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Medline ® Abstracts for References 66-76

of 'Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis'

66
TI
Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1.
AU
Ricciardone MD, Ozçelik T, Cevher B, OzdağH, Tuncer M, Gürgey A, Uzunalimoğlu O, Cetinkaya H, Tanyeli A, Erken E, Oztürk M
SO
Cancer Res. 1999;59(2):290.
 
Heterozygous germ-line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer. The disease susceptibility of individuals who constitutionally lack both wild-type alleles is unknown. We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age, and at least two of them displayed signs of neurofibromatosis type 1 (NF1). DNA sequence analysis and allele-specific amplification in two siblings revealed a homozygous MLH1 mutation (C676T-->Arg226Stop). Thus, a homozygous germ-line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and/or lymphoma associated with neurofibromatosis type 1.
AD
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
PMID
67
TI
A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots.
AU
Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE
SO
Cancer Res. 2002;62(2):359.
 
Individuals with a germ-line mutation in one of the DNA mismatch repair (MMR) genes are at significant risk for colorectal cancer and other tumors. Three families have previously been reported with individuals homozygous for mutations in the MMR gene MLH1 that are predicted to compromise MMR. These individuals develop hematological malignancies and/or neurofibromatosis type 1 at an early age. Here, in an individual, we demonstrate that a homozygous novel mutation in the MMR gene MSH2 is associated with leukemia and multiple café-au-lait spots, a feature of neurofibromatosis type 1. Because the hematological malignancies observed in the individuals homozygous for the loss of MMR are reflective of the lymphomas seen in mice lacking MMR, the mice may provide a useful model for human neoplasia.
AD
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, T6G 2H7 Canada.
PMID
68
TI
Early onset brain tumor and lymphoma in MSH2-deficient children.
AU
Bougeard G, Charbonnier F, Moerman A, Martin C, Ruchoux MM, Drouot N, Frébourg T
SO
Am J Hum Genet. 2003;72(1):213.
 
AD
PMID
69
TI
Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.
AU
Gallinger S, Aronson M, Shayan K, Ratcliffe EM, Gerstle JT, Parkin PC, Rothenmund H, Croitoru M, Baumann E, Durie PR, Weksberg R, Pollett A, Riddell RH, Ngan BY, Cutz E, Lagarde AE, Chan HS
SO
Gastroenterology. 2004;126(2):576.
 
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. The 11-year-old proband had café-au-lait macules and developed metastatic duodenal adenocarcinoma that arose in a tubulovillous adenoma. His 9-year-old sister with café-au-lait macules and axillary freckling presented with malignant colon polyps. A 6-year-old sister with café-au-lait macules, hairy nevi, and a plexiform neurofibroma of the tongue has no malignancies to date. The family history did not fulfill the Amsterdam criteria for hereditary nonpolyposis colorectal cancer, but 2 relatives in their 60s had gastric cancer and colorectal cancer, whereas the parents, who are first cousins, remain cancer free. The proband's metastatic duodenal cancer and his sister's malignant colon polyps had high-frequency microsatellite instability but had detectable MLH1, MSH2, and MSH6 proteins by immunohistochemistry. Because some germline DNA mismatch repair gene deficiencies are associated with apparently intact immunohistochemical DNA mismatch repair gene expression in tumors, we proceeded to DNA sequencing, which showed that all 3 children had a germline homozygous MLH1 missense mutation (exon 18, codon 687, CGG-->TGG), whereas both parents were heterozygous for this mutation.
AD
Familial Gastrointestinal Cancer Registry and Centre for Cancer Genetics and Department of Surgery, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, ON, Canada.
PMID
70
TI
A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer.
AU
Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ
SO
Fam Cancer. 2004;3(2):123.
 
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition due to heterozygous germline mutations in DNA mismatch repair genes, in particular MLH1, MSH2 and MSH6. Recently, a syndrome was recognized in which children develop haematological malignancies, solid tumours and signs of neurofibromatosis type 1 due to bi-allelic MMR gene mutations in MLH1, MSH2 and PMS2. Here we describe the child of healthy consanguineous parents who had café-au-lait spots, oligodendroglioma, and rectal cancer. The patient was homozygous for the MSH6 mutation c.3386_3388delGTG in exon 5 which has a predicted pathogenic effect. Germline NF1 gene mutation testing was negative. The rectal tumour showed microsatellite instability and absence of MSH6 staining, whereas the brain tumour was MSI stable and showed normal immunohistochemical expression of MSH6. Apparently, not only MLH1, MSH2 and PMS2, but also MSH6 is involved in the syndrome of childhood cancer and signs of neurofibromatosis type 1.
AD
Department of Clinical Genetics and Human Genetics, VU University Medical Center, Amsterdam, The Netherlands. fh.menko@vumc.nl
PMID
71
TI
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.
AU
Nakagawa H, Lockman JC, Frankel WL, Hampel H, Steenblock K, Burgart LJ, Thibodeau SN, de la Chapelle A
SO
Cancer Res. 2004;64(14):4721.
 
The MutLalpha heterodimer formed by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpolyposis colorectal cancer. Evidence from five published cases suggested that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal cancer or Turcot syndrome only when they are biallelic in the germline or abnormally expressed. As candidates for PMS2 mutations, we selected seven patients whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry. After conversion to haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deletion of exon 8). These mutations abrogated PMS2 protein in germline cells by Western analysis. In two additional patients, PMS2 protein from one allele also was abrogated. Novel or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermined. We detected and characterized a new transcript, PMS2CL, showing 98% sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p. Its predicted protein productwas not detected. Thus, in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of PMS2. In conclusion, both detectable and presently undefined germline mutations are deleterious and produce susceptibility to cancer by the two-hit mechanism. Paralogous genes interfere with mutation detection, resulting in underdiagnosis of PMS2 mutations. Mutation detection in PMS2 requires haploid DNA.
AD
Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, 420 West 12th Avenue, Columbus, OH 43210, USA.
PMID
72
TI
Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.
AU
Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G
SO
Gastroenterology. 2005;128(5):1160.
 
BACKGROUND&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. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene.
RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene.
CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.
AD
Institute of Molecular Cancer Research, University of Zurich, Switzerland.
PMID
73
TI
Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer.
AU
Worthley DL, Walsh MD, Barker M, Ruszkiewicz A, Bennett G, Phillips K, Suthers G
SO
Gastroenterology. 2005;128(5):1431.
 
BACKGROUND&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. We reviewed a cohort of patients for evidence of an autosomal dominant disorder caused by a mutation in the PMS2 gene.
METHODS: A cohort of tumor samples from patients with features suggestive of HNPCC was tested for microsatellite instability, the molecular hallmark of HNPCC, and exclusive loss of expression of the PMS2 gene in tumor tissue.
RESULTS: A kindred was identified with autosomal dominant HNPCC due to a familial loss-of-function mutation in the PMS2 gene. This is the first description of such a kindred.
CONCLUSION: Mutations in the PMS2 gene can, like mutations in other mismatch repair genes, cause both autosomal dominant HNPCC in adults and an autosomal recessive cancer syndrome in children.
AD
Repatriation General Hospital, South Australia, Australia. danielworthley@bigpond.com
PMID
74
TI
Constitutive deficiency in DNA mismatch repair.
AU
Felton KE, Gilchrist DM, Andrew SE
SO
Clin Genet. 2007;71(6):483.
 
Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir-Torre.
AD
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
PMID
75
TI
Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.
AU
Will O, Carvajal-Carmona LG, Gorman P, Howarth KM, Jones AM, Polanco-Echeverry GM, Chinaleong JA, Günther T, Silver A, Clark SK, Tomlinson I
SO
Gastroenterology. 2007;132(2):527. Epub 2006 Nov 29.
 
BACKGROUND&AIMS: We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis.
METHODS: Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1.
RESULTS: The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found.
CONCLUSIONS: Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.
AD
Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research, London, UK.
PMID
76
TI
Gastrointestinal Findings in the Largest Series of Patients With Hereditary Biallelic Mismatch Repair Deficiency Syndrome: Report from the International Consortium.
AU
Aronson M, Gallinger S, Cohen Z, Cohen S, Dvir R, Elhasid R, Baris HN, Kariv R, Druker H, Chan H, Ling SC, Kortan P, Holter S, Semotiuk K, Malkin D, Farah R, Sayad A, Heald B, Kalady MF, Penney LS, Rideout AL, Rashid M, Hasadsri L, Pichurin P, Riegert-Johnson D, Campbell B, Bakry D, Al-Rimawi H, Alharbi QK, Alharbi M, Shamvil A, Tabori U, Durno C
SO
Am J Gastroenterol. 2016;111(2):275. Epub 2016 Jan 5.
 
OBJECTIVES: Hereditary biallelic mismatch repair deficiency (BMMRD) is caused by biallelic mutations in the mismatch repair (MMR) genes and manifests features of neurofibromatosis type 1, gastrointestinal (GI) polyposis, and GI, brain, and hematological cancers. This is the first study to characterize the GI phenotype in BMMRD using both retrospective and prospective surveillance data.
METHODS: The International BMMRD Consortium was created to collect information on BMMRD families referred from around the world. All patients had germline biallelic MMR mutations or lack of MMR protein staining in normal and tumor tissue. GI screening data were obtained through medical records with annual updates.
RESULTS: Thirty-five individuals from seven countries were identified with BMMRD. GI data were available on 24 of 33 individuals (73%) of screening age, totaling 53 person-years. The youngest age of colonic adenomas was 7, and small bowel adenoma was 11. Eight patients had 19 colorectal adenocarcinomas (CRC; median age 16.7 years, range 8-25), and 11 of 18 (61%) CRC were distal to the splenic flexure. Eleven patients had 15 colorectal surgeries (median 14 years, range 9-25). Four patients had five small bowel adenocarcinomas (SBC; median 18 years, range 11-33). Two CRC and two SBC were detected during surveillance within 6-11 months and 9-16 months, respectively, of last consecutive endoscopy. No patient undergoing surveillance died of a GI malignancy. Familial clustering of GI cancer was observed.
CONCLUSIONS: The prevalence and penetrance of GI neoplasia in children with BMMRD is high, with rapid development of carcinoma. Colorectal and small bowel surveillance should commence at ages 3-5 and 8 years, respectively.
AD
Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.
PMID