Childhood brain tumours may be due to germline bi-allelic mismatch repair gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological... Show moreChildhood brain tumours may be due to germline bi-allelic mismatch repair gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of mismatch repair protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies. Show less
Vos J, Oosterwijk JC, Gómez-García E, Menko FH, Jansen AM, Stoel RD, van Asperen CJ, Tibben A, Stiggelbout AM. Perceiving cancer-risks and heredity-likelihood in genetic-counseling: how counselees... Show moreVos J, Oosterwijk JC, Gómez-García E, Menko FH, Jansen AM, Stoel RD, van Asperen CJ, Tibben A, Stiggelbout AM. Perceiving cancer-risks and heredity-likelihood in genetic-counseling: how counselees recall and interpret BRCA 1/2-test results. Previous studies on the counsellees' perception of DNA test results did not clarify whether counsellees were asked about their recollections or interpretations, and focused only on patients' own risks and not on the likelihood that cancer is heritable in the family. We tested differences and correlations of four perception aspects: recollections and interpretations of both cancer risks and heredity likelihood. In a retrospective study, women tested for BRCA1/2 on average, 5 years ago, completed questionnaires about their perception. Participants had received an unclassified variant (n = 76), uninformative (n = 76) or pathogenic mutation (n = 51) result in BRCA1/2. Analyses included t-tests, correlations and structural equation modelling. The counsellees' perception showed to consist of four distinctive phenomena: recollections and interpretations of cancer risks and of heredity likelihood. This distinctiveness was suggested by significant differences between these perception variables. Moderate to strong correlations were found between these variables, suggesting that these differences between variables were consistent. The relationships between these variables were not influenced by actually communicated DNA test results, sociodemographics, medical and pedigree information, or framing of cancer risk questions. The largest differences between recollections and interpretations were found in the unclassified variant group and the smallest in uninformatives. Cancer risks and heredity likelihood correlated least in the pathogenic mutation group. Communication of ambiguous genetic information enlarged the differences. To understand the counsellees' perception of genetic counselling, researchers should study recollections and interpretations of cancer risks and heredity likelihood. Genetic counsellors should explicitly address the counsellees' recollections and interpretations, and be aware of possible inaccuracies. Show less
Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations.... Show moreBackground Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome. Most families fulfilling the classical diagnostic criteria harbour TP53 germline mutations. However, TP53 germline mutations may also occur in less obvious phenotypes. As a result, different criteria are in use to decide which patients qualify for TP53 mutation analysis, including the LFS, Li-Fraumeni-like (LFL) and Chompret criteria. We investigated which criteria for TP53 mutation analysis resulted in the highest mutation detection rate and sensitivity in Dutch families. We describe the tumour spectrum in TP53-positive families and calculated tumour type specific relative risks. Method A total of 180 Dutch families referred for TP53 mutation analysis were evaluated. Tumour phenotypes were verified by pathology reports or clinical records. Results A TP53 germline mutation was identified in 24 families. When the Chompret criteria were used 22/24 mutations were detected (sensitivity 92%, mutation detection rate 21%). In LFS and LFL families 18/24 mutations were found (sensitivity 75%). The two mutations detected outside the 'Chompret group' were found in a child with rhabdomyosarcoma and a young woman with breast cancer. In the mutation carriers, in addition to the classical LFS tumour types, colon and pancreatic cancer were also found significantly more often than in the general population. Conclusion We suggest TP53 mutation testing for all families fulfilling the Chompret criteria. In addition, TP53 mutation testing can be considered in the event of childhood sarcoma and breast cancer before 30 years. In addition to the risk for established LFS tumour types, TP53-positive individuals may also have an elevated risk for pancreatic and colon cancer. Show less
