Germline PMS2 Mutations: One Hit or Two?
2005; Elsevier BV; Volume: 128; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2005.03.054
ISSN1528-0012
AutoresRobert Gryfe, Steven Gallinger,
Tópico(s)Colorectal Cancer Treatments and Studies
ResumoTo date, heterozygous inactivating germline mutations of the DNA mismatch repair genes MSH2 and MLH1 appear to account for the majority of individuals with hereditary nonpolyposis colorectal cancer (HNPCC).1de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Google Scholar In accordance with the Knudson 2-hit hypothesis, colorectal cancer and high frequency microsatellite instability (MSI) in tumors arise in individuals with HNPCC secondary to a colonic epithelial somatic event that inactivates the second copy of the same mismatch repair gene that is mutated in the germline.1de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Google Scholar, 2Gryfe R. Gallinger S. Microsatellite instability, mismatch repair deficiency, and colorectal cancer.Surgery. 2001; 130: 17-20Google Scholar Other malignancies, including cancers of the endometrium, stomach, small bowel, ureter, and renal pelvis have been observed to occur in increased frequency in individuals with HNPCC and germline mismatch repair gene mutations.1de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Google Scholar, 3Umar A. Boland C.R. Terdiman J.P. et al.Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Google Scholar In addition to MSH2 and MLH1, other human mismatch repair genes including MSH3, MSH6, MLH3, PMS1, and PMS2 have been identified.1de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Google Scholar, 3Umar A. Boland C.R. Terdiman J.P. et al.Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.J Natl Cancer Inst. 2004; 96: 261-268Google Scholar However, with the exception of MSH6, heterozygous germline mutations of these other mismatch repair genes have rarely been identified in cases of familial colorectal cancer. Nonetheless, the PMS2 gene has previously been implicated as the cause of colorectal cancer in a small number of individuals.1de la Chapelle A. Genetic predisposition to colorectal cancer.Nat Rev Cancer. 2004; 4: 769-780Google Scholar, 4Nicolaides N.C. Papadopoulos N. Liu B. et al.Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.Nature. 1994; 371: 75-80Google Scholar, 5Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Google Scholar Similar to MSH2 and MLH1, initial reports linking PMS2 to HNPCC appeared consistent with an autosomal dominant cancer predisposition pattern of transmission.4Nicolaides N.C. Papadopoulos N. Liu B. et al.Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.Nature. 1994; 371: 75-80Google Scholar, 5Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Google Scholar One of the first PMS2 mutation carriers reported was an 18-year-old patient with a history of colorectal cancer, a high-grade astrocytoma and café au lait spots.5Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Google Scholar Early onset colorectal tumors and malignant tumors of the central nervous system are the hallmark features of Turcot syndrome, considered to be a phenotypic variant of either HNPCC or familial adenomatous polyposis (FAP). In contrast, café au lait spots are generally considered clinical feature of neurofibromatosis 1 (NF1), not HNPCC or FAP.6Trimbath J.D. Petersen G.M. Erdman S.H. Ferre M. Luce M.C. Giardiello F.M. Cafe-au-lait spots and early onset colorectal neoplasia a variant of HNPCC?.Fam Cancer. 2001; 1: 101-105Google Scholar Of further genetic interest, MSI, a feature of the biallelic mismatch repair gene loss observed in HNPCC tumors, was evident in normal germline tissues from this PMS2 carrier and was thought to be the result of a dominant negative germline PMS2 mutation.7Parsons R. Li G.M. Longley M. et al.Mismatch repair deficiency in phenotypically normal human cells.Science. 1995; 268: 738-740Google Scholar, 8Nicolaides N.C. Littman S.J. Modrich P. Kinzler K.W. Vogelstein B. A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.Mol Cell Biol. 1998; 18: 1635-1641Crossref Scopus (88) Google Scholar A second study revealed a similar patient with Turcot syndrome diagnosed with an astrocytoma at age 7, colorectal cancer at 13, lymphoma at 15, and MSI in both tumor and normal tissues.9Miyaki M. Nishio J. Konishi M. et al.Drastic genetic instability of tumors and normal tissues in Turcot syndrome.Oncogene. 1997; 15: 2877-2881Google Scholar A single missense germline PMS2 mutation in this individual was identified. An autosomal recessive predisposition to Turcot syndrome offered a mechanistically favorable explanation for the observation of MSI in the normal tissues of PMS2 carriers, and their phenotypic presentation of not only very early onset colorectal, but also brain cancers and café au lait spots. This possibility was soon realized in a report of 2 sisters who died in their teenage years after being diagnosed with brain and colorectal cancers.10De Rosa M. Fasano C. Panariello L. et al.Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.Oncogene. 2000; 19: 1719-1723Google Scholar In addition to both germline and tumor tissue MSI, both sisters were found to be compound heterozygous carriers of truncating germline PMS2 mutations. Similarly, another study of consanguineous half-siblings with café au lait spots and early onset colorectal and brain cancers revealed both to be homozygous germline carriers of a truncating PMS2 mutation.6Trimbath J.D. Petersen G.M. Erdman S.H. Ferre M. Luce M.C. Giardiello F.M. Cafe-au-lait spots and early onset colorectal neoplasia a variant of HNPCC?.Fam Cancer. 2001; 1: 101-105Google Scholar A follow-up study of the patient with Turcot syndrome, café au lait spots and normal tissue MSI described above, revealed that, rather than being a PMS2 heterozygote as originally reported, this patient was a compound heterozygote carrier of truncating PMS2 mutations.5Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Google Scholar, 11De Vos M. Hayward B.E. Picton S. Sheridan E. Bonthron D.T. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.Am J Hum Genet. 2004; 74 (Epub 2004 Apr 7.): 954-964Google Scholar Furthermore, the phenotype of very early onset cancer and café au lait spots has also well been recognized in homozygous or compound heterozygous mutation carriers of the MLH1, MSH2, and MSH6 genes as well.12Wang Q. Montmain G. Ruano E. et al.Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type.Hum Genet. 2003; 112 (Epub 2002 Nov 21.): 117-123Google Scholar, 13Ricciardone M.D. Ozcelik T. Cevher B. et al.Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1.Cancer Res. 1999; 59: 290-293Google Scholar, 14Vilkki S. Tsao J.L. Loukola A. et al.Extensive somatic microsatellite mutations in normal human tissue.Cancer Res. 2001; 61: 4541-4544Google Scholar, 15Whiteside D. McLeod R. Graham G. et al.A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots.Cancer Res. 2002; 62: 359-362Google Scholar, 16Bougeard G. Charbonnier F. Moerman A. et al.Early onset brain tumor and lymphoma in MSH2-deficient children.Am J Hum Genet. 2003; 72: 213-216Google Scholar, 17Gallinger S. Aronson M. Shayan K. et al.Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.Gastroenterology. 2004; 126: 576-585Google Scholar, 18Menko F.H. Kaspers G.L. Meijer G.A. Claes K. van Hagen J.M. Gille J.J. A homozygous MSH6 mutation in a child with cafe-au-lait spots, oligodendroglioma and rectal cancer.Fam Cancer. 2004; 3: 123-127Google Scholar Interestingly, colorectal cancer appears to be relatively rare in most of these autosomal recessive mismatch repair gene mutation cases, perhaps due to very premature death from hematological cancers commonly reported in the MSH2, MLH1, and MSH6 associated cases. The findings described previously, along with germline mutation screening efforts involving large numbers of HNPCC kindreds in which no further heterozygous PMS2 mutations were identified, lead to the conclusion that PMS2 mutations rarely, if ever, predispose to HNPCC in an autsomal dominant fashion.19Wang Q. Lasset C. Desseigne F. et al.Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6 genes in 75 French kindreds with nonpolyposis colorectal cancer.Hum Genet. 1999; 105: 79-85Google Scholar, 20Viel A. Novella E. Genuardi M. et al.Lack of PMS2 gene-truncating mutations in patients with hereditary colorectal cancer.Int J Oncol. 1998; 13: 565-569Google Scholar, 21Liu T. Yan H. Kuismanen S. et al.The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.Cancer Res. 2001; 61: 7798-7802Google Scholar However, unlike other DNA mismatch repair genes, mutational analyses of the PMS2 gene have been complicated by a large number of paralogues with significant sequence homology to PMS211De Vos M. Hayward B.E. Picton S. Sheridan E. Bonthron D.T. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.Am J Hum Genet. 2004; 74 (Epub 2004 Apr 7.): 954-964Google Scholar, 22Horii A. Han H.J. Sasaki S. Shimada M. Nakamura Y. Cloning, characterization and chromosomal assignment of the human genes homologous to yeast PMS1, a member of mismatch repair genes.Biochem Biophys Res Commun. 1994; 204: 1257-1264Google Scholar, 23Nicolaides N.C. Kinzler K.W. Vogelstein B. Analysis of the 5′ region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene.Genomics. 1995; 29: 329-334Google Scholar, 24Kondo E. Horii A. Fukushige S. The human PMS2L proteins do not interact with hMLH1, a major DNA mismatch repair protein.J Biochem (Tokyo). 1999; 125: 818-825Google Scholar, 25Nakagawa H. Lockman J.C. Frankel W.L. et al.Mismatch repair gene PMS2 disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.Cancer Res. 2004; 64: 4721-4727Google Scholar and historically most reports of PMS2 mutational screening preceded the later identification of many of these homologous pseudogenes. Using mutational analysis strategies that account for the large number of PMS2 paralogues, reports by Truninger et al26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar and Worthley et al,27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar in this issue of Gastroenterology, along with a third study recently reported by Nakagawa et al,25Nakagawa H. Lockman J.C. Frankel W.L. et al.Mismatch repair gene PMS2 disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.Cancer Res. 2004; 64: 4721-4727Google Scholar once again make a strong case for heterozygous germline mutations of the PMS2 gene predisposing to colorectal cancer. Thus, it appears that similar to MSH2, MLH1, and MSH6, a co-dominant model of cancer risk is associated with PMS2. Heterozygous mutation carriers of these DNA mismatch repair genes are predisposed to HNPCC or familial colorectal cancer, while homozygous or compound heterozygous germline carriers develop very early onset and aggressive hematogical and brain cancers, in addition to café au lait skin spots and colorectal neoplasms. In both studies reported in this issue of Gastroenterology,26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar, 27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar initial screening was performed by immunohistochemistry for MSH2, MLH1, MSH6, and PMS2. These studies show that PMS2 expression may be lost either alone, or concurrently with MLH1-deficiency, as the PMS2 protein is thought to be degraded in the absence of MLH1. In these studies and others,28Hendriks Y.M. Wagner A. Morreau H. et al.Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations impact on counseling and surveillance.Gastroenterology. 2004; 127: 17-25Google Scholar, 29Plaschke J. Kruger S. Pistorius S. Theissig F. Saeger H.D. Schackert H.K. Involvement of hMSH6 in the development of hereditary and sporadic colorectal cancer revealed by immunostaining is based on germline mutations, but rarely on somatic inactivation.Int J Cancer. 2002; 97: 643-648Google Scholar a similar association of MSH6 instability and absent MSH2 expression was also observed. Consequently, MSH2 and MLH1 germline mutations may be observed in individuals where cancers are MSH2/MSH6-deficienct or MLH1/PMS2-deficient, respectively. In contrast, PMS2 or MSH6 germline mutations may be sought when expression of only one of these specific mismatch repair genes is lost alone. The report by Worthey et al27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar details a single kindred with phenotypic evidence of HNPCC and where a heterozygous truncating mutation of the PMS2 gene segregated with 3 individuals affected with PMS2-deficient, MSI colorectal or endometrial cancers, or adenomatous polyps. The PMS2 mutation was not observed in 2 relatives with esophageal or breast cancer, malignancies that are not typically part of the HNPCC tumor spectrum. This marks the first time that a heterozygous germline PMS2 mutation appears to segregate with disease in a kindred fulfilling the Amsterdam II criteria for HNPCC. In the report by Truninger et al,26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar more than 1000 consecutive colorectal cancers were screened by immunohistochemistry for MSH2, MLH1, MSH6, and PMS2 deficiency. Approximately 13% of tumors showed loss of at least one of these 4 mismatch repair proteins, a frequency typical of large screens for MSI in colorectal cancer.30Halling K.C. French A.J. McDonnell S.K. et al.Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.J Natl Cancer Inst. 1999; 91: 1295-1303Google Scholar, 31Gryfe R. Kim H. Hsieh E.T. et al.Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Google Scholar, 32Ribic C.M. Sargent D.J. Moore M.J. et al.Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.N Engl J Med. 2003; 349: 247-257Google Scholar Of these, 11.5% lacked expression of PMS2 only. In 6 of 16 PMS2-deficient cancers, heterozygous truncating mutations of the PMS2 gene were identified. Nine of 10 of the remaining patients fulfilled either the Bethesda criteria or had significant cancer family histories, suggesting that a germline predisposition was present, but perhaps undetected. While epigenetic silencing of PMS2 by promoter hypermethylation was ruled out in all PMS2-deficient colorectal cancers, biallelic somatic mutation also remains a possible mechanistic genetic explanation for the remaining cancers. In the Truninger series, all PMS2-deficient colorectal cancers showed MSI and were located predominantly proximal to the splenic flexure, and rarely metastasized to regional lymph nodes, features typical of other MSI colorectal cancers.31Gryfe R. Kim H. Hsieh E.T. et al.Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Google Scholar The authors reported likely somatic PMS2 loss of heterozygosity (LOH) in cancers from 6 of 16 of these patients. However, this conclusion should be interpreted cautiously, as a dinucleotide marker, typically subject to MSI, was used for this LOH evaluation. Perhaps most importantly, this large case series raises the possibility that heterozygous germline mutations of PMS2, previously thought to be rare, may be as common as those observed in MSH2 and MLH1, and more common than those in MSH6. If reproduced in other large studies, this suggests that an underlying genetic cause of HNPCC may now be identifiable in the majority of individuals with this syndrome. A total of 12 different truncating germline mutations of PMS2 have now been reported (Truninger et al,26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar Worthey et al,27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar and other studies4Nicolaides N.C. Papadopoulos N. Liu B. et al.Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.Nature. 1994; 371: 75-80Google Scholar, 5Hamilton S.R. Liu B. Parsons R.E. et al.The molecular basis of Turcot's syndrome.N Engl J Med. 1995; 332: 839-847Google Scholar, 6Trimbath J.D. Petersen G.M. Erdman S.H. Ferre M. Luce M.C. Giardiello F.M. Cafe-au-lait spots and early onset colorectal neoplasia a variant of HNPCC?.Fam Cancer. 2001; 1: 101-105Google Scholar, 10De Rosa M. Fasano C. Panariello L. et al.Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.Oncogene. 2000; 19: 1719-1723Google Scholar, 11De Vos M. Hayward B.E. Picton S. Sheridan E. Bonthron D.T. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.Am J Hum Genet. 2004; 74 (Epub 2004 Apr 7.): 954-964Google Scholar, 25Nakagawa H. Lockman J.C. Frankel W.L. et al.Mismatch repair gene PMS2 disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.Cancer Res. 2004; 64: 4721-4727Google Scholar). Two of these represent large genomic losses, and 9 of 10 of the remaining mutations have involved insertions, deletions or substitutions of 1–4 base pairs of which all but one have occurred in short tandem nucleotide repeats or pallindromic sequences. Interestingly, in the 2 studies in this issue of Gastroenterology,26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar, 27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar only 2 mutations, both occurring in (A)4 mononucleotide tracts accounted for 6 of 7 mutations observed in seemingly unrelated individuals from Switzerland (n = 6) and Australia (n =1). Future studies will be needed to determine if the 1045delA mutation (nucleotide numbering based on PMS2 reference sequence NM_00535 and referred to as 1018delA by Truninger et al,26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar and 1021delA by Worthey et al27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar), or the 1855insA (referred to as 1828insA by Truninger et al26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar) represent recurrent genetic hotspots or founder mutations. In practical terms, unlike MLH1-deficiency which is commonly observed in sporadic cancers arising from somatic epigenetic loss of MLH1 expression,33Cunningham J.M. Kim C.Y. Christensen E.R. et al.The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas.Am J Hum Genet. 2001; 69 (Epub 2001 Aug 24.): 780-790Google Scholar the reports by Truninger26Truninger K. Menigatti M. Luz J. Russell A. Haider R. Gebbers J.-O. Bannwart F. Yurtsever H. Neuweiler J. Riehle H.-M. Cattaruzza M.S. Heinimann K. Schär P. Jiricny J. Marra G. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.Gastroenterology. 2005; 128: 1160-1171Abstract Full Text Full Text PDF Scopus (151) Google Scholar and Worthey27Worthley D.L. Walsh M.D. Barker M. Ruszkiewicz A. Bennett G. Phillips K. Suthers G. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.Gastroenterology. 2005; 128: 1431-1436Google Scholar as well as others,25Nakagawa H. Lockman J.C. Frankel W.L. et al.Mismatch repair gene PMS2 disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation.Cancer Res. 2004; 64: 4721-4727Google Scholar now indicate that lack of PMS2 expression alone is highly indicative of an underlying germline PMS2 mutation. It therefore appears that simpler and less expensive screening based on immunohistochemistry may soon be able to supplant MSI testing to provide a sensitive and specific method of identifying individuals and families who will benefit from germline MSH2, MSH6, and PMS2 testing. In the case of MLH1, a combination of immunohistochemistry, family history details, and promoter hypermethylation testing will continue to be important to differentiate germline and somatic causation. Finally, future studies may soon be able to address whether significant clinical phenotypes such as improved survival30Halling K.C. French A.J. McDonnell S.K. et al.Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.J Natl Cancer Inst. 1999; 91: 1295-1303Google Scholar, 31Gryfe R. Kim H. Hsieh E.T. et al.Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N Engl J Med. 2000; 342: 69-77Google Scholar or poor response to adjuvant 5-FU-based chemotherapy,32Ribic C.M. Sargent D.J. Moore M.J. et al.Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.N Engl J Med. 2003; 349: 247-257Google Scholar, 34Carethers J.M. Smith E.J. Behling C.A. et al.Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer.Gastroenterology. 2004; 126: 394-401Google Scholar previously attributed to MSI colorectal cancer in general, may be the result of specific mismatch repair deficiency (ie, MLH1 vs. MSH2 vs. MSH6 vs. PMS2) or the specific mechanism of mismatch repair inactivation (ie, mutation vs. hypermethylation). Immunohistochemical Analysis Reveals High Frequency of PMS2 Defects in Colorectal CancerGastroenterologyVol. 128Issue 5PreviewBackground & Aims: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. Methods: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Full-Text PDF Familial Mutations in PMS2 Can Cause Autosomal Dominant Hereditary Nonpolyposis Colorectal CancerGastroenterologyVol. 128Issue 5PreviewBackground & Aims: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by familial mutations in some of the genes responsible for DNA mismatch repair. Mutations in the MLH1, MSH2, and MSH6 genes have been documented in this disorder, but there have been limited and conflicting data about the role of another mismatch repair gene, PMS2. It has recently been suggested that mutations in the PMS2 gene do not cause an autosomal dominant disorder. In addition, mutations in each of these 4 mismatch repair genes have been shown to cause an autosomal recessive cancer syndrome in children that is distinct from hereditary nonpolyposis colorectal cancer. Full-Text PDF
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