Surveillance in von Hippel-Lindau disease (vHL).

von Hippel-Lindau disease (vHL) is a hereditary multisystem cancer syndrome requiring lifelong prophylactic surveillance. Current surveillance recommendations rely on best medical judgement and no evidence of effect exists. We aimed to evaluate the capability of surveillance in manifestation detection, before these turn symptomatic, in order to prevent disabling or even fatal outcomes. We focus on surveillance of central nervous system (CNS) hemangioblastomas, retinal hemangiomas and renal cell carcinoma (RCC) as these have the most severe consequences. On the basis of full medical records from 54 living vHL-mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent manifestation risks (1.7% and 1.2%, respectively), whereas recommendations of biennial CNS imaging corresponded to a risk of 7.2%. Annual CNS examinations, however, significantly reduces this risk to 2.7%. Furthermore, most CNS manifestations found due to surveillance (71%, 106 of 150) had clinical consequence for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes.

MUTYH Associated Polyposis (MAP).

MUTYH Associated Polyposis (MAP), a Polyposis predisposition caused by biallelic mutations in the Base Excision Repair (BER) gene MUTYH, confers a marked risk of colorectal cancer (CRC). The MAP phenotype is difficult to distinguish from other hereditary CRC syndromes. Especially from Familial Adenomatous Polyposis (FAP) and to a lesser extend Lynch Syndrome, which are caused by germline mutations in the APC and Mismatch Repair (MMR) genes, respectively.Here we review research findings regarding MUTYH interactions, genotypic and phenotypic characteristics of MAP, as well as surveillance and treatment of the disease. The applied papers, published between 1/1 2002- 1/2 2008, were found through PubMed.The exact role of MUTYH in CRC tumorgenesis is still uncertain, although MAP tumors show distinct molecular features, including somatic G:C>T:A transversions in the APC gene. Furthermore, cooperation between the BER and the MMR systems exists, as MUTYH interacts with MMR gene-products. Possibly, monoallelic defects in both pathways are of significance to CRC development.Specific MUTYH variants are found to be characteristic in distinct ethnic populations, which could facilitate future genetic screening. Knowledge concerning functional consequences of many MUTYH germline mutations remains sparse. Most thoroughly investigated are the two most common MUTYH variants, Y179C and G396D, both generating dysfunctional gene products.PHENOTYPIC FEATURES OF MAP INCLUDE: development of 10-100 colorectal adenomas, debuting at 46-47 years, often CRC at time of clinical diagnosis, and in some, development of extracolonic manifestations.

Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32-31.1.

BACKGROUND: The best known hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constitute about 2% of all colorectal cancers, and there are at least as many non-FAP, non-HNPCC cases where the family history suggests a dominantly inherited colorectal cancer risk. Recently, a locus on chromosome 9q22.2-31.2 was identified by linkage analysis in sib pairs with colorectal cancer or adenoma. METHODS: Linkage analysis for the suggested locus on chromosome 9 was carried out in an extended Swedish family. This family had previously been investigated but following the identification of adenomas in several previously unaffected family members, these subjects were now considered to be gene carriers. RESULTS: In the present study, we found linkage of adenoma and colorectal cancer to chromosome 9q22.32-31.1 with a multipoint LOD score of 2.4. We were also able to define the region for this locus to 7.9 cM between the markers D9S280 and D9S277. CONCLUSIONS: Our result supports the presence of a susceptibility locus predisposing to adenoma and colorectal cancer in this chromosomal region.

The role of hPMS1 and hPMS2 in predisposing to colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.

MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer.

A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.

Characterization and structural impact of five novel PROS1 mutations in eleven protein S-deficient families.

Heterozygozity for four novel missense mutations (W108C, W342R. E349K and L485S) and one novel 4 bp deletion (ACdelAAAG affecting codons 632-633) was identified in PROS1 of unrelated thrombosis prone Danish families with protein S type I or III deficiency. The 4 bp deletion results in a frameshift leading to replacement of the coding sequence for the 3 C-terminal amino acids by an abnormal extended sequence that codes for 9 amino acids. The E349K substitution was found in 7 families. Haplotype analysis using 7 microsatellite markers flanking PROS1 was consistent with a common founder for this mutation. The mutations reported here are most likely the cause of the protein S deficiency. Firstly, the four missense mutations cosegregate with the abnormal plasma protein S phenotype and lead to the loss of highly conserved amino acids. Secondly, computer analysis of structural models of protein S predicts that the substitutions could affect proper protein folding and/or stability. Analysis of platelet mRNA from subjects with the W108C, E349K, L485S mutation or the 4 bp deletion showed that mutated mRNA was expressed in significant amounts suggesting that mutated molecules are synthesized. Our results are compatible with defective protein folding/unstable molecules, impaired secretion and intracellular degradation of mutated protein, which appear to be the major molecular disease mechanisms for missense mutations and certain other mutations found in genetic disorders.

The establishment of an HNPCC register.

Guidelines for the establishment of an HNPCC-register are presented. The aims of a register are discussed. Steps in identification of families and persons at risk are suggested, and possible sources of family and pedigree data are mentioned. The role of a register in surveillance, information of family members and medical colleagues, research and international collaboration are discussed.

[Von Hippel-Lindau disease and molecular genetic diagnosis]. / Von Hippel-Lindaus sygdom og molekylaergenetisk diagnostik.

Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited disorder, characterized by cysts and neoplastic formations mainly in the cerebellum, retina, pancreas, kidneys and adrenal glands. The disease is subdivided into two groups depending on absence or presence of phaeochromocytomas. VHL is caused by changes in a tumour suppressor gene, which was cloned in 1993 after having been mapped to chromosome 3p25-26 in 1988. We present two cases with VHL type 1. The first patient belonged to a family with 24 verified affected members, the second was the descendent of a patient carrying a presumed de novo mutation. By direct sequencing of the VHL gene, the mutation was identified in both families, thus enabling preclinical diagnosis of persons at risk in the families.

[Registration of hereditary non-polyposis colorectal cancer]. / Registrering af hereditaer non-polypøs kolorektal cancer.

Hereditary non-polyposis colorectal cancer is a dominant inherited disease, with development of colorectal cancer (CRC) and other cancers too. About 3% of all CRC-cases belong to an HNPCC-family. Mutations responsible for the disease has been identified in five genes, all of them involved in DNA mismatch repair. Since the establishment of the Danish HNPCC Register 345 families have been referred, and 101 of these families had HNPCC. Median age of onset for CRC was 50 years: Approximately 60% of the tumors were situated on the right side, 9% had synchronous tumors and the risk of metachronous tumours was 40% in 20 years. Tumours were localised in 64% of the cases, and the 5-year crude survival rate was better in HNPCC compared to sporadic CRC. The number of CRC diagnosed as Dukes A in HNPCC has risen since 1990, and the survival after CRC in HNPCC has increased. The disease specific mutation is identified in 21 families, from which 152 persons at risk have had a molecular genetic diagnose, and 83 could afterwards evade screening protocols. Few years after the establishment of the HNPCC-registry, it is indicated that information, registration and screening lead to an earlier diagnosis and a better prognosis after CRC.

[Hereditary non-polyposis colorectal cancer]. / Hereditaer non-polyposis kolorektal cancer.

Hereditary non-polyposis colorectal cancer (HNPCC) probably constitutes 5% of all the cases of sporadic colorectal cancer. At present, the diagnosis can only be established on the basis of a family history which should fulfill the "Amsterdam criteria": 1) Colorectal cancer in at least three family members, 2) One family member must be a close relative of the other two, and 3) The diagnosis must have been established prior to the age of 50 years in at least one relative. Other forms of cancer also occur in the HNPCC syndrome, particularly endometrial cancer. The syndrome has a dominant inheritance and, therefore, all close relatives should be submitted to control examinations for the most important forms of cancer associated with the syndrome.

[Preclinical and prenatal diagnosis of familial adenomatous polyposis]. / Praeklinisk og praenatal diagnostik af familiaer adenomatøs polypose.

In order to investigate the possibility of preclinical and prenatal genetic diagnosis of familial adenomatous polyposis (FAP) by means of DNA-systems and other markers, blood samples were collected from 246 persons in 29 families, including 90 with the clinical diagnosis FAP and 73 clinically unaffected first degree relatives (persons at risk). The material was studied with up to 4 DNA-marker systems located in the region around the disease gene. Among the first degree relatives eight (11%) had probably inherited the disease gene, while 31 persons (42%) in this risk group had probably not inherited the gene. It was not possible to evaluate the risk in the remaining 34 persons (47%). In 45 (85%) out of 53 persons under 40 years the DNA-systems were informative, so that it would be possible to offer the option of prenatal diagnosis. It is concluded that preclinical and possibly prenatal genetic diagnosis may be offered; but the current practice of prophylactic proctosigmoidoscopic surveillance should be maintained.

Linkage between alpha 1B-glycoprotein (A1BG) and Lutheran (LU) red blood group system: assignment to chromosome 19: new genetic variants of A1BG.

alpha 1B-glycoprotein (A1BG) polymorphism was examined in a Danish family material (no. 604-1505) with particular regard to markers on chromosome 19. For A1BG-LU we found a lod score z = 3.06 at theta = 0.05 in males, and z = 1.42 at theta = 0.10 in females, which assigns A1BG to chromosome 19. Close linkage to C3, SE, PEPD, APOC2, D19S7, D19S8 and D19S9 was excluded. The most likely order would appear to be C3-SE-LU-A1BG.

Familial adenomatous polyposis patients without an identified APC germline mutation have a severe phenotype.

BACKGROUND: Development of more than 100 colorectal adenomas is diagnostic of the dominantly inherited autosomal disease familial adenomatous polyposis (FAP). Germline mutations can be identified in the adenomatous polyposis coli (APC) gene in approximately 80% of patients. The APC protein comprises several regions and domains for interaction with other proteins, and specific clinical manifestations are associated with the mutation assignment to one of these regions or domains. AIMS: The phenotype in patients without an identified causative APC mutation was compared with the phenotype in patients with a known APC mutation and with the phenotypes characteristic of patients with mutations in specific APC regions and domains. PATIENTS: Data on 121 FAP probands and 149 call up patients from 70 different families were extracted from the Danish Polyposis register. METHODS: Differences in 16 clinical manifestations were analysed according to the patient's mutational status. Two sided independent t sample test, two sided chi(2) test, and odds ratios were calculated. RESULTS: Patients without identified APC mutations had a unique and severe phenotype, which was roughly described as: young age at diagnosis and subsequent death in spite of development of few colorectal adenomas; low risk of involvement of the upper gastrointestinal tract, as reflected by a low mean Spigelman stage, and a low risk of fundic gland polyposis. Finally, they had significantly fewer affected family members, although they do not themselves more often represent an isolated case. CONCLUSIONS: The severe phenotype should be considered when counselling FAP families in which attenuated FAP is excluded and in which a causative APC mutation has not been identified.

Dyslexia and chromosome 15 heteromorphism: negative lod score in a Danish material.

From a large Danish material of random families we selected families with dyslexia as reported by the families themselves and as recorded by a dyslexia institute. Among five "backcross families" studied for chromosome 15 polymorphisms we found only negative lod scores, and at theta = 0.10 a negative score of -3.42; i.e., in our material we did not find any confirmation of the indication of linkage between dyslexia and a chromosome 15 polymorphism found in part of their material by Smith et al. (1983, 1986).

Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate.

The nationwide Danish polyposis register includes all known Danish cases of familial adenomatous polyposis (FAP) and their relatives. By identifying all FAP patients born between 1920 and 1949, we found the frequency of the disease to be 1 in 13,528. By comparing the number of affected and nonaffected offspring born to affected parents during the same period we found the penetrance of the disease for inherited cases to be close to 100% at the age of 40 years. The mutation rate found by the direct method was 9 mutations per million gametes per generation and the proportion of new mutants was estimated to 25%. Fitness for patients between 15 and 29 years was found close to one, while for patients older than 30 the fitness was reduced, but increasing during the three decades (from 0.44 to 0.71) probably because treatment became more widespread and efficient. As we have used the overall fitness in the period, 0.87, to estimate the mutation rate by the indirect method, we found a lower value than by the direct method, namely 5 mutations per million gametes per generation.

The incidence rate of familial adenomatous polyposis. Results from the Danish Polyposis Register.

Based on the Danish Polyposis Register epidemiological calculations on familial adenomatous polyposis (FAP) were carried out. The mean annual incidence was 1.85 x 10(-6) during the years 1971-1992, and the prevalence increasing to about 32 x 10(-6) at the end of 1992. FAP patients constituted a decreased percentage of all Danish patients with colorectal cancer (0.07% in 1980-1992). The completeness of registration was 97% in 1983-1992. The results are similar to Finnish estimates based on the same direct method of calculation, and as both series are based on almost complete national polyposis registration in well-registered populations we regard our results to be close to the true incidence rate.

Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis.

BACKGROUND & AIMS: This study reevaluates the risk of rectal cancer and the frequency of subsequent proctectomy for nonmalignant causes in patients with familial adenomatous polyposis (FAP) who have undergone colectomy with ileorectal anastomosis (IRA). Potential risk factors for rectal cancer in this setting are also examined, and recommendations for the choice of surgical procedure are made. METHODS: The national polyposis registries in Denmark, Finland, The Netherlands, and Sweden included 659 patients undergoing surgery with IRA in 1940-1997. Kaplan-Meier analysis and Cox regression analysis were performed to evaluate cumulative risk, survival, and predictive risk factors. RESULTS: Rectal carcinoma was diagnosed in 47 patients, with a cumulative 40-year risk of 0.32. The cumulative risk according to chronologic age was 0.30 at age 60, and higher in patients undergoing surgery above age 25 (P = 0.0016). Chronologic age was the only independent risk factor (P = 0.0016). The cumulative 5-year survival rate after rectal carcinoma was 0.60. The apc mutation was known in 167 patients, of whom 7 had rectal cancer. The cumulative 40-year risk of secondary proctectomy was 0.70, and higher in patients with a mutation in codon 1250-1500 than outside this region (P = 0.005). However, all 7 rectal cancers were found in the latter group. None of the 18 patients with attenuated FAP (mutation in codon 0-200 or >1500) had a secondary proctectomy. CONCLUSIONS: IRA is recommended in (1) young patients with few rectal adenomas and a family history of a mild phenotype and (2) patients with attenuated FAP (a mutation in codon 0-200 or >1500), provided there is acceptance of life-long rectal surveillance. Patients with many rectal polyps and/or a family history of severe polyposis should be offered a restorative proctocolectomy with an ileal pouch-anal anastomosis.

Linkage between serum cholinesterase 2 (CHE2) and gamma-crystallin gene cluster (CRYG): assignment to chromosome 2.

Serum cholinesterase 2 (CHE2) was examined in a Danish material of normal families that has been tested earlier for 70-78 classical marker systems and 25 RFLP systems. DNA for RFLP typing was provided by transforming 16-year-old frozen lymphocytes. The frequency of allele CHE2*C5+ in the Danish population was found to be 0.0430. The highest lod score was between CHE2 and the gamma-crystallin gene cluster (CRYG) (zeta = 4.21 at theta = 0.00 in females). The scores were from a single family with 15 children. CHE2 may, accordingly, be assigned to the location of CRYG: chromosome 2, bands q33-q35.