In the carcinogenesis of colorectal cancer (CRC) genetic instability and dysfunction of the Wnt-signalling pathway play important roles. Most Wnt-signalling dysfunctions lead to the nuclear accumulation of ß-catenin. The aim of the present study was to investigate whether nuclear accumulation of ß-catenin is associated with prognosis and genetic instability. We used immunohistochemistry to study nuclear ß-catenin expression in 67 CRCs. The expression was evaluated in the entire tumour section as mean values and in tumour budding at the invasive margin. We compared the results with chromosomal and microsatellite instability (CIN vs. MSI), p53 accumulation, and clinicopathological variables including survival. The nuclear accumulation of ß-catenin was significantly associated with abnormal p53 expression and aneuploidy, typically for CIN, whereas no tumour with nuclear ß-catenin expression at the invasive margin displayed MSI. The ß-catenin expression pattern did not correlate significantly with CRC patient prognosis when including all stages. However, in the clinically most interesting prognostic group, Dukes' stage B patients, high nuclear accumulation of ß-catenin was associated with a poor prognosis (p=0.01). Our results suggest that nuclear accumulation of ß-catenin in CRC is related to CIN and may be of prognostic importance. However, larger studies are needed to verify these findings.

SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

Objectives ‐ To assess the prevalence of Kennedy's disease in the Vasa region of Western Finland. Patients and methods ‐ Verification of diagnosis by molecular genetic techniques since 1995. Results ‐ Within 2 years we have been able to identify a large number of families with this disorder. We have arrived at a point prevalence of Kennedy's disease in the district of Vasa Central Hospital of 13 patients per 85,000 male inhabitants. Assuming an even distribution throughout the country, this would suggest hundreds of patients with this disorder in Finland. Conclusion ‐ Kennedy's disease is the most common motor neuron disorder in the Vasa region, exceeding the prevalence of ALS by a factor of two, and far more common than any of the other motor neuron disorders. The fact that none of our patients, despite previous examinations, had correct diagnoses before 1995, indicates that Kennedy's disease still might be relatively underdiagnosed.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. nl).A germline mutation in one of the MMR genes in HNPCC patients predisposes to an early onset colon cancer: 30% risk to age 40 and over 80% lifetime risk, 9 compared to 3-4% in the general population. In addition, affected individuals are prone to develop multiple primary cancers, both from the colorectum and extracolonic sites, of which endometrial cancers are the most common with a lifetime risk of 20 -43% in women, 10 followed by carcinoma of the ovary, stomach, small intestine and upper urinary tract. 11 When the MMR system is defective, especially when due to MLH1 and MSH2 mutations, replication errors arising during DNA replication are not corrected, which results in widespread genomic instability. Through their repetitive nature, microsatellites are particularly prone to replication errors and therefore microsatellite instability (MSI) is a hallmark of MMR deficiency. MSI is found in more than 90% of all HNPCC tumours 12 but only in 10 -15% of sporadic colorectal tumours. 13 Moreover, MMR deficiency leads to an increased mutation rate in specific cancer related genes, including BAX, 14 IGFIIR 15 and TGF-␤ type II receptor, 16 which may enhance tumour progression. While MLH1 and MSH2 defects give instability primarily in dinucleotide repeats, 13 MSH6-defective tumours show alterations in predominantly mononucleotide repeats. [17][18][19] This is in congruence with the biological function, where MLH1 and MSH2 manage repair of small insertion/deletion loops, 20,21 while MSH6 mostly is involved in repair of base-base and single nucleotide insertion/deletion mismatches. 22,23 Double primary cancers within the HNPCC spectrum is a hallmark of HNPCC and an indicator to clinically suspect HNPCC. 24 In a previous population-based study, 25 we observed an increased risk of HNPCC-associated cancers in first-degree relatives to patients diagnosed with double primary cancers of the colorectum or the colorectum/endometrium. The overall standardised incidence ratio (SIR) was 1.69 (95% CI; 1.39 -2.03). The SIR was highest among relatives to the patients with young age of onset (Ͻ50 years) and MSI positive tumours. The aim of our study was to investigate the MLH1, MSH2 and MSH6 mutation spectrum in the patients with MSI positive double primary tumours. MATERIAL AND METHODS PatientsSeventy-eight patients with double primary cancers of the colorectum or the colorectum and the endometrium (Fig. 1) were identified in a population-based cohort study previously reported. 25 The MSI status of one of the patie...