Cristabelle De Souza1,2,3, Jill Madden4, Devin C Koestler5, Dennis Minn6, Dennis J Montoya1, Kay Minn7, Alan G Raetz1, Zheng Zhu1, Wen-Wu Xiao1, Neeki Tahmassebi1, Harikumara Reddy1, Nina Nelson1, Anthony N Karnezis8, Jeremy Chien1,9. 1. Department of Biochemistry and Molecular Medicine, UC Davis Medical Center, Sacramento, CA, USA. 2. University of New Mexico Biomedical Sciences Graduate Program, Albuquerque, NM, USA. 3. Current affiliation: Stanford University School of Medicine, Institute for Regenerative Medicine and Stem Cell Research, Stanford, CA, USA. 4. The Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA. 5. Department of Biostatistics and Data Science, Kansas University Medical Center, Kansas City, KS, USA. 6. College of Information and Computer Sciences, University of Massachusetts, Amherst, MA, USA. 7. Novogene Corporation, Sacramento, CA, USA. 8. Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA, USA. 9. Department of Obstetrics and Gynecology, UC Davis Medical Center, Sacramento, CA, USA.
Abstract
BACKGROUND: TP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53. METHODS: P72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model. The SNP effect on mutant p53 was determined in p53-negative cancer cell lines. RNA-sequencing, chromatin immunoprecipitation, and survival analysis were performed to describe the SNP effect. All statistical tests were 2-sided. RESULTS: Among 409 patients with germline heterozygous P72R SNP who harbored somatic mutations in TP53, we observed a selection bias against missense TP53 mutants encoding the P72 SNP (P = 1.64 x 10-13). Exogenously expressed hotspot p53 mutants with the P72 SNP were negatively selected in cancer cells. Gene expression analyses showed the enrichment of p53 pathway genes and inflammatory genes in cancer cells transduced with mutants encoding P72 SNP. Immune gene signature is enriched in patients harboring missense TP53 mutations with homozygous P72 SNP. These patients have improved overall survival as compared with those with the R72 SNP (P = .04). CONCLUSION: This is the largest study demonstrating a selection against the P72 SNP. Missense p53 mutants with the P72 SNP retain partial wild-type tumor-suppressive functions, which may explain the selection bias against P72 SNP across cancer types. Ovarian cancer patients with the P72 SNP have a better prognosis than with the R72 SNP. Our study describes a previously unknown role through which the rs1042522 SNP modifies tumor suppressor activities of mutant p53 in patients.
BACKGROUND: TP53 mutations occur in more than 50% of cancers. We sought to determine the effect of the intragenic P72R single nucleotide polymorphism (SNP; rs1042522) on the oncogenic properties of mutant p53. METHODS: P72R allelic selection in tumors was determined from genotype calls and a Gaussian distributed mixture model. The SNP effect on mutant p53 was determined in p53-negative cancer cell lines. RNA-sequencing, chromatin immunoprecipitation, and survival analysis were performed to describe the SNP effect. All statistical tests were 2-sided. RESULTS: Among 409 patients with germline heterozygous P72R SNP who harbored somatic mutations in TP53, we observed a selection bias against missense TP53 mutants encoding the P72 SNP (P = 1.64 x 10-13). Exogenously expressed hotspot p53 mutants with the P72 SNP were negatively selected in cancer cells. Gene expression analyses showed the enrichment of p53 pathway genes and inflammatory genes in cancer cells transduced with mutants encoding P72 SNP. Immune gene signature is enriched in patients harboring missense TP53 mutations with homozygous P72 SNP. These patients have improved overall survival as compared with those with the R72 SNP (P = .04). CONCLUSION: This is the largest study demonstrating a selection against the P72 SNP. Missense p53 mutants with the P72 SNP retain partial wild-type tumor-suppressive functions, which may explain the selection bias against P72 SNP across cancer types. Ovarian cancer patients with the P72 SNP have a better prognosis than with the R72 SNP. Our study describes a previously unknown role through which the rs1042522 SNP modifies tumor suppressor activities of mutant p53 in patients.
Authors: Pingping Fang; Jill A Madden; Lisa Neums; Ryan K Moulder; M Laird Forrest; Jeremy Chien Journal: Mol Cancer Res Date: 2018-03-15 Impact factor: 5.852
Authors: Mohamed Mounir; Marta Lucchetta; Tiago C Silva; Catharina Olsen; Gianluca Bontempi; Xi Chen; Houtan Noushmehr; Antonio Colaprico; Elena Papaleo Journal: PLoS Comput Biol Date: 2019-03-05 Impact factor: 4.475
Authors: Kumar Sachin Singh; Julia I-Ju Leu; Thibaut Barnoud; Prashanthi Vonteddu; Keerthana Gnanapradeepan; Cindy Lin; Qin Liu; James C Barton; Andrew V Kossenkov; Donna L George; Maureen E Murphy; Farokh Dotiwala Journal: Nat Commun Date: 2020-01-24 Impact factor: 14.919