Hansjakob Müller

Surveillance in hereditary nonpolyposis colorectal cancer: An international cooperative study of 165 families

During its second meeting at Amsterdam in 1990, the International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) decided to carry out a pilot study on colorectal cancer surveillance in HNPCC. The objectives of the study were to ascertain in each of the participating centers the number of HNPCC families, the recommended screening procedures, the age at diagnosis of colorectal cancer (CRC), and the occurrence of interval cancers. Nine centers in seven countries including Denmark, Finland, Italy, Japan, The Netherlands, Switzerland, and the United States participated. Data were derived from a total of 165 families. With respect to screening, half of the centers advise colonoscopy as the only procedure. The interval between the consecutive examinations varies from one to three years. In the majority of the centers, screening begins at 20 to 25 years. Lifelong screening is recommended by three centers, while the rest advise discontinuation at age 60 to 75 years. The family material included 840 patients with colorectal cancer. The mean age at diagnosis was 45 years, and about 15 percent were diagnosed at age 60 or later. A total of 682 high-risk relatives are being followed. After the follow-up of 1 to 10 years in these families, only six cases of interval cancers were encountered.

Estimating the frequency of nonpaternity in Switzerland.

In linkage analysis and gene mapping in general, typing error and/or errors in specifying pedigree relationships between individuals typically lead to an upwards bias in recombination fraction estimates and to a loss of power for detecting linkage. [Ott J: Analysis of Human Genetic Linkage. Baltimore, Johns Hopkins University Press, 1991]. The presence of nonpaternity is the most common source of error of misspecification of pedigree relationships between individuals that can have a negative impact on pedigree analysis. We have developed estimates of underlying nonpaternity probabilities based on observed Mendelian inconsistencies. The methods were applied to a sample of 1,607 children and their parents. Genetic marker data were investigated to test for exclusions due to nonpaternity. Among the 1,607 children, 11 or 0.68% exclusions were found. When a constant nonpaternity rate was assumed for each child, its maximum likelihood estimate turned out to be 0.78% with asymptotic 95% confidence limits of 0.41% and 1.35%. When varying nonpaternity rates were assumed, its mean was estimated as 0.83% with asymptotic 95% confidence limits of 0.32% and 1.33%.

Cytogenetics of breast cancer

Chromosome counts were performed on 1,100 cells from 17 malignant breast carcinomas and on 168 cells of four normal tissue samples after amethopterin treatment and G-banding. Karyotypes were established from 216 cells of 11 tumor-derived cultures and from 47 cells of four nonmalignant tissue-derived cultures. Karyotypes of cells from nonmalignant samples showed a normal diploid chromosomal constitution with no consistent loss or gain of a specific chromosome. Structural chromosomal abnormalities were not observed. Tumor-derived cultures could be distinguished from normal cultures on the basis of a significantly increased incidence of numerical changes and structural chromosomal aberrations. In nine of 11 tumor-derived cultures, numerically normal cells were shown to be pseudodiploid, with frequencies ranging to 43% (mean, 13.2%) of the diploid cells. In agreement with previous reports, cytogenetic analyses showed predominantly diploid cells. Clonal numerical changes of chromosomes 17, 18, 20, and 21 could be detected in three tumor samples. Clonal structural abnormalities could be observed in two of 11 analyzed tumours. A t(6;12)(p21;p13) and an enlarged chromosome 7 (7q+) were found in a patient with invasive ductal carcinoma. An inversion of chromosome 7 [inv(7)(q11.2q32)] was observed in one case, also diagnosed as invasive ductal carcinoma. The significance of these findings in relation to clinical data is discussed.

Increased prevalence of minor anomalies in childhood malignancy

Body measurements were taken and the prevalence of major malformations and of 57 minor anomalies was determined in 106 children with malignant disease, in 81 of their sibs, and in 106 control subjects matched to the patients according to sex, age and ethnic origin.Leukaemic children had a significantly smaller head circumference than the corresponding control children, but no significant differences in height, anthropometric and syndromologic indices were found.No differences were observed in the frequency of associated major malformations including renal malformations detectable by sonography. The prevalence of minor anomalies was significantly higher in the patients with malignant disease and their sibs than in the control children: 69.2% of the patients, 63.0% of the sibs and 34.6% of the control subjects had at least one minor anomaly. When two and more minor anomalies were considered, the prevalence figures were 36.5%, 29.6% and 12.5%, respectively. Among the single minor anomalies only the Sydney line was significantly more frequent in patients with solid tumours. No specific association of an individual dysplasia or a pattern of minor anomalies with a given tumour could be established.

Cat-eye syndrome, a partial trisomy 22

SummaryA family is presented in which a phenotypically normal mother and her healthy daughter both had abnormal children with a small supernumerary chromosome. Both had clinical symptoms suggestive of cat-eye syndrome. In both women 1 G-chromosome was found to be replaced by a small submetacentric satellited chromosome. Its fluorescence pattern was compatible with that of a chromosome 22, and so was the fluorescence pattern of the supernumerary chromosome in one of the phenotypically abnormal children. Since complete monosomy G in addition to partial autosomal trisomy would not be compatible with clinical “normality” the respective karyotypes must be interpreted as a small deletion of a chromosome 22 in the healthy mother and daughter and a partial trisomy 22 in their abnormal children. Therefore it can be concluded that a deletion of a chromosome 22 is compatible with a normal phenotype and that the cat-eye syndrome results, at least in this family, from a partial trisomy 22.ZusammenfassungEs wird über eine Familie berichtet, in der eine phänotypisch normale Mutter und ihre gesunde Tochter je ein abnormes Kind mit einem kleinen überzähligen Chromosom zur Welt gebracht hatten. Die Kinder hatten klinische Zeichen des Cat eye-Syndroms. Im Chromosomensatz beider Frauen war 1 G-Chromosom durch ein kleines submetazentrisches, satellitentragendes Chromosom ersetzt, dessen Fluorescenzumuster dem eines Chromosoms 22 entsprechen könnte. Das gleiche Muster wurde in dem überzähligen Chromosom bei einem der Kinder gefunden. Da eine totale G-Monosomie zusätzlich zu einer autosomalen Trisomie eines anderen Chromosoms nicht vereinbar ist mit vollkommener klinischer Unauffälligkeit, muß die Chromosomenanomalie der gesunden Mutter und Tochter als kleine Deletion 22 angesehen werden und die der abnormalen Kinder infolgedessen als partielle Trisomie 22. Aus diesen Befunden kann geschlossen werden, daß eine Deletion des Chromosoms 22 mit einem normalen Phänotyp vereinbar ist und daß, zumindest in dieser Familie, das Cat eye-Syndrom die Folge einer partiellen Trisomie 22 ist.

A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer†

Germ‐line mutations in MLH1 and MSH2 genes predispose to hereditary non‐polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease. We speculated that the ataxia‐telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ‐line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ‐line mutations co‐segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC‐related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC‐related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant. Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ‐line mutations. Int. J. Cancer 88:928–931, 2000.

Xeroderma pigmentosum-Cockayne syndrome complex in two patients: Absence of slun tumors despite severe deficiency of DNA excision repair

Two brothers had a complex combination of two DNA repair disorders: Cockayne syndrome and xeroderma pigmentosum. This rare combination has previously been observed in only two other patients. The clinical signs shared by these two brothers and the two other previously described patients include severe sun sensitivity, freckling, diminished stature, hearing and movement impairment, and neurologic degeneration. Although defective UV-induced unscheduled DNA synthesis has been demonstrated (5% of normal), no skin cancers have appeared in these 38- and 41-year-old brothers, whereas skin cancers developed at a relatively early age in the two previously described patients who also had defective UV-induced unscheduled DNA synthesis.

A strongly fluorescing abnormal chromosome in a malformed child

SummaryThe case of a sexchromatin negative “girl” with multiple malformations is presented. A small metacentric chromosome was found to replace her second X chromosome, half of which was strongly fluorescing after staining with Quinacrinedihydrochloride, and late replicating after labelling with tritiated thymidine. The chromosome was interpreted as a translocation chromosome between the long arms of a Y and a partially trisomic autosome.

Germline alterations in the cyclooxygenase‐2 gene are not associated with the development of extracolonic manifestations in a large Swiss familial adenomatous polyposis kindred

Familial adenomatous polyposis (FAP) is an autosomal dominant condition leading to the development of multiple colorectal polyps and other features. Intrafamilial variation in phenotype is known to occur in FAP; despite carrying the same causing mutation in the APC gene, disease expression may considerably differ in affected individuals, likely due to the existence of modifier genes. Several lines of evidence suggest the cyclooxygenase‐2 (COX‐2) gene to be a candidate modifier in FAP. Since COX‐2 appears to be expressed in tissues prone to be affected in FAP, it might influence the occurrence of extracolonic manifestations in this disorder. Herein, we investigated whether alterations in the COX‐2 gene are involved in the development of extracolonic polyps and extragastrointestinal features. Mutational analysis using single‐strand conformation polymorphism (SSCP) in 130 members of a FAP family displaying strong phenotype variation revealed 3 polymorphic sites within the coding region of the COX‐2 gene. None of these allelic variants, however, segregated with a particular disease phenotype. In addition, expression analysis was performed in 31 family members with representative phenotypes. Neither of the two polymorphisms detected within the COX‐2 promoter was associated with a given phenotype nor was there a significant difference in quality or quantity of COX‐2 mRNA in lymphocytes as measured by reverse transcription‐ and real time quantitative reverse transcription PCR (RT‐PCR and TaqMan). In conclusion, germline alterations in the COX‐2 gene are unlikely to account for the development of extracolonic disease in FAP patients. Int. J. Cancer 87:812–817, 2000.

Secretory phospholipase A2 does not appear to be associated with phenotypic variation in familial adenomatous polyposis

Abstract Recent studies in mice have provided strong evidence for a modifier gene that is capable of effecting the expression of the mouse equivalent of familial adenomatous polyposis (FAP). A candidate gene has been proposed, namely secretory phospholipase A2 (sPLA2). Increased tumor number in mice was correlated with low levels of sPLA2 expression and the presence of truncating mutations within the sPLA2 gene. In an attempt to determine whether any genetic alterations in the sPLA2 gene were associated with the expression of FAP in man, we investigated the genetic structure of sPLA2 in 97 polyposis coli patients presenting with various disease phenotypes, and its expression in 8 FAP patients displaying markedly different disease characteristics. In the current study no inactivating mutations in the sPLA2 gene were identified, suggesting that human sPLA2 is not associated with phenotypic variation in FAP.