Rmw Hofstra

Familial endometrial cancer in female carriers of MSH6 germline mutations.

Hereditary non-polyposis colorectal cancer (HNPCC) is a common autosomal dominant condition characterized by early onset colorectal cancer as well as other tumour types at different anatomical sites1. HNPCC tumours often display a high level of genomic instability, characterized by changes in repeat numbers of simple repetitive sequences (microsatellite instability, MSI), which reflects the malfunction of the DNA mismatch repair machinery2, 3. Accordingly, HNPCC was shown to be caused by germline mutations in the DNA mismatch repair genes (MMR) MSH2, MLH1, PMS1, PMS2 and MSH6 (refs 3, 4, 5, 6). So far, more than 220 predisposing mutations have been identified, most in MSH2 and MLH1 and in families complying with the clinical Amsterdam criteria3, 7, 8 (AMS+). Many HNPCC families, however, do not fully comply with these criteria, and in most cases the causative mutations are unknown.

Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 andMLH1. Recently, mutations in another MMR gene, MSH6 (also known asGTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related toMSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 andMLH1. u2003Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from aMSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 andMLH1 carriers (32% by the age of 80v >80%). u2003Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). u2003Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 yearsv 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 yearsv 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. u2003The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.

Impact of KRAS and TP53 mutations on survival in patients with left- and right-sided Dukes' C colon cancer

OBJECTIVE:It has been suggested that KRAS and TP53 mutated tumors might influence the phenotypic behavior of left- and right-sided colon tumors. We investigated the incidence of these mutations in left- and right-sided colon tumors and their possible influence on survival in a homogeneous group of patients with Dukes’ C colon cancers.METHODS:The primary tumors of 55 patients with a sporadic Dukes’ C colon cancer, all treated with adjuvant chemotherapy were analyzed for the presence of KRAS and TP53 mutations. Mutation detection of the KRAS and TP53 genes was performed on paraffin-embedded tumor material, using denaturating gradient gel electrophoresis. The 5-yr survival rates of KRAS and TP53 mutated tumors were analyzed regarding right-sided tumors (defined as tumors up to the splenic flexure) and left-sided tumors (defined as tumors from the splenic flexure to the rectosigmoid peritoneal reflection).RESULTS:KRAS mutations occurred more frequently in the right colon compared to the left colon (R = 38% (10/26); L = 10% (3/29); χ2 test: p = 0.014). KRAS mutations did not influence survival in patients with right-sided colon tumors. Patients with KRAS mutation–negative tumors in the right colon, however, had a significantly worse survival than patients with left-sided KRAS mutation–negative tumors (5-yr survival; R: 34% vs L: 65%, log-rank test: p = 0.007). TP53 mutations of a possible causative nature were found in 24 tumors (44%). Neither the incidence (R = 42% (11/26); L = 45% (13/29)) nor the survival of TP53 mutated tumors differed significantly between left- and right-sided tumors. Furthermore, survival of patients with TP53 mutation–negative tumors did not differ significantly between left- and right-sided tumors.CONCLUSIONS:There seems to be no difference in survival rate between patients with KRAS mutated and KRAS negative Dukes’ C colon tumors; however, KRAS mutations are more frequently found in the right colon compared to the left colon. TP53 mutations do not have predominance for either side of the colon, and there are no differences in survival in patients with left-sided versus right-sided tumors. Patients with KRAS-nonmutated tumors in the right colon did have a worse survival compared to those with such tumors in the left colon. This suggests that other genetic factors may play a role in tumor genesis in this subgroup of patients.

Three novel KCNA1 mutations in episodic ataxia type I families

Hereditary paroxysmal ataxia, or episodic ataxia (EA), is a rare, genetically heterogeneous neurological disorder characterized by attacks of generalized ataxia. By direct sequence analysis, a different missense mutation of the potassium channel gene (KCNA1) has been identified in three families with EA.

Colorectal cancer and the CHEK2 1100delC mutation

The CHEK2 1100delC mutation was recently identified as a low‐penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low‐penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high‐risk patients (12.5%), followed by moderate‐risk patients (3.3%), and was lowest in low‐risk patients (1.0%, Ptrend 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low‐penetrance effect (OR 1.5–2.0) of the CHEK2 1100delC on CRC risk. Large case–control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC.

Prognostic significance of K-ras and TP53 mutations in the role of adjuvant chemotherapy on survival in patients with Dukes C colon cancer

PURPOSE: Mutations in K-ras andTP53 genes are common in colorectal cancer. They affect biologic behavior and might influence chemotherapy susceptibility in these tumors. We investigated whether the survival of patients with Dukes C colon cancer treated with adjuvant chemotherapy is influenced by K-ras andTP53 mutations. METHODS: Mutation screening of the hot spots of the K-ras gene and of the evolutionarily conserved regions of theTP53 gene was performed by denaturing gradient gel electrophoresis technique in formalin-fixed paraffin-embedded specimens of 55 consecutive patients with Dukes C colon cancer treated with adjuvant 5-fluorouracil-based chemotherapy. The median follow-up was 47 (range, 32–66) months. RESULTS: Alterations in the mutation hot spots of K-ras were found at codon 12 (n=11) and 13 (n=4) in 15 of the 55 carcinomas (27 percent). No mutation was found at codon 61. Mutations of a probably causative nature in the evolutionarily conserved regions (exons 5–8) of theTP53 gene were found in 24 tumors (44 percent). K-ras andTP53 mutations were found equally in the group with recurrent disease (7/26 (26 percent) and 12/27 (44 percent), respectively) and in the group without recurrences (8/28 (24 percent) and 12/28 (43 percent), respectively). Cancer-specific survival did not differ significantly between patients with K-ras orTP53 or both mutated and nonmutated tumors, respectively (log-rank test: K-ras, P=0.72 andTP53, P=0.77; K-ras andTP53, P=0.8). Also, potentially aggressive K-ras codon 12 and 13 mutations had the same survival as tumors without these mutations (log-rank test;P=0.73). CONCLUSIONS: Patients with K-ras orTP53 or both mutated Dukes C colon tumors have the same survival as nonmutated tumors when treated with adjuvant chemotherapy. These data suggest that mutations in K-ras orTP53 alone are not prognostic indicators in patients with Dukes C colon cancer receiving adjuvant 5-Fluorouracil-based therapy.

Hirschsprung disease and L1CAM: is the disturbed sex ratio caused by L1CAM mutations?

HSCR is a congenital disorder characterised by an absence of enteric ganglia over various lengths of the bowel and proliferation of nerve fibres in the distal bowel. The absence of enteric ganglia is thought to be caused by a defective migration of neural crest cells. It results in functional obstruction and life threatening bowel distension shortly after birth with an incidence of 1 in 5000 live births. In about 80% of cases, the rectosigmoid colon is the only part affected and in most of the remaining cases the aganglionosis extends to the ileocaecal junction. In a small percentage of cases, the entire small bowel and colon are aganglionic.1nnHSCR can be associated with a large number of syndromes, such as Waardenburg syndrome, Smith-Lemli-Opitz syndrome, Goldberg-Shprintzen syndrome, and Ondines curse. This variety of associated syndromes implies considerable genetic heterogeneity in the aetiology of HSCR, although associations by chance cannot be excluded. Genetic analysis of HSCR has confirmed the heterogeneity. So far, mutations, alone or in combination, have been identified in seven genes, namely RET ,2,3 GDNF , 4,5 NTN ,6 EDNRB ,7 EDN3 ,8,9 ECE1 ,10 and SOX10 .11 It is thought that they account for 50-60% of familial cases and 10-30% of sporadic cases.nnBesides an association with several syndromes, a difference in sex ratio has also been observed. A male predominance of 3:1 to 5:1 in Hirschsprung disease has been reported.12,13 Badner et al 13 performed complex segregation analysis of data on 487 probands and their families. They observed an increased sex ratio, 3.9 males to 1 female, with a decrease when the aganglionosis became more extensive. It is this disturbed sex ratio which made us hypothesise that there might well be a HSCR susceptibility gene on …

What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration

Ketelaar ME, Hofstra RMW, Hayden MR. What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration.

Absence of mutations in the RET gene in acute myeloid leukemia

Abstractu2002Expression of the tyrosine kinase receptor RET has previously been detected in normal hematopoietic cells, and especially in cells of the myeloid lineage. Furthermore, RET was shown to be differentially expressed in acute myeloid leukemia (AML), a disease characterized by excessive cell growth and aberrant maturation of cells, with the highest levels of expression in leukemias with monocytic differentiation. RET is known to be expressed in cells from the excretory system and from the developing central and peripheral nervous system. Both activating and inactivating aberrations in the RET gene have been detected in disorders derived from these tissues. To investigate whether the differential expression is a primary defect in AML, the presence of RET alterations was scanned by Southern blot analysis on DNA of blasts obtained from 17 AML patients. However, no RET gene aberrations were found. Subsequently, denaturing gradient gel electrophoresis (DGGE) analysis was performed on the DNA of blasts from ten selected cases. All five variants detected turned out to represent neutral DNA polymorphisms, including a novel polymorphism in exon 14. Since we were unable to detect mutations of RET in AML, it is unlikely that it plays an important role in leukemogenesis.

Clinical Definition of Hereditary Non-polyposis Colorectal Cancer: A Search for the Impossible?

Hereditary non-polyposis colorectal cancer is an autosomal dominant inherited disorder that predisposes its carriers to an almost 100% lifetime risk of cancer, in particular colorectal and endometrial cancer. Germline mutations, resulting in a deficient DNA mismatch repair system, are responsible for the disease. Because of the lack of specific phenotypical features, clinical diagnosis in an individual patient is impossible and relies heavily on family history. Genetic diagnosis by mismatch detection is now possible in a substantial proportion of families. Thus there is a great need for reliable but simple criteria that will help clinicians to recognize patients and families who can be referred for genetic diagnostics. In this article the different criteria that have been formulated and published in recent years are reviewed and the results, in terms of the proportions of subjects satisfying the criteria who were found to have a germline mutation, are discussed. In most studies the criteria were evaluated in only a small number of subjects. A population-based study is currently being carried out in the north of The Netherlands that aims to include 400 patients fulfilling one of a few simple criteria. Mutation analysis will be performed in all patients. The results of this study will help in the formulation of accurate and simple criteria for use in clinical practice.