Valérie Bonadona - Academia.edu (original) (raw)

Papers by Valérie Bonadona

Research paper thumbnail of Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Research paper thumbnail of A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Nature, 2011

So far, no common environmental and/or phenotypic factor has been associated with melanoma and re... more So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes 1 ; risk factors associated with RCC include smoking, obesity and hypertension 2 . A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers 3 . The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene 4 ; it also stimulates the transcription of hypoxia inducible factor 5 (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes 6 . We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (YKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318Koccupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

Research paper thumbnail of Breast cancer risk associated with oestrogen exposure and truncating mutation location in BRCA1/2 carriers

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 22, 2015

Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values ... more Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values of this risk vary. A genotype-phenotype correlation has been found in both genes and the effect of reproductive factors differs according to mutation location. We hypothesize that such a variation may exist for other factors related to estrogen exposure. Methods: We used a weighted Cox regression model to assess variation in BC risk with these factors using location of mutation in homogeneous BC risk region of BRCA1/2 in the GENEPSO study. Results: We found that late age at menarche reduced BC risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 35% and 48%, respectively). Among premenopausal women, overweight was associated with a 39% decrease in BC risk while underweight was associated with an increased risk (hazard ratio [HR]=2.09). A natural menopause, mainly after age 50, was associated with a high BC risk (HR=2.46) and a significant intera...

Research paper thumbnail of Corrigendum: A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Research paper thumbnail of A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Nature, 2011

So far, no common environmental and/or phenotypic factor has been associated with melanoma and re... more So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes 1 ; risk factors associated with RCC include smoking, obesity and hypertension 2 . A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers 3 . The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene 4 ; it also stimulates the transcription of hypoxia inducible factor 5 (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes 6 . We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (YKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318Koccupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

Research paper thumbnail of Breast cancer risk associated with oestrogen exposure and truncating mutation location in BRCA1/2 carriers

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jan 22, 2015

Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values ... more Background: Mutations in BRCA1/2 confer a high risk of breast cancer (BC), but literature values of this risk vary. A genotype-phenotype correlation has been found in both genes and the effect of reproductive factors differs according to mutation location. We hypothesize that such a variation may exist for other factors related to estrogen exposure. Methods: We used a weighted Cox regression model to assess variation in BC risk with these factors using location of mutation in homogeneous BC risk region of BRCA1/2 in the GENEPSO study. Results: We found that late age at menarche reduced BC risk by 31% and that among BRCA1 carriers, a long or a short menstrual cycle increased risk (by 35% and 48%, respectively). Among premenopausal women, overweight was associated with a 39% decrease in BC risk while underweight was associated with an increased risk (hazard ratio [HR]=2.09). A natural menopause, mainly after age 50, was associated with a high BC risk (HR=2.46) and a significant intera...