Daphne W. Bell, Ph.D.
Cancer Genetics and Comparative Genomics Branch
Reproductive Cancer Genetics Section
B.S. Queen's University, Northern Ireland, 1988
Ph.D. Queen's University, Northern Ireland, 1992
Dr. Bell is a senior investigator at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. She received her B.Sc. (Honors) in Zoology and Genetics and her Ph.D. in Biology and Biochemistry from The Queen's University of Belfast in Northern Ireland. She conducted her postdoctoral training at Fox Chase Cancer Center, Philadelphia, before joining Harvard Medical School and Massachusetts General Hospital, where she was an instructor of medicine from 1997-2004 and an assistant professor of medicine from 2004-2006.
Dr. Bell's graduate and postdoctoral studies focused on the fine-mapping of genomic deletions in ovarian cancer and in malignant mesothelioma as a means to home in on regions of the genome containing putative tumor suppressor genes. While at Massachusetts General Hospital/Harvard Medical School, Dr. Bell and her colleagues made a number of seminal discoveries including the landmark discovery that mutations in the EGFR gene explain the dramatic clinical responses of non-small cell lung cancer patients to gefitinib, a small molecule inhibitor of EGFR.
Upon joining NHGRI in 2006, Dr. Bell launched a new research program to identify genomic alterations that cause clinically aggressive forms of endometrial cancer. Her laboratory has since identified novel, high-frequency somatic mutations in PI3-kinase in endometrial tumors, thus uncovering previously unrecognized cohorts of patients who might benefit clinically from therapies targeting the PI3-kinase pathway. Her group reported one of the first whole-exome sequencing studies of serous endometrial carcinomas, in which they discovered frequent mutations in genes that regulate chromatin-remodeling and ubiquitin-mediated protein degradation. Dr. Bell's ongoing research aims to identify additional genomic alterations that drive clinically aggressive endometrial tumors, and to understand their functional consequences.
Dr. Bell received a 2007 PECASE award, which is the highest honor bestowed by the U.S. government on outstanding scientists and engineers beginning their independent careers.
Dr. Bell has devoted her career to understanding the genetic and genomic alterations that drive solid tumors. In her previous position at Massachusetts General Hospital/Harvard Medical School, she and a team of colleagues and collaborators made a number of seminal discoveries uncovering novel somatic mutations that drive sporadic forms of human cancer, as well as germline variants in individuals with early onset cancer or a strong family history of the disease. Their findings included the groundbreaking discovery that somatic mutations in EGFR explain the dramatic clinical responses of non-small cell lung cancer patients to gefitinib, a small molecule inhibitor of EGFR.
In 2006, Dr. Bell moved to the National Human Genome Research Institute (NHGRI) where the goals of her laboratory are to identify genomic alterations that cause clinically aggressive forms of endometrial carcinoma, and to understand their functional consequences and potential clinical relevance. Endometrial carcinomas can be classified into numerous histological subtypes including serous, clear cell, and endometrioid carcinomas, as well as uterine carcinosarcomas. Serous and clear cell endometrial carcinomas, and uterine carcinosarcomas, are clinically aggressive forms of the disease. Identifying the somatic genomic alterations that are present in these tumors is a prerequisite to uncovering pathogenic alterations that might be exploited therapeutically.
To achieve their goals, the Bell group has capitalized on the unique genomic resources within the NHGRI cores and affiliated centers to identify somatic mutations in serous and clear cell endometrial carcinomas and in uterine carcinosarcomas. In early studies, Dr. Bell's laboratory used high-throughput Sanger sequencing, coupled with a candidate gene approach, to search for somatic mutations among protein kinases, because activated kinases can represent druggable targets. Using this approach, her laboratory discovered novel, high-frequency somatic mutations in the PI3-kinase (PI3K) pathway. Specifically, the Bell group was the first to show that exons 1-7 of PIK3CA, which encode the p85α-binding region of the catalytic subunit (p110α) of PI3K, are highly mutated in endometrial cancer. They were also the first to show that PIK3R1, which encodes the regulatory subunit (p85α) of PI3K, is highly mutated in endometrial tumors, including some serous and clear cell endometrial carcinomas. Further, they demonstrated that the novel mutations within the p110α and p85α proteins activate PI3K-mediated signaling. These discoveries pointed to new subgroups of endometrial cancer patients who might benefit clinically from targeted therapies directed against the PI3K pathway, and will inform ongoing clinical trials of these agents in endometrial cancer patients.
Dr. Bell's laboratory has also exploited state-of-the-art, next-generation sequencing to gain a more comprehensive understanding of the mutational landscape of clinically aggressive endometrial cancers. In 2012, the Bell laboratory published one of the first whole-exome sequencing studies of serous endometrial carcinomas, in which they reported the seminal discovery that chromatin-remodeling genes and genes that regulate ubiquitin-mediated protein degradation are highly mutated in these tumors. Specifically, they showed that CHD4, a component of the NuRD chromatin-remodeling complex, as well as FBXW7 and SPOP, components of the SKP1-CUL1-FBXW7 and RBX1-CUL3-SPOP ubiquitin ligase complexes, are mutated at high frequencies and at statistically significantly elevated rates in serous endometrial carcinoma. Together with their observations that FBXW7 and SPOP mutations are clustered in specific functional domains, these findings provide compelling genetic evidence that mutations in CHD4, FBXW7, and SPOP are likely to be pathogenic and contribute to serous endometrial tumorigenesis. In follow-up studies, the Bell laboratory has evaluated the functional impact of recurrent FBXW7 mutations in the context of serous endometrial cancer. Their findings provide the first biochemical evidence implicating mutant FBXW7 in the dysregulation of other cancer-related proteins in serous endometrial cancer cells, specifically, phosphorylated forms of Cyclin E1, SRC-3, c-MYC, Rictor, GSK3, P70S6 kinase, and AKT. In recent studies, using a combination of exome sequencing and targeted gene sequencing, the Bell laboratory validated and extended early findings, by others, that some clear cell endometrial carcinomas have molecular alterations that are shared with serous and endometrioid endometrial carcinomas. In their genomic studies of uterine carcinosarcomas, they found frequent truncating mutations in FOXA2, which encodes apioneer transcription factor that was not previously implicated in the molecular etiology of this tumor type.
In ongoing studies, the Bell laboratory, together with intramural and extramural collaborators, continues to leverage next-generation sequencing approaches, coupled with functional studies, to identify and functionally annotate genomic alterations that drive clinically aggressive forms of endometrial cancer.
Bell DW, Jhanwar SC, and Testa JR. Multiple regions of allelic loss from chromosome arm 6q in malignant mesothelioma. Cancer Res, 57:4057-4062. 1997. [PubMed]
Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DCR, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, and Haber DA. Heterozygous germline hCHK2 mutations in Li-Fraumeni Syndrome. Science, 286:2528-2531. 1999. [PubMed]
Cantor S, Bell DW, Ganesan S, Kass E, Drapkin R, Grossman S, Wahrer DCR, Sgroi DC, Lane W, Haber DA, and Livingston DM. BACH1, a novel helicase-like protein, interacts with BRCA1 and contributes to its biochemical and clinical functions. Cell, 105:149-160. 2001. [PubMed]
Moberg KH, Bell DW, Wahrer DCR, Haber DA, and Hariharan IK. Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature, 413:311-316. 2001. [PubMed]
*Lynch TJ, *Bell DW, *Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, and Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 350:2129-2139. 2004. * Equal authorship. [PubMed]
Sordella R, Bell DW, Haber DA, and Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science, 305:1163-1167. 2004. [PubMed]
*Kwak EL, *Sordella R, *Bell DW, *Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch T, Sharma SV, Settleman J, and Haber DA. Irreversible inhibitors of the epidermal growth factor receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci (USA), 102:7665-7670. 2005. * Equal authorship. [PubMed]
Bell DW, Gore I, Okimoto RA, Godin-Heymann N, Sordella R, Mulloy R, Sharma SV, Brannigan BW, Mohapatra G, Settleman J, and Haber DA. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet, 37:1315-1316. 2005. [PubMed]
Cohen EE, Lingen MW, Martin LE, Harris PL, Brannigan BW, Haserlat SM, Okimoto RA, Sgroi DC, Dahiya S, Muir B, Clark JR, Rocco JW, Vokes EE, Haber DA, and Bell DW. The response of some head and neck cancers to EGFR tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clin Cancer Res, 11:8105-8108. 2005. [PubMed]
Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, Kim JC, Feinberg AP, Gerald WL, Vargas SO, Chin L, Iafrate AJ, Bell DW, and Haber DA. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science, 315:642-645. 2007. [PubMed]
Bell DW. Our changing view of the genomic landscape of cancer. J Pathol, 220:231-43. 2010. [PubMed]
Rudd ML, Price JC, Fogoros SK, Godwin AK, Sgroi, DC, Merino M, and Bell DW. A unique spectrum of PIK3CA (p110alpha) mutations within primary endometrial carcinomas. Clin Cancer Res, 17:1331-40. 2011. [PubMed]
Urick ME, Rudd ML, Godwin AK, Sgroi, DC, Merino M, and Bell DW. PIK3R1 (p85a) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res, 71:4061-67. 2011. [PubMed]
Bell DW, Sikdar N, Lee Y-Y, Price JC, Chatterjee R, Park H-D, Fox J, Ishiai M, Rudd ML, Pollock LM, Fogoros SF, Mohamed H, Hanigan CL, NISC, Zhang S, Cruz P, Renaud G, Hansen NF, Cherukuri PF, Borate B, McManus KJ, Stoepel J, Sipahimalani P, Godwin AK, Sgroi DC, Merino MJ, Elliot G, Elkahloun A, Vinson C, Takata M, Mullikin JC, Wolfsberg TG, Hieter P, Lim D-S, and Myung K. Predisposition to cancer caused by genetic and functional defects of mammalian Atad5. PLoS Genetics, 7:e1002245, 2011. [PubMed]
O'Hara AJ, and Bell DW. The genomics and genetics of endometrial cancer (Review). Adv Genomics Genet, 2012:33-47, 2012. [PubMed]
Le Gallo M, O'Hara AJ, Rudd ML, Urick ME, Hansen NF, O'Neil NJ, Price JC, Zhang S, England BM, Godwin AK, Sgroi DC, NISC Comparative Sequencing Program, Hieter P, Mullikin JC, Merino MJ, and Bell DW. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet, 44:1310-1315. 2012. [PubMed]
Sánchez-Vega F, Gotea V, Petrykowska HM, Margolin G, Krivak TC, DeLoia JA, Bell DW, and Elnitski L. Recurrent patterns of DNA methylation in the ZNF154, CASP8 and VHL promoters across a wide spectrum of human solid epithelial tumors and cancer cell lines. Epigenetics, 8:1355-1372. 2013. [https://www.ncbi.nlm.nih.gov/pubmed/24149212]
Price JC, Pollock LM, Rudd ML, Fogoros SK, Mohamed H, Hanigan CL, Le Gallo M, NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program, Zhang S, Cruz P, Cherukuri P, Hansen NF, McManus KJ, Godwin AK, Sgroi DC, Mullikin JC, Merino MJ, Hieter P, and Bell DW. Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. PLoS One, 8:e63313, 2013. [PubMed]
The Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, and Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature, 497:67-7. 2013. [PubMed]
Le Gallo M and Bell DW. The emerging genomic landscape of endometrial cancer (Review). Clin Chem, 60:98-110. 2014. [PubMed]
Bell DW. Novel genetic targets in endometrial cancer (Editorial). Expert Opin Ther Targets, 18:10.1517/14728222.2014.909414, 2014. [PubMed]
Rudd ML, Mohamed H, Price JC, O’Hara AJ, Le Gallo M, Urick ME, NISC Comparative Sequencing Program, Cruz P, Zhang S, Hansen NF, Godwin AK, Sgroi DC, Wolfsberg TG, Mullikin JC, Merino MJ, and Bell DW. Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1. BMC Cancer, 14:884. 2014. [PubMed]
Hong B, Le Gallo M, and Bell DW. The mutational landscape of endometrial cancer. (Review). Curr Opin Genetics Dev, 30:25-31. 2015. [PubMed]
Margolin G, Petrykowska HM, Jameel N, Bell DW, Young A, and Elnitski L. Robust detection of DNA hypermethylation of ZNF154 as a pan-cancer locus with in silico modeling for blood-based diagnostic development. J Mol Diagn, 18:283-298. 2016. [PubMed]
Felix AS, Yang HP, Bell DW, and Sherman ME. Epidemiology of endometrial carcinoma: Etiologic importance of hormonal and metabolic influences. (Review). Adv Exp Med Biol, 943:3-46. 2017. [PubMed]
Le Gallo M, Lozy F, and Bell DW. Next-generation sequencing. (Review). Adv Exp Med Biol, 943:119-148. 2017. [PubMed]
Le Gallo M, Rudd ML, Urick ME, Hansen NF, Zhang S, NISC Comparative Sequencing Program, Lozy F, Sgroi DC, August Vidal Bel A, Matias-Guiu X, Broaddus RR, Lu KH, Levine DA, Mutch DG, Goodfellow, PJ, Salvesen HB, Mullikin JC, and Bell DW. Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing. Cancer, 123:3261-3268. 2017. [PubMed]
MacKay H, Levine DA, Bae-Jump V, Bell DW, McAlpine JN, Santin A, Fleming G, Mutch DG, Nephew K, Wentzensen N, Goodfellow PJ, Dorigo O, Nijman H, Broaddus RR, and Kohn E. Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials. Oncotarget, 8:84579-84594. 2017. [PubMed]
Urick ME, and Bell DW. The genomics of endometrial cancer. In: Birrer, MJ, and Ceppi L (eds). Translational advances in gynecologic cancers. 2017. Elsevier Inc, Cambridge, MA. pp 199-227.
Urick ME, Rudd ML, and Bell DW. Molecular pathology of serous carcinoma. In: Deavers MT and Coffey DM (eds). Precision molecular pathology of uterine cancer. 2017. Springer. pp 87-122.
Le Gallo M, Rudd ML, Urick ME, Hansen NF, NISC Comparative Sequencing Program, Merino MJ, Mutch DG, Goodfellow PJ, Mullikin JC, and Bell DW. The FOXA2 transcription factor is frequently somatically mutated in uterine carcinosarcomas and carcinomas. Cancer, 124:65-73. 2018. [PubMed]
Urick ME, and Bell DW. In vitro effects of FBXW7 mutation in serous endometrial cancer: increased levels of potentially druggable proteins and sensitivity to SI-2 and dinaciclib. Mol Carcinog, doi: 10.1002/mc.22867. 2018. [PubMed]
Reproductive Cancer Genetics Section Staff
- Staff Scientist
- Reproductive Cancer Genetics Section
- Reproductive Cancer Genetics Section
- Postdoctoral Fellow
- Reproductive Cancer Genetics Section
Last updated: September 11, 2018