLH1, MSH2, and MSH6 and MSI analysis in tumors from known MMR gene mutation carriers; and to evaluate the use of tissue microarrays for IHC (IHC-TMA) of colon tumors in its ability to identify potential carriers of MMR gene mutations, and compare it with IHC on whole slides...
February 2003: American Journal of Pathology
P Schweizer, A L Moisio, S A Kuismanen, K Truninger, R Vierumäki, R Salovaara, J Arola, R Butzow, J Jiricny, P Peltomäki, M Nyström-Lahti
Hereditary nonpolyposis colorectal cancer syndrome is associated with an inherited predisposition to primarily colorectal cancer (CRC) and endometrial cancer (EC); however, the biological basis of the organ involvement remains unknown. As an attempt to explore whether the expression levels of MLH1, MSH2, and MSH6 may play a role, we used immunohistochemistry to study 42 ECs and 35 CRCs from patients carrying the same predisposing mutations. Among MSH2 mutation carriers, MLH1 was expressed in both tumor types, whereas MSH2 and, in many cases, also MSH6, were absent...
April 1, 2001: Cancer Research
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