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C Pottier,
D Hannequin,
S Coutant,
A Rovelet-Lecrux,
D Wallon,
S Rousseau,
S Legallic,
C Paquet,
S Bombois,
J Pariente, [......],
F Etcharry-Bouyx,
C Berr,
J-F Dartigues,
P Amouyel,
H Dauchel,
C Boutoleau-Bretonnière,
C Thauvin, T Frebourg,
J-C Lambert,
D Campion
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ABSTRACT: Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.
Molecular psychiatry 04/2012; 17(9):875-9. · 15.05 Impact Factor
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British Journal of Cancer 12/2011; 106(2):426-7; author reply 428. · 5.04 Impact Factor
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British Journal of Cancer 04/2011; 104(9):1517-8; author reply 1519-20. · 5.04 Impact Factor
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ABSTRACT: Since 2004, the clinical impact of monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) on patients with metastatic colorectal cancer (MCRC) has been clearly established. The combination of these biological agents with conventional chemotherapy has led to a significant improvement in response rate, progression-free survival and overall survival in first-line as well as in second- or third-line treatment of MCRC. However, the high variability of response and outcome in MCRC patients treated with these anti-EGFR mAbs has highlighted the need of identifying clinical and/or molecular predictive markers to ensure appropriate use of targeted therapies. The presence of somatic KRAS mutations has been clearly identified as a predictive marker of resistance to anti-EGFR in MCRC, and the use of anti-EGFR mAbs is now restricted to patients with no detectable KRAS mutation. Several studies have indicated that amplification of EGFR, overexpression of the EGFR ligands and inactivation of the anti-oncogene TP53 are associated with sensitivity to anti-EGFR mAbs, whereas mutations of BRAF and PIK3CA and loss of PTEN expression are associated with resistance. Besides these somatic variations, germline polymorphisms such as those affecting genes involved in the EGFR pathway or within the immunoglobulin receptors may also modulate response to anti-EGFR mAbs. Until now, all these markers are not completely validated and only KRAS genotyping is mandatory in routine practice for use of the anti-EGFR mAbs in MCRC.
British Journal of Cancer 12/2010; 103(12):1765-72. · 5.04 Impact Factor
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ABSTRACT: Lefevre JH, Colas C, Coulet F, Baert-Desurmont S, Mongin C, Tiret E, Frebourg T, Soubrier F, Parc Y. Frequent mutation in North African patients with MUTYH-associated polyposis. MUTYH-associated polyposis (MAP) has been characterized as an autosomal recessive disease predisposing to a variable number of colorectal adenomas with a high risk of cancer. Numerous studies have indicated that two missense mutations (Y179C and G396D) account for about 80% of MUTYH allelic variants in Europeans. Ethnic and geographic differences in the mutation spectrum have been observed. The aim of this study was to report mutations in patients from North Africa, determine the incidence of the c.1227_1228dup mutation in our cohort of MUTYH patients and to evaluate the existence of a founder effect. Within a group of 36 families with MAP, 11 were shown to have a homozygous c.1227_1228dup mutation. These families came from Algeria (n = 5), Tunisia (n = 4), Morocco (n = 1) and Portugal (n = 1). Probands belonging to families of North African origin showed a significantly higher frequency of c.1227_1228dup (78.6% vs 4.5%, p < 0.0001). Haplotype analyses were performed using 10 microsatellite markers surrounding the MUTYH gene spanning a region of 4.4 cM. We identified a common haplotype of at least 1.3 cM in all families suggesting a founder effect for this mutation.
Clinical Genetics 08/2010; · 3.13 Impact Factor
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A Oden-Gangloff,
F Di Fiore,
F Bibeau,
A Lamy,
G Bougeard,
F Charbonnier,
F Blanchard,
D Tougeron,
M Ychou,
F Boissière,
F Le Pessot,
J-C Sabourin,
J-J Tuech,
P Michel, T Frebourg
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ABSTRACT: Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.
British Journal of Cancer 05/2009; 100(8):1330-5. · 5.04 Impact Factor
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Neurology 01/2009; 71(23):1925-6. · 8.31 Impact Factor
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British Journal of Cancer 08/2008; 99(3):551-2. · 5.04 Impact Factor
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ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal disorder caused by mutations in DNA mismatch repair (MMR) genes. Tumors of the HNPCC-spectrum are associated with microsatellite instability (MSI) and loss of MMR protein expression. Lymphomas are not considered to be HNPCC-related tumors. We report and analyze a case of an HNPCC patient with three colorectal cancers and a B-cell non-Hodgkin lymphoma. Quantitative multiplex PCR of short fluorescent fragments detected a novel MSH2 rearrangement involving exons 9 and 10, which proved to be the pathogenic cause of the disease in the family. Tumor tissues including the lymphoma showed MSI and loss of MSH2 expression. Multiplex ligation-dependent probe amplification analysis revealed a somatic loss of the wild-type MSH2 allele in the lymphoma. These results support the fact that the total loss of a MMR gene can lead to lymphomagenesis, as seen in biallelic MMR-deficient families and knockout mice. Moreover, this is the first report of a B-cell non-Hodgkin lymphoma with a loss of the MSH2 protein expression, linked to a heterozygous germline MSH2 mutation in an HNPCC family.
Genes Chromosomes and Cancer 05/2008; 47(4):326-32. · 3.31 Impact Factor
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Journal of neurology, neurosurgery, and psychiatry 11/2007; 78(10):1158-9. · 4.87 Impact Factor
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F Di Fiore,
F Blanchard,
F Charbonnier,
F Le Pessot,
A Lamy,
M P Galais,
L Bastit,
A Killian,
R Sesboüé,
J J Tuech,
A M Queuniet,
B Paillot,
J C Sabourin,
F Michot,
P Michel, T Frebourg
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ABSTRACT: The predictive value of KRAS mutation in metastatic colorectal cancer (MCRC) patients treated with cetuximab plus chemotherapy has recently been suggested. In our study, 59 patients with a chemotherapy-refractory MCRC treated with cetuximab plus chemotherapy were included and clinical response was evaluated according to response evaluation criteria in solid tumours (RECIST). Tumours were screened for KRAS mutations using first direct sequencing, then two sensitive methods based on SNaPshot and PCR-ligase chain reaction (LCR) assays. Clinical response was evaluated according to gene mutations using the Fisher exact test. Times to progression (TTP) were calculated using the Kaplan-Meier method and compared with log-rank test. A KRAS mutation was detected in 22 out of 59 tumours and, in six cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, P=0.015). Our study confirms that KRAS mutation is highly predictive of a non-response to cetuximab plus chemotherapy in MCRC and highlights the need to use sensitive molecular methods, such as SNaPshot or PCR-LCR assays, to ensure an efficient mutation detection.
British Journal of Cancer 05/2007; 96(8):1166-9. · 5.04 Impact Factor
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L Guyant-Maréchal,
A Rovelet-Lecrux,
L Goumidi,
E Cousin,
D Hannequin,
G Raux,
C Penet,
S Ricard,
S Macé,
P Amouyel,
J-F Deleuze, T Frebourg,
A Brice,
J-C Lambert,
D Campion
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ABSTRACT: We genotyped five polymorphisms, including two polymorphisms with known effects on transcriptional activity, in a large cohort of 427 Alzheimer disease (AD) cases and 472 control subjects. An association between rs463946 (-3102 G/C) and AD was found and was confirmed in a replication sample of a similar size. By contrast, analysis of three recently described rare mutations influencing APP transcription did not confirm their association with AD risk.
Neurology 03/2007; 68(9):684-7. · 8.31 Impact Factor
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ABSTRACT: On a routine basis we performed systematic molecular screening for FGFR3 and TP53 mutations in 121 bladder tumors. We then specifically analyzed the predictive value of the recurrence of FGFR3 and TP53 genotypes in superficial lesions.
The FGFR3 gene was analyzed by direct sequencing of exons 7, 10 and 15, whereas TP53 status was determined using the p53 functional assay in yeast.
We identified a missense FGFR3 mutation in 66% of pTa, 26% of pT1 and 12% of pT2 tumors. Of activating FGFR3 mutations 54% and 85% were found in low G1 and intermediate G2 grade tumors, respectively, but in only 20% of high grade G3 tumors. We detected inactivating TP53 mutations in 10% of pTa, 42% of pT1 and 58% of pT2 tumors. Moreover, TP53 mutations were found only in 23% of grade G1 and 3% of grade G2 tumors but in 44% of high grade G3 tumors. When the 2 genotypes were combined, we observed that 58% of pTa tumors had the (mutant FGFR3, WT TP53) genotype, whereas 58% of invasive lesions harbored the inverse genotype (WT FGFR3, mutant TP53). The (mutant FGFR3, WT TP53) genotype and the (WT FGFR3, mutant TP53) genotype were detected in 23% and 38% of pT1G3 tumors, respectively. In the subgroup of 92 patients with superficial pTa-T1 bladder tumors we did not find that the TP53 or FGFR3 genotype alone or combined had a predictive value for tumor recurrence.
Our data again represent solid proof for the pivotal role of FGFR3 and TP53 mutations in superficial and invasive bladder tumors, respectively. However, other molecular markers should be identified for borderline pT1G3 bladder tumors, which are probably at the crossroads of these 2 distinct molecular pathways.
The Journal of Urology 01/2007; 176(6 Pt 1):2686-9. · 3.75 Impact Factor
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G Bougeard,
S Baert-Desurmont,
I Tournier,
S Vasseur,
C Martin,
L Brugieres,
A Chompret,
B Bressac-de Paillerets,
D Stoppa-Lyonnet,
C Bonaiti-Pellie, T Frebourg
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ABSTRACT: Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.
Journal of Medical Genetics 07/2006; 43(6):531-3. · 6.36 Impact Factor
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T Frebourg,
C Oliveira,
P Hochain,
R Karam,
S Manouvrier,
C Graziadio,
M Vekemans,
A Hartmann,
S Baert-Desurmont,
C Alexandre, [......],
E W Jabs,
J Cai,
Ph Pellerin,
J P Triboulet,
M Scotte,
F Le Pessot,
A Hedouin,
F Carneiro,
M Blayau,
R Seruca
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ABSTRACT: We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.
Journal of Medical Genetics 03/2006; 43(2):138-42. · 6.36 Impact Factor
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ABSTRACT: Autosomal dominant early onset Alzheimer's disease (ADEOAD) is genetically heterogeneous. Mutations of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes have been identified.
To further clarify the respective contribution of these genes to ADEOAD.
31 novel families were investigated. They were ascertained using stringent criteria (the occurrence of probable or definite cases of Alzheimer's disease with onset before 60 years of age in three generations). All cases fulfilled the NINCDS-ADRDA criteria for probable or definite Alzheimer's disease. The entire coding regions of PSEN1 and PSEN2 genes and exons 16 and 17 of APP gene were sequenced from genomic DNA RESULTS: PSEN1 mutations, including eight previously unreported mutations, were detected in 24 of the 31 families, and APP mutations were found in five families. In this sample, the mean ages of disease onset in PSEN1 and APP mutation carriers were 41.7 and 51.2 years, respectively.
Combining these data with previously published data, yielding 65 ADEOAD families, 66% of the cases were attributable to PSEN1 mutations and 16% to APP mutations, while 18% remained unexplained.
Journal of Medical Genetics 11/2005; 42(10):793-5. · 6.36 Impact Factor
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E Houy,
G Raux,
F Thibaut,
A Belmont,
C Demily,
G Allio,
S Haouzir,
G Fouldrin,
M Petit, T Frebourg,
D Campion
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ABSTRACT: As suggested by several studies, abnormal sensory gating measured by the P50 paradigm could be an endophenotype predisposing to schizophrenia. In a previous work, we have shown a significant association between the presence of at least one -2 bp deletion located within exon 6 of the CHRNA7-like gene and the P50 abnormality in the general population. A recent study involved polymorphisms located in the core promoter region of the CHRNA7 gene as risk factors for the P50 inhibitory deficit. Screening for promoter variants in a large population of schizophrenic patients (n=111) and control subjects (85), for whom auditory-evoked potentials had been recorded did not allow us to replicate these results. By contrast, we showed a significant association between the -194 C allele and a T/C ratio <0.45, thus demonstrating a protective effect of this variant for the sensory gating deficit. Such conflicting results can be reconciled if we consider that the -194 C polymorphism has no causative effect, but is in linkage disequilibrium with other causal variations for the P50 sensory gating deficit, and that different alleles are in disequilibrium in different populations.
Molecular Psychiatry 03/2004; 9(3):320-2. · 13.67 Impact Factor
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F Di Fiore,
F Charbonnier,
C Martin,
S Frerot,
S Olschwang,
Q Wang,
C Boisson,
M-P Buisine,
M Nilbert,
A Lindblom, T Frebourg
Journal of Medical Genetics 02/2004; 41(1):18-20. · 6.36 Impact Factor
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Journal of Medical Genetics 02/2003; 40(1):e7. · 6.36 Impact Factor
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Journal of Medical Genetics 03/2002; 39(2):E2. · 6.36 Impact Factor
