XAF1 as a modifier of p53 function and cancer susceptibility

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and 42,438 newborns. The compound mutant haplotype was enriched in patients with cancer, conferring risk for sarcoma (P = 0.003) and subsequent malignancies (P = 0.006). Functional analyses demonstrated that wild-type XAF1 enhances transactivation of wild-type and hypomorphic TP53 variants, whereas XAF1-E134* is markedly attenuated in this activity. We propose that cosegregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone, with implications for genetic counseling and clinical management of hypomorphic TP53 mutant carriers.Fil: Pinto, Emilia M.. St. Jude Children's Research Hospital; Estados UnidosFil: Figueiredo, Bonald C.. Instituto de Pesquisa Pelé Pequeno Principe; BrasilFil: Chen, Wenan. St. Jude Children's Research Hospital; Estados UnidosFil: Galvao, Henrique C.R.. Hospital de Câncer de Barretos; BrasilFil: Formiga, Maria Nirvana. A.c.camargo Cancer Center; BrasilFil: Fragoso, Maria Candida B.V.. Universidade de Sao Paulo; BrasilFil: Ashton Prolla, Patricia. Universidade Federal do Rio Grande do Sul; BrasilFil: Ribeiro, Enilze M.S.F.. Universidade Federal do Paraná; BrasilFil: Felix, Gabriela. Universidade Federal da Bahia; BrasilFil: Costa, Tatiana E.B.. Hospital Infantil Joana de Gusmao; BrasilFil: Savage, Sharon A.. National Cancer Institute; Estados UnidosFil: Yeager, Meredith. National Cancer Institute; Estados UnidosFil: Palmero, Edenir I.. Hospital de Câncer de Barretos; BrasilFil: Volc, Sahlua. Hospital de Câncer de Barretos; BrasilFil: Salvador, Hector. Hospital Sant Joan de Deu Barcelona; EspañaFil: Fuster Soler, Jose Luis. Hospital Clínico Universitario Virgen de la Arrixaca; EspañaFil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; EspañaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. St. Jude Children's Research Hospital; Estados UnidosFil: Vaur, Dominique. Comprehensive Cancer Center François Baclesse; FranciaFil: Odone Filho, Vicente. Universidade de Sao Paulo; BrasilFil: Brugières, Laurence. Institut de Cancerologie Gustave Roussy; FranciaFil: Else, Tobias. University of Michigan; Estados UnidosFil: Stoffel, Elena M.. University of Michigan; Estados UnidosFil: Maxwell, Kara N.. University of Pennsylvania; Estados UnidosFil: Achatz, Maria Isabel. Hospital Sirio-libanês; BrasilFil: Kowalski, Luis. A.c.camargo Cancer Center; BrasilFil: De Andrade, Kelvin C.. National Cancer Institute; Estados UnidosFil: Pappo, Alberto. St. Jude Children's Research Hospital; Estados UnidosFil: Letouze, Eric. Centre de Recherche Des Cordeliers; FranciaFil: Latronico, Ana Claudia. Universidade de Sao Paulo; BrasilFil: Mendonca, Berenice B.. Universidade de Sao Paulo; BrasilFil: Almeida, Madson Q.. Universidade de Sao Paulo; BrasilFil: Brondani, Vania B.. Universidade de Sao Paulo; BrasilFil: Bittar, Camila M.. Universidade Federal do Rio Grande do Sul; BrasilFil: Soares, Emerson W.S.. Hospital Do Câncer de Cascavel; BrasilFil: Mathias, Carolina. Universidade Federal do Paraná; BrasilFil: Ramos, Cintia R.N.. Hospital de Câncer de Barretos; BrasilFil: Machado, Moara. National Cancer Institute; Estados UnidosFil: Zhou, Weiyin. National Cancer Institute; Estados UnidosFil: Jones, Kristine. National Cancer Institute; Estados UnidosFil: Vogt, Aurelie. National Cancer Institute; Estados UnidosFil: Klincha, Payal P.. National Cancer Institute; Estados UnidosFil: Santiago, Karina M.. A.c.camargo Cancer Center; BrasilFil: Komechen, Heloisa. Instituto de Pesquisa Pelé Pequeno Principe; BrasilFil: Paraizo, Mariana M.. Instituto de Pesquisa Pelé Pequeno Principe; BrasilFil: Parise, Ivy Z.S.. Instituto de Pesquisa Pelé Pequeno Principe; BrasilFil: Hamilton, Kayla V.. St. Jude Children's Research Hospital; Estados UnidosFil: Wang, Jinling. St. Jude Children's Research Hospital; Estados UnidosFil: Rampersaud, Evadnie. St. Jude Children's Research Hospital; Estados UnidosFil: Clay, Michael R.. St. Jude Children's Research Hospital; Estados UnidosFil: Murphy, Andrew J.. St. Jude Children's Research Hospital; Estados UnidosFil: Lalli, Enzo. Institut de Pharmacologie Moléculaire et Cellulaire; FranciaFil: Nichols, Kim E.. St. Jude Children's Research Hospital; Estados UnidosFil: Ribeiro, Raul C.. St. Jude Children's Research Hospital; Estados UnidosFil: Rodriguez-Galindo, Carlos. St. Jude Children's Research Hospital; Estados UnidosFil: Korbonits, Marta. Queen Mary University of London; Reino UnidoFil: Zhang, Jinghui. St. Jude Children's Research Hospital; Estados UnidosFil: Thomas, Mark G.. Colegio Universitario de Londres; Reino UnidoFil: Connelly, Jon P.. St. Jude Children's Research Hospital; Estados UnidosFil: Pruett-Miller, Shondra. St. Jude Children's Research Hospital; Estados UnidosFil: Diekmann, Yoan. Colegio Universitario de Londres; Reino UnidoFil: Neale, Geoffrey. St. Jude Children's Research Hospital; Estados UnidosFil: Wu, Gang. St. Jude Children's Research Hospital; Estados UnidosFil: Zambetti, Gerard P.. St. Jude Children's Research Hospital; Estados Unido

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Faisabilité et intérêt diagnostique de la recherche de mutations dans les cancers thyroïdiens à partir des produits de cytoponctions

CAEN-BU Médecine pharmacie (141182102) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Postablation 131I scintigraphy with neck and thorax SPECT–CT and stimulated serum thyroglobulin level predict the outcome of patients with differentiated thyroid cancer

International audienc

Stimulated thyroglobulin level at ablation in differentiated thyroid cancer: the impact of treatment preparation modalities and tumor burden

International audienc