Anu-Liisa Moisio

Molecular Analysis of Familial Endometrial Carcinoma: A Manifestation of Hereditary Nonpolyposis Colorectal Cancer or a Separate Syndrome?

PURPOSE Familial clustering of endometrial carcinoma (EC) may occur as part of hereditary nonpolyposis colorectal cancer (HNPCC), a multiorgan cancer syndrome with mismatch repair (MMR) deficiency. Clustering of EC alone, termed as familial site-specific EC, may constitute a separate entity. Because its genetic basis is unknown, our purpose was to characterize such families molecularly. MATERIALS AND METHODS Twenty-three families with site-specific EC were identified among 519 consecutive patients diagnosed with EC during 1986 to 1997. Tumor tissues were examined for MMR protein expression by immunohistochemical (IHC) analysis, and MMR genes pinpointed by IHC changes were screened for germline mutations by exon-by-exon sequencing, multiplex ligation-dependent probe amplification, and direct tests for mutations common in the population. RESULTS Among 33 ECs from 23 families, MLH1 protein was lost in seven tumors (21%), MSH2 together with MSH6 was lost in four tumors (12%), and MSH6 alone was lost in five tumors (15%). A truncating germline mutation in MSH6 (3261insC) was identified in one family and a likely pathogenic missense mutation in MSH2 (D603N) was identified in another family. Among the original 519 patients, nine (all with colon cancer in the family) were diagnosed with HNPCC at the outset-six with MLH1 and three with MSH2 mutations. CONCLUSION Our study gives a minimum overall frequency of 2.1% (11 of 519) for germline MMR defects ascertained through EC in the index patients. The fact that only two of 23 families with site-specific EC (8.7%) had germline mutations in MMR genes suggests another as yet unknown etiology in most families with site-specific EC.

Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the well-defined colorectal cancer syndromes, accounting for at least 2% of the total colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer. Significant reduction in cancer morbidity and mortality can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes. Thus, it is desirable to identify individuals who are mutation-positive. In individuals with cancer, mutation detection can be accomplished relatively efficiently by germline mutation analysis of individuals whose cancers show microsatellite instability (MSI). This study was designed to assess the feasibility of screening colorectal adenoma patients for HNPCC in the same manner. Among 378 adenoma patients, six (1.6%) had at least one MSI adenoma. Five out of the six patients (83%) had a germline MMR gene mutation. We conclude that MSI analysis is a useful method of prescreening colorectal adenoma patients for HNPCC.

Genetic polymorphisms in carcinogen metabolism and their association to hereditary nonpolyposis colon cancer.

BACKGROUND & AIMS The phenotype of hereditary nonpolyposis colorectal cancer shows interfamilial and intrafamilial variation even in the presence of identical predisposing mutations, suggesting the existence of additional phenotype determinants. The modifying role of genetic polymorphisms in loci involved in carcinogen metabolism was studied. METHODS We focused on colon cancers from kindreds sharing one of two predisposing mutations (mutation 1 or 2) in the mismatch repair gene MLH1 (78 and 14 tumors, respectively). Polymorphisms in N-acetyltransferase 1 (NAT1) and glutathione S-transferase (GST) M1 and GSTT1 were investigated. RESULTS The NAT1 allele 10 was associated with lower median age at diagnosis in both groups. In mutation 1 group, the NAT1 allele 10 was a risk factor for distal tumor location, both alone (P = 0.028) and combined with the GSTT1-positive genotype (P = 0.008). On the other hand, the combined null genotype of GSTM1 and GSTT1 was associated with proximal tumors. Associations with tumor location were not observed in patients with mutation 2, probably reflecting a small sample size. CONCLUSIONS The results suggest that genetic polymorphisms in carcinogen metabolism modify the age of onset and tumor location in individuals with inherited deficiency of DNA mismatch repair.

Sluggish cognitive tempo in children and adolescents with higher functioning autism spectrum disorders: Social impairments and internalizing symptoms

Sluggish cognitive tempo (SCT) was introduced in 1980s in the field of attention deficit hyperactivity disorder (ADHD). Studies indicate that symptoms of SCT are separate from symptoms of ADHD and independently associated with multiple domains of functioning in clinical groups and in typical development. We assessed whether similar pattern would apply to higher functioning autism spectrum disorders (ASD). Children with higher functioning ASD (N = 55; 5-15 years) were divided into the ASD+High SCT (n = 17), the ASD+Medium SCT (n = 18) and the ASD+Low SCT (n = 20) groups based on parent-rated daydreaming and slowness on the Five to Fifteen questionnaire (FTF). The groups were compared on SCT-related impairments found in previous studies: social skills, academic functioning, psychiatric symptoms, and processing speed. Assessment methods were the FTF, the Development and Well-Being Assessment, and the Coding subtest of the WISC-III. The ADHD symptoms were statistically controlled due to the overlap between SCT and ADHD. The ASD+High SCT and ASD+Medium SCT groups were significantly more likely to have the most pronounced social impairments, and the ASD+High SCT group had significantly higher rate of internalizing disorders compared to the ASD+Low SCT group. Our results suggest that children with higher functioning ASD and high or medium levels of SCT symptoms could be at higher risk for psychosocial impairments than children with higher functioning ASD with low levels of SCT symptoms. Co-occurring ADHD symptoms do not explain the finding. Recognizing SCT symptoms in higher functioning ASD would be important to targeting preventive support.