• Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation.

• Missense mismatch repair gene alterations, microsatellite instability, and hereditary nonpolyposis colorectal cancer.

• A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of

• Current status of genetic testing for colorectal cancer susceptibility.

• [Glioblastoma multiforme as a manifestation of Turcot syndrome]

• Debate surges over the origins of genomic defects in cancer.

• Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer.

• A hMLH1 genomic mutation and associated novel mRNA defects in a hereditary non-polyposis colorectal cancer family.

• DNA mismatch repair defects: role in colorectal carcinogenesis.

• Genetic insights into familial cancers-- update and recent discoveries.

1
UI - 12112654
AU - Bisgaard ML; Jager AC; Myrhoj T; Bernstein I; Nielsen FC
TI - Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation.
SO - Hum Mutat 2002 Jul;20(1):20-7
AD - Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark. mls.bisgaard@get2net.dk
Affected members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at an early age (mean 45 yr) and frequently get extracolonic cancers particularly in the uterus, urinary tract, and small intestine. They have a high risk of developing more than one primary colorectal cancer if not treated with subtotal colectomy at first operation and have more frequent right-sided colon cancers and less frequent rectum cancers, compared to patients with sporadic colorectal cancer. We have screened 31 families fulfilling the Amsterdam criteria and 54 families with a colorectal cancer clustering but not fulfilling the Amsterdam criteria for mutations in MLH1 and MSH2 by direct sequencing, and detected a mutation in 61% of the Amsterdam positive families but only in 15% of the Amsterdam negative families. Genotype-phenotype correlation was compared between 141 affected individuals with an identified mutation and 78 affected individuals from Amsterdam positive families in which a mutation was not identifiable in MLH1 or MSH2. In the affected persons with identified mutations, all expected phenotypic traits were represented, whereas affected persons in whom no mutation was detected fell into two clearly distinguishable subgroups. The minor subgroup, in which no mutation was identified, generally had the same characteristics as found in affected persons with identified mutations. The major subgroup differed significantly in clinical features and exhibited phenotypic traits similar to those found in late-onset families, including abundance of rectal cancer, few HNPCC-related cancers, lower frequency of multiple colorectal cancers, and later age at onset. Finally, for six missense mutations and one single codon deletion, the pathogenic potential was evaluated by domain localization, lod score calculation or segregation analysis when possible, and mutation-induced biochemical change. The results indicate that the majority of missense mutations are pathogenic, although further characterization by functional assays is necessary before implementation in predictive testing programs. Copyright 2002 Wiley-Liss, Inc.

2
UI - 12118033
AU - Samowitz WS; Slattery ML
TI - Missense mismatch repair gene alterations, microsatellite instability, and hereditary nonpolyposis colorectal cancer.
SO - J Clin Oncol 2002 Jul 15;20(14):3178; discussion 3178-9

3
UI - 12124320
AU - Gazzoli I; Loda M; Garber J; Syngal S; Kolodner RD
TI - A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor.
SO - Cancer Res 2002 Jul 15;62(14):3925-8
AD - Ludwig Institute of Cancer Research, University of California San Diego School of Medicine, La Jolla, California 92093, USA. igazzoli@ucsd.edu
Fourteen suspected hereditary nonpolyposis colorectal carcinoma cases with microsatellite unstable(microsatellite instability-high; MSI-H) tumors but no germ-line MSH2, MSH6, or MLH1 mutations were examined for hypermethylation of CpG sites in the critical promoter region of MLH1. The methylation patterns were determined using methylation-specific PCR and by sequence analysis of sodium bisulfite-treated genomic DNA. In one case, DNA hypermethylation of one allele was detected in DNA isolated from blood. In the MSI-H tumor from this case, the unmethylated MLH1 allele was eliminated by loss of heterozygosity, and the methylated allele was retained. This biallelic inactivation resulted in loss of expression of MLH1 in the tumor as confirmed by immunohistochemistry. These results suggest a novel mode of germ-line inactivation of a cancer susceptibility gene.

4
UI - 11866134
AU - Solomon CH; Pho LN; Burt RW
TI - Current status of genetic testing for colorectal cancer susceptibility.
SO - Oncology (Huntingt) 2002 Feb;16(2):161-71; discussion 176, 179-80
AD - Division of Gastroenterology, Huntsman Cancer Institute at the University of Utah, Salt Lake City 84112, USA.
Over 130,000 new cases of colon cancer are diagnosed annually. Approximately 20% to 30% of these are attributable to familial risk, and 3% to 5% belong to a hereditary colorectal cancer predisposition syndrome. Recent discoveries of the genes responsiblefor the inherited colorectal cancer conditions have expanded the field of commercial genetic testing. Health-care providers who use genetic testing in clinical practice are aware of the benefits that genetic testing can confer on screening, prevention, and treatment options for patients with a personal and/or family history of colon cancer. When genetic test results are correctly interpreted, the information they provide can offer medical guidance for the entire family. The psychological impact, however, of presymptomatic testing can be multifaceted. There are unprecedented benefits but also complex issues surrounding genetic testing. For these reasons, the practice of offering genetic testing to individuals at high risk for colon cancer is heavily fortified with guidelines and recommendations. This review covers the current availability and limitations of genetic testing for inherited colorectal cancer syndromes and focuses on guidelines that address the psychological, ethical, and social concerns stemming from genetic testing.

5
UI - 11975096
AU - Grips E; Wentzensen N; Sutter C; Sedlaczek O; Gebert J; Weigel R;
TI - Schwartz A; von Knebel-Doeberitz M; Hennerici M [Glioblastoma multiforme as a manifestation of Turcot syndrome]
SO - Nervenarzt 2002 Feb;73(2):177-82
AD - Neurologische Universitatsklinik Mannheim, Ruprecht-Karls-Universitat Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim.
Turcot's syndrome, clinically characterized by the coincident occurrence of primary tumors of the colon and the central nervous system, can genetically be divided into two syndromes: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon carcinoma (HNPCC). In the present case, a 60-year-old patient with glioblastoma multiforme and a history of hereditary malignomas is described as an example of a HNPCC-associated Turcot's syndrome. New molecular biological methods and results give deeper insight into clinical syndromes, and the better understanding improves diagnostics, therapy, and outcome estimations, even in rare diseases. In the present case, a new germinal mutation could be identified.

6
UI - 12142522
AU - Marx J
TI - Debate surges over the origins of genomic defects in cancer.
SO - Science 2002 Jul 26;297(5581):544-6

7
UI - 11788565
AU - Lindgren G; Liljegren A; Jaramillo E; Rubio C; Lindblom A
TI - Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer.
SO - Gut 2002 Feb;50(2):228-34
AD - Department of Clinical Genetics, Karolinska Hospital, S 171 76 Stockholm, Sweden.
BACKGROUND AND AIMS: Polypectomy in the colon has been shown to prevent colorectal cancer in both the general population and in familial colorectal cancer. Individuals with a family history of colorectal cancer have an increased risk of the disease. Over a period of 10 years, 304 subjects at risk were included in ongoing surveillance with regular colonoscopies. To compile the medical findings and experience generated during this period, a retrospective cross sectional study was performed. SUBJECTS: Subjects were classified into three family groups: families with hereditary non-polyposis colorectal cancer (HNPCC); families with hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third group of families with only empirical risk estimates based on a family history of two close relatives (TCR) with colorectal cancer. METHODS: The risk population was studied with regard to age at onset, prevalence, number, cancer risk, size, dysplasia, and distribution of adenomas. A comparison was made within the family groups and with a reference group representing the general population. RESULTS: In total, 195 adenomas and six cancers were detected among 85 individuals. The relative risk of having an adenoma in the whole risk population compared with the general population was 2.6. Subjects from TCR families had most adenomas and HNPCC subjects had the least. A shift from proximal adenomas to distal carcinomas in families with HCC and TCR suggested a higher cancer risk in distal adenomas in these syndromes. HNPCC families showed a younger age at onset and adenomas with a higher degree of dysplasia. In HNPCC, there was a similar localisation of adenomas and carcinomas, suggesting a high risk of cancer in all adenomas. CONCLUSIONS: There was clear overrepresentation of adenomas in all three family types compared with the reference population. In HNPCC, we found earlier onset of adenomas and faster progression to cancer. Families with HCC, and even more so TCR subjects, had a later onset and lower risk of cancer from proximal adenomas. Based on these results, surveillance protocols in Sweden have been revised.

8
UI - 12052501
AU - Tanko Q; Franklin B; Lynch H; Knezetic J
TI - A hMLH1 genomic mutation and associated novel mRNA defects in a hereditary non-polyposis colorectal cancer family.
SO - Mutat Res 2002 Jun 19;503(1-2):37-42
AD - School of Medicine, Department of Biomedical Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome I, is responsible for as high as 10% of all colorectal cancers (CRCs) newly diagnosed in any given year. This disorder has an autosomal dominant inheritance pattern and is almost fully penetrant (>85%). It occurs when there is a mutation in any one of six mismatch repair genes: hMLH1, hMSH2, hPMS1, hPMS2, hMSH3 and hMSH6. Mutations in these genes allow mistakes in tumor suppressor genes and oncogenes to accumulate which eventually leads to cancer. The founder of an HNPCC family in the Creighton University Hereditary Cancer Institute database was known to produce truncated hMLH1 protein, a product of one of the aforementioned mismatch repair genes. Lymphoblasts were isolated from ten members of this HNPCC family (six affected and four unaffected) and two persons from outside this family (both unaffected controls). RNA and DNA were purified from these lymphoblasts which had been transformed by the Epstein-Barr virus (EBV). The hypothesis was that a mutation in the hMLH1 gene perpetuated defects in its mRNA and functional protein. hMLH1 RNA transcripts were detected in reverse transcriptase polymerase chain reactions (RT-PCR) whereby total poly A(+) RNA was converted to a complementary DNA (cDNA), amplified using hMLH1 specific primers, purified and cycle sequenced. Likewise, DNA was employed as template for PCR amplification of hMLH1 exons; PCR products were then directly cycle sequenced. Affected family members were found to produce hMLH1 mRNA lacking exons 6 and 7 (and wild-type mRNA). A splicing mutation at 546--2 (two bases 5' to exon 7) was located in the genomic DNA samples from the six family members with the HNPCC phenotype. This mutation caused deletion of exon 7 from the mRNA. None of the four unaffected family members or the two unaffected persons outside of this family had the above defects in their hMLH1 mRNA and DNA.

9
UI - 11900875
AU - Jacob S; Praz F
TI - DNA mismatch repair defects: role in colorectal carcinogenesis.
SO - Biochimie 2002 Jan;84(1):27-47
AD - CNRS, Unite Propre de Recherches 2169, Genetic Instability and Cancer, 7, rue Guy-Moquet, 94800 Villejuif, France.
The inactivation of the DNA mismah repair (MMR) system, which is associated with the predisposition to the hereditary non-polyposis colorectal cancer (HNPCC), has also been documented in nearly 20% of the sporadic colorectal cancers. These tumors are characterized by a high frequency of microsatellite instability (MSI(+) phenotype), resulting from the accumulation of small insertions or deletions that frequently arise during replication of these short repeated sequences. A germline mutation of one of the two major MMR genes (hMSH2 or hMLH1) is found in half to two-thirds of the patients with HNPCC, whereas in sporadic cases hypermethylation of the hMLH1 promoter is the major cause of the MMR defect. Germline mutations in hMSH6 are rare and rather confer predisposition to late-onset familial colorectal cancer, and frequent extracolonic tumors. Yet, the genetic background of a number of HNPCC patients remains unexplained, indicating that other genes participate in MMR and play important roles in cancer susceptibility. The tumor-suppressor genes that are potential targets for the MSI-driven mutations because they contain hypermutable repeated sequences are likely to contribute to the etiology and tissue specificity of the MSI-associated carcinogenesis. Because the prognosis and the chemosensitivity of the MSI(+) colorectal tumors differ from those without instability, the determination of the MSI phenotype is expected to improve the clinical management of patients. This review gives an overview of various aspects of the biochemistry and genetics of the DNA mismah repair system, with particular emphasis in its role in colorectal carcinogenesis.

10
UI - 12175530
AU - Marsh D; Zori R
TI - Genetic insights into familial cancers-- update and recent discoveries.
SO - Cancer Lett 2002 Jul 26;181(2):125-64
AD - Cancer Genetics, Kolling Institute of Medical Research and Department of Molecular Medicine, The University of Sydney, Royal North Shore Hospital, St. Leonards, NSW 2065, Sydney, Australia. debbie_marsh@med.usyd.edu.au
While the vast majority of cancers are believed to occur sporadically, most forms of cancer, both adult and paediatric, have a hereditary equivalent. In the case of adult malignancies, these include hereditary breast and ovarian cancer and syndromes such as the multiple endocrine neoplasias types 1 and 2 characterised by specific tumours of the endocrine gland system. In the case of paediatric malignancies, these include syndromes such as retinoblastoma and Wilms tumour. In a little over a single decade, we have seen a tremendous increase in the knowledge of the primary genetic basis of many of the familial cancer syndromes. The majority of familial syndromes are inherited as autosomal dominant traits including hereditary colon cancer and familial malignant melanoma, however, the genetics behind autosomal recessive disorders such as Bloom syndrome and Fanconi anaemia are also being elucidated. A third mode of inheritance less well understood in the setting of familial cancer is that of imprinting recently observed in a subset of families with inherited paraganglioma. In this review, we discuss 31 genes inherited in an autosomal dominant manner associated with 20 familial cancer syndromes. Genes inherited in an autosomal recessive manner linked to familial cancer syndromes are also discussed. The identification of genes associated with familial cancer syndromes has in some families enabled a 'molecular diagnosis' that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at-risk of disease.

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