Showing papers by "Fred H. Menko published in 2010"

TP53 germline mutation testing in 180 families suspected of Li–Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes

Abstract: BACKGROUND 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.

A New Locus-Specific Database (LSDB) for Mutations in the Folliculin (FLCN) Gene

Abstract: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant condition characterised by the presence of facial fibrofolliculomas, pulmonary cysts which may be associated with spontaneous pneumothorax and renal tumours. Germline mutations in the gene Folliculin (FLCN) were first identified in BHD patients in 2002. In addition FLCN mutations have also been described in families with isolated primary spontaneous pneumothorax (PSP) and also familial clear cell renal carcinomas (FcRCC). We have established a locus-specific database based on the Leiden Open (source) Variation Database (LOVD) software. The version of the database contains 60 previously published mutations and 10 previously unpublished novel germline FLCN mutations. The mutations are comprised of deletions (44.3%), substitutions (35.7%), duplications (14.3%) and deletion/insertions (5.7%). The database is accessible online at http://www.lovd.nl/flcn.

Investigation of the Birt–Hogg–Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer

Abstract: Background Birt–Hogg–Dube (BHD) syndrome is an autosomal dominant multisystem disorder with skin (fibrofolliculomas or trichodiscomas), lung (cysts and pneumothorax) and kidney (renal cell carcinoma) tumours. Although colorectal neoplasia was reported initially to be part of the BHD phenotype, some recent studies have not confirmed this association. Methods A series of clinical and laboratory studies was undertaken to investigate possible relationships between colorectal neoplasia and the BHD gene ( FLCN ). The studies investigated whether individuals with familial colorectal cancer of unknown cause might have unsuspected germline FLCN mutations, looked for somatic FLCN C 8 tract mutations in microsatellite unstable sporadic colorectal cancers, and assessed the risk of colorectal neoplasia and possible genotype–phenotype correlations in BHD patients. Results Although it was found previously that germline FLCN mutations can be detected in ∼5% of patients with familial renal cell carcinoma, germline FLCN mutations were not detected in 50 patients with familial non-syndromic colorectal cancer. Analysis of genotype-phenotype correlations for two recurrent FLCN mutations identified in a subset of 51 families with BHD demonstrated a significantly higher risk of colorectal neoplasia in c.1285dupC mutation (within the exon 11 C 8 mononucleotide tract) carriers than in c.610delGCinsTA mutation carriers (χ 2 =5.78, p=0.016). Somatic frameshift mutations in the FLCN exon 11 C 8 mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability, suggesting that FLCN inactivation might contribute to colorectal tumourigenesis. Conclusions These findings suggest that the previously reported clinical heterogeneity for colorectal neoplasia may reflect allelic heterogeneity and the risk of colorectal neoplasia in BHD syndrome requires further investigation.

Informing family members about a hereditary predisposition to cancer: attitudes and practices among clinical geneticists

Abstract: If a hereditary predisposition to colorectal cancer or breast cancer is diagnosed, most guidelines state that clinical geneticists should request index patients to inform their at-risk relatives about the existence of this condition in their family, thus enabling them to consider presymptomatic genetic testing. Those identified as mutation carriers can undertake strategies to reduce their risk of developing the disease or to facilitate early diagnosis. This procedure of informing relatives through the index patient has been criticised, as it results in relatively few requests for genetic testing, conceivably because a certain number of relatives remain uninformed. This pilot study explored attitudes toward informing family members and relevant practices among clinical geneticists. In general, clinical geneticists consider it to be in the interests of family members to be informed and acknowledge that this goal is not accomplished by current procedures. The reasons given for maintaining present practices despite this include clinical 'mores', uncertainty about the legal right of doctors to inform family members themselves, and, importantly, a lack of resources. We discuss these reasons from an ethical point of view and conclude that they are partly uninformed and inconsistent. If informing relatives is considered to be in their best interests, clinical geneticists should consider informing relatives themselves. In the common situation in which index patients do not object to informing relatives, no legal obstacles prevent geneticists from doing so. An evaluation of these findings among professionals may lead to a more active approach in clinical practice.

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

Abstract: Background: An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives. Methods: We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples. Results: The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families. Conclusions: We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.

Desmoid tumour as indication of familial adenomatous polyposis

Abstract: In two patients, a man aged 43 and a woman aged 40 years, who presented with a desmoid tumour, familial adenomatous polyposis (FAP) was diagnosed three and six years later, respectively. The second patient had developed metastatic rectal cancer. Desmoid-type fibromatoses usually develop sporadically, but may also be an extracolonic manifestation of FAP. All patients with desmoids diagnosed who are under age 60, or with desmoids located intra-abdominally or in the abdominal wall, should be referred for colonic and genetic evaluation. In all further patients with a desmoid tumour, the possibility of FAP should be considered and patient data and the family history should be evaluated thoroughly. If FAP is suspected, patients should be referred for colonoscopic examination and genetic evaluation.

Desmoïdtumoren als aanwijzing voor familiaire adenomateuze polyposis

Abstract: Dames en Heren, Een desmoïdtumor, ook wel agressieve fibromatose genoemd, is een zeldzaam neoplasma. De tumoren komen ofwel sporadisch voor, of als onderdeel van het autosomaal dominant overervende kankerpredispositiesyndroom ‘familiare adenomateuze polyposis’ (FAP). FAPpatiënten ontwikkelen door een kiembaanmutatie in het ‘adenomateuze polyposisi coli’(APC)-gen honderden tot duizenden adenomateuze poliepen in colon en rectum. Indien geen profylactische colectomie wordt verricht, is de kans dat zich een colorectaal carcinoom ontwikkelt rond het 40e levensjaar vrijwel 100%. Veel FAP-patiënten hebben bovendien afwijkingen buiten het colon, waaronder desmoïdtumoren. De combinatie van FAP en andere afwijkingen werd in het verleden beschreven als het syndroom van Gardner. In deze les beschrijven wij 2 patiënten die geopereerd werden wegens een desmoïdtumor. Zij presenteerden zich respectievelijk 3 en 6 jaar later met respectievelijk adenomateuze polyposis van de dikke darm en gemetastaseerd rectumcarcinoom. Bij bloedonderzoek werd bij beiden een pathogene APC-mutatie gevonden, waarmee de diagnose ‘FAP’ bevestigd werd.