@article{f43f8c659c9e47e3b1d5449dbd5dba1e,
title = "A rare TP53 mutation predominant in ashkenazi jews confers risk of multiple cancers",
abstract = "Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS.",
author = "Jacquelyn Powers and Pinto, {Emilia M.} and Thibaut Barnoud and Leung, {Jessica C.} and Tetyana Martynyuk and Kossenkov, {Andrew V.} and Philips, {Aaron H.} and Heena Desai and Ryan Hausler and Gregory Kelly and Le, {Anh N.} and Li, {Marilyn M.} and MacFarland, {Suzanne P.} and Pyle, {Louise C.} and Kristin Zelley and Nathanson, {Katherine L.} and Domchek, {Susan M.} and Slavin, {Thomas P.} and Weitzel, {Jeffrey N.} and Stopfer, {Jill E.} and Garber, {Judy E.} and Vijai Joseph and Kenneth Offit and Dolinsky, {Jill S.} and Stephanie Gutierrez and Kelly McGoldrick and Couch, {Fergus J.} and Brooke Levin and Edelman, {Morris C.} and Levy, {Carolyn Fein} and Spunt, {Sheri L.} and Kriwacki, {Richard W.} and Zambetti, {Gerard P.} and Ribeiro, {Raul C.} and Murphy, {Maureen E.} and Maxwell, {Kara N.}",
note = "Funding Information: We thank Jinling Wang (St. Jude Children's Research Hospital) for technical assistance and Rhonda Kitlas GIllete (University of Pennsylvania) for generation and formatting of pedigrees. Research support for this study was generously provided by NIH grants K08CA215312 (K.N. Maxwell), P30CA016520 (Abramson Cancer Center), R01CA102184 (M.E. Murphy), P30CA021765 (St. Jude's Cancer Center), K99CA241367 (T. Barnoud), K08CA234394 (T.P. Slavin), KL2TR00187903 (L.C. Pyle), R01CA242218 (J.N. Weitzel), RC4CA153828 (J.N. Weitzel), R01CA225662 (F.J. Couch); Basser Center for BRCA at the University of Pennsylvania (K.N. Maxwell, K.L. Nathanson, and S.M. Domchek); Breast Cancer Research Foundation (F.J. Couch, S.M. Domchek, K.L. Nathanson, J.N. Weitzel, J.E. Garber, K. Offit); Burroughs Wellcome Foundation (K.N. Maxwell); International Pediatric Adrenocortical Tumor Registry (St. Jude IPACTR); and American Lebanese Syrian Associated Charities (Emilia M. Pinto, A.H. Philips, R.C. Ribeiro, R.W. Kriwacki, and G.P. Zambetti). Funding Information: J. Powersreports receiving personal feesfrom Myriad Genetic Laboratories, personal fees from Ambry Genetic Laboratories, personal fees from CareVive Systems, Inc., outside the submitted work. M.M. Li reports receiving personal fees from Roche Sequencing Solutions {"}On the SAB{"} outside the submitted work. S.M. Domchek reports receiving personal fees from AstraZeneca, personal fees from BMS, and personal fees from Clovis outside the submitted work. J.N. Weitzel reports grants from NIH/NCI R01 CA242218-01 during the conduct of the study; personal fees from AstraZeneca {"}speakers bureau{"} outside the submitted work. J.E. Stopfer reports being a paid consultant for AstraZeneca as a member of its Personalized Medicine and Nursing Education Advisory Board. J.S. Dolinsky reports personal fees from Ambry Genetics during the conduct of the study. S. Gutierrez reports personal fees from Ambry Genetics as a full-time employee outside the submitted work. F.J. Couch reports receiving personal fees from Ambry Genetics and grants from NIH during the conduct of the study. No potential conflicts of interest were disclosed by the other authors. Funding Information: We thank Jinling Wang (St. Jude Children{\textquoteright}s Research Hospital) for technical assistance and Rhonda Kitlas GIllete (University of Pennsylvania) for generation and formatting of pedigrees. Research support for this study was generously provided by NIH grants K08CA215312 (K.N. Maxwell), P30CA016520 (Abram-son Cancer Center), R01CA102184 (M.E. Murphy), P30CA021765 (St. Jude{\textquoteright}s Cancer Center), K99CA241367 (T. Barnoud), K08CA234394 (T.P. Slavin), KL2TR00187903 (L.C. Pyle), R01CA242218 (J.N. Weitzel), RC4CA153828 (J.N. Weitzel), R01CA225662 (F.J. Couch); Basser Center for BRCA at the University of Pennsylvania (K.N. Maxwell, K.L. Nathanson, and S.M. Domchek); Breast Cancer Research Foundation (F.J. Couch, S.M. Domchek, K.L. Nathanson, J.N. Weitzel, J.E. Garber, K. Offit); Burroughs Wellcome Foundation (K.N. Maxwell); International Pediatric Adrenocortical Tumor Registry (St. Jude IPACTR); and American Lebanese Syrian Associated Charities (Emilia M. Pinto, A.H. Philips, R.C. Ribeiro, R.W. Kriwacki, and G.P. Zambetti). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = sep,
day = "1",
doi = "10.1158/0008-5472.CAN-20-1390",
language = "English (US)",
volume = "80",
pages = "3732--3744",
journal = "Cancer Research",
issn = "0008-5472",
number = "17",
}