Dr. Bell has devoted her career to understanding the genetic 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) and launched a new research program 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. Serous and clear cell endometrial carcinomas are clinically aggressive; together they account for more than half of all deaths from endometrial carcinoma even though they are rare at diagnosis. Identifying the somatic genomic alterations that are present in these tumors is a prerequisite to uncovering pathogenic alterations that may be exploited therapeutically.
To achieve their goals, the Bell group has established a large, high-quality, endometrial tumor bank and capitalized on the unique genomic resources within the NHGRI cores and affiliated centers to search for somatic mutations in serous and clear cell endometrial carcinomas. 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 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.
Because candidate gene approaches are inherently biased, Dr. Bell's laboratory has recently 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 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 seeks to determine the functional impact of recurring FBXW7 and SPOP mutations in the context of endometrial cancer.
The Bell laboratory, together with intramural and extramural collaborators, continues to leverage next-generation sequencing approaches to search for somatic driver mutations in clear cell endometrial carcinomas and in endometrial carcinosarcomas, which represent another form of clinically aggressive endometrial cancer.
Reproductive Cancer Genetics Section Members
Fred Lozy, Ph.D., Postdoctoral Fellow
Meghan L. Rudd, M.S., Biologist
Last Updated: June 2, 2015