- Associate Professor, Cellular and Molecular Medicine
- Chair, Genetics - GIDP
- Associate Professor, Cancer Biology - GIDP
- Co-Program Leader, Cancer Biology Research Program
In Ellis’ early years, he studied X chromosome inactivation with Stanley M. Gartler at the University of Washington and sex determination with Peter N. Goodfellow at the Imperial Cancer Research Fund. His work on the molecular genetic structure of the transition from pseudoautosomal region to the sex-chromosome-specific regions, referred to as the pseudoautomosomal boundary, was key to identification of the sex-determining gene SRY (1-3), which made Peter “rich and famous.” Ellis obtained his first independent investigator position at the New York Blood Center, where he worked closely with James L. German III, M.D. At the Blood Center, following the work on the pseudoautosomal boundary, he cloned and characterized the XG blood group gene (4,5). XG deserved special interest because it is co-regulated, with the upstream, pseudoautosomal gene MIC2, by a cis-acting, polymorphic regulatory element, referred to as XGR (6). The molecular mechanisms of XGR’s action remain to be characterized to this day.
An introduction to homologous recombination and replication fork stability
Other sirens were calling. Ellis’ odyssey was grounded by his rendezvous with the rare, autosomal recessive entity Bloom’s syndrome. Bloom’s syndrome is characterized by excessive homologous recombination with excessive mitotic exchange between homologous chromosomes and with high levels of sister chromatic exchanges (SCEs)—a phenotype that is pathognomonic of the clinical entity. Using the molecular genetic tools of the day, Ellis and German localized the gene mutated in Bloom’s syndrome BLM to chromosome 15 using homozygosity mapping—a linkage technique that relies on the inheritance of the mutant gene identical-by-descent from a common ancestor in families whose parents are related (7). Bloom’s syndrome was known to be a “Jewish genetic disease,” because the syndrome, albeit rare, is relatively more frequent is persons whose parents are Ashkenazi Jewish than in other human populations. Here too, Ellis and German found strong linkage disequilibrium between a subset of genetic polymorphisms of distal chromosome 15 and the mutant gene in persons with Bloom’s syndrome whose parents were Ashkenazi Jewish (8).
With these genetic aspects of Bloom’s syndrome clarified, the time seemed right to tackle one of the most mysterious aspects of Bloom’s syndrome’s genetics: In Bloom’s syndrome, about one third of patients exhibit somatic mosaicism, that is, the presence of functionally normal, low-SCE cells and mutant, high-SCE cells in blood lymphocytes of the same patient. This unusual observation had been unexplained. German noticed that, of the persons with Bloom’s syndrome who exhibited the high-SCE/low-SCE somatic mosaicism, very few had parents who were related as cousins or who were Ashkenazi Jewish. When BLM was inherited in a person identical-by-descent from a common ancestor, the occurrence of moscaicism was rare. This observation suggested that, in order for a person with Bloom’s syndrome to exhibit the high-SCE/low-SCE mosaicism, that person had to be a genetic compound with disease-causing mutations at different positions within BLM. This revelation suggested a hypothesis that a mitotic recombination event between the maternal and paternal chromosomes localized to a region bounded by the two different BLM mutations could produce a functionally normal BLM on one of the two recombinant chromosomes. An important prediction of this model was that half of the time genetic polymorphisms distal to the site of the exchange would be reduced to homozygosity.
Ellis and German tested the hypothesis by genotyping genetic polymorphisms proximal and distal to BLM in matching DNAs—DNA from cells that were low-SCE and DNA from cells that were high-SCE—from each of 11 persons with Bloom’s syndrome. They identified the expected reduction to homozygosity distal to BLM in 5 of the 11 persons, whereas heterozygous loci proximal to BLM remained heterozygous (9). Ellis and German also showed that there is at least one other molecular mechanism in Bloom’s syndrome (back mutation) that can explain the somatic mosaicism (10). Both of these mechanisms have the effect of correcting the mutated BLM gene to generate a functionally normal BLM gene. Somatic reversion has been described in many different autosomal recessive disorders. For example, somatic reversion by somatic intragenic recombination has been described in Fanconi anemia. Other mutational mechanisms have been described as well (for example, gene conversion). Somatic reversion is known to exert an ameliorating effect in several immunodeficiency syndromes, such as adenosine deaminase deficiency and Wiskott-Aldrich syndrome, but its importance as a corrective or ameliorating influence in Bloom’s syndrome has not been demonstrated. The excessive homologous recombination in Bloom’s syndroem is mutagenic when the recombination occurs between homologous chromosomes. The reduction to homozygosity illustrated in Figure 1 is also a mechanism by which somatic mutations in tumor suppressor genes can become homozygous in a cell, resulting in ablation of tumor suppressor activity. This somatic mutational mechanism is fundamental to driving carcinogenesis in general, and it is pathogenic in Bloom’s syndrome in particular, where cancer is often a fatal consequence of the hypermutability inherent in the syndrome.
Somatic intragenic recombination in Bloom’s syndrome provided an elegant method for molecular cloning BLM. Having identified, through the study of somatic mosaicism, recombination events within the BLM gene, the cloning of BLM followed quickly (11). Mutations were soon identified in BLM that cause Bloom’s syndrome. Subsequently, Ellis showed that re-introduction of normal BLM into Bloom’s syndrome cells corrects their high-SCE phenotype (12,13), demonstrating the gene isolated is a functional BLM. The work at this stage had identified BLM—a gene known for its role in maintenance of genome integrity—and it made connections between the RecQ helicase family—a family of DNA helicases conserved from bacteria to mammals of which BLM is a member—and human disease. Other human RecQ genes that are mutated in rare syndromes include WRN, which is mutated in Werner syndrome, and RECQL4, which is mutated in a subset of persons with Rothmund-Thomson syndrome, Baller Gold syndrome, and RAPIDALINO. The RecQ helicases are intricately involved in maintaining the stability of replication forks, both during challenge with drugs that stress them and during an S phase that is unperturbed by such drugs. The connection between Bloom’s syndrome and RecQ helicases has brought into intense focus the connection between the regulation of homologous recombination and the stability of the replication fork during chromosome duplication. The mechanisms by which homologous recombination stabilizes replication forks are studied by many groups, including the Ellis group, to this day.
Passage to cancer genetic epidemiology
In 1997, Ellis moved to Memorial Sloan-Kettering Cancer Center, where he was able to expand his research program to study cancer susceptibility more broadly. He was particularly fortunate during this time to collaborate with Ken Offit, who ran the Clinical Genetics Services in the erstwhile Department of Human Genetics. Offit and Ellis initially worked together to examine the role of heterozygosity of caretaker genes like BLM and ATM in conferring risk to cancer. This was an important question because disease gene heterozygotes are much more frequent than disease gene homozygotes, and increased risk in heterozygotes might help explain some of the cancer susceptibility in the general population. A weapon in their arsenal was the population genetics of Ashkenazi Jews. The BLM mutation that is common in the Ashkenazi Jewish population, which we refer to as blmAsh, is a unique Bloom’s syndrome-causing mutation specific to Ashkenazi Jews; consequently, a straightforward PCR assay could be devised to test whether BLM+/- heterozygotes are at increased risk of cancer. By comparing Ashkenazi Jewish cancer cases and controls, Ellis with Steve Gruber, Gad Rennert, and Ken Offit found that BLM+/- heterozygotes have approximately two times the risk of developing colorectal cancer (CRC) compared to BLM+/+ (14). Some investigators consider this result controversial because reports from several other groups of smaller series did not observe an effect of BLM+/- on cancer susceptibility. It is worth pointing out that the Gruber et al. result was based on 1,244 Ashkenazi Jewish colorectal cancer cases and, with more than a two fold excess frequency of blmAsh in cases compared to controls observed, the result will be difficult to overturn without very large series (on the order to >15,000 cases). From the statistical perspective, estimation of the frequency of rare variants (minor allele frequency less than 1%) is plagued by power issues (15). Despite this difficulty, in recent years investigators have been returning to the idea that genetically-determined cancer susceptibility in the general population might be caused by rare mutations that have moderate effects, just as BLM heterozygosity appears to have.
Besides blmAsh, Ellis and collaborators have studied, in multiple cancer types, multiple cancer-causing mutations that are specific to the Ashkenazi Jewish population, including MSH2 A636P, the three common BRCA1/BRCA2 mutations, and CHEK2 S428F (16-20). A common theme of these stories is that the disease-causing mutation, which is inherited identical-by-descent, derived from a fairly recent common ancestor (in general <50 generations) creating strong linkage disequilibrium (LD) between the mutation and surrounding genetic polymorphisms. LD is defined as the excess co-occurrence of two alleles over that which is expected at random. Ellis hypothesized that the LD flanking Jewish founder mutations might facilitate the identification of disease genes using an association-based strategy. The association strategy should have increased power to identify novel disease genes in the Jewish population, because the number of different mutations in disease genes is small (often a single mutation as is the case for blmAsh) and the genetic distance over which LD spreads can be large (from 1 to 10 million base pairs). As a proof of principle, his group found that they could “re-discover” BLM, MSH2, and BRCA2 using this strategy (21,22), and the strategy subsequently formed the basis of a genome-wide association study from the Offit group to identify breast cancer genes in Ashkenazi Jews (23).
Persons who do not know themselves to be related can in fact carry the same DNA change identical by descent from a recent common ancestor. This scenario is referred to as cryptic relatedness and there is a lot of it out there. Ellis and German conducted a detailed mutational analysis of BLM in all available Bloom’s syndrome patients, identifying cryptic relatedness as a recurrent genetic theme in human populations (24). Although the mutational analysis in Bloom’s syndrome and other rare human genetic disorders has demonstrated the widespread character of cryptic relatedness in human populations, we do not fully appreciate its impact on human diseases. Increased cancer susceptibility could be caused by homozygosity for rare variants that confer susceptibility, even in the absence of other phenotypic effects.
Cancer health disparities
Before the large-scale population movements that accompanied the discovery of the New World, proximity was a strong force in partner selection. While many factors cause population structure (genetic aggregations) such as social status, religious and moral values, shared language, customs and so on, if the potential mate lived on another continent, the probability of a marriage was very small. Sub-Saharan African populations and European populations developed separately for tens of thousands of years with minimal admixture over this period. During this time, the peoples of these continents diverged genetically. Some of the genetic divergences represent functional changes born on waves of selective forces and other changes represent random forces, such as genetic drift, which is caused by small population sizes. Some changes are adaptive, fewer are mal-adaptive, many more are neutral. In the time frame of evolution, the genetic aggregations that are contained in these populations are merely variations of the species over its range—the time being insignificant and unlikely to generate genetic, i.e., reproductive isolation for us humans.
The term “race” refers to groups of people that are thought by the socially dominant group as similar (appearance, geographic location of origins, language, and so on). The US government officially recognizes racial categories when it collects census data, and these are the categories that are used by the government to analyze incidence and mortality statistics from the state cancer registries. There are obvious limitations to this approach due to its lack of granularity on social aggregations and lack of information about ancestry and ethnicity. From the standpoint of genetic epidemiology, the variation in ancestry is a possible source of confounding, for example, if cases and controls draw on persons with different proportions of genetic ancestries. Ancestry can also be a powerful force, because disease-associated factors are sometimes associated with ancestry.
Cancer health disparities are differences amongst groups in cancer statistics (morbidities, mortality, health outcomes, access, screening, and so on). The groups can be races, age groups, economic strata, and so on. In the U.S., African Americans have higher rates of incidence and mortality in colorectal cancer. Ellis has been using genetics to compare genetic factors in different ethnic groups to investigate colorectal cancer susceptibility genes. Although genome-wide association studies have localized many new susceptibility alleles, we still have not identified the DNA changes that cause the increased risk of cancer. Comparing the risk signals in African Americans and whites, the Ellis group has learned that only 30-40% of the risk alleles that are detectable in whites can be detected in African Americans (25,26). Thus, some of the risk alleles are shared, whilst other risk alleles localized to the same regions but are not shared. What is needed are larger genome wide association studies in African American colorectal cancer to map the overall landscape of risk alleles, shared and novel. The results will very likely lead only to better localization of those shared risk alleles but also to new genetic risk factors at play in CRC susceptibility.
Identification of the true, functionally relevant DNA changes that cause increased cancer risk remains a significant challenge to our field. Solving this problem will require genetic analysis of the risk genes using DNA sequencing, bioinformatics, and analysis in genetic model systems (cell culture and animal models) in which to test functional consequences of candidate risk-causing alleles. With its experience spanning these areas of analysis, the Ellis laboratory is in a unique position to combine the genetic and functional analyses to identify and characterize functionally important cancer-causing genetic variation.
Most recently, the Ellis laboratory has pivoted to the analysis of the cancer genome to better understand the role of genetic and environmental factors in cancer health disparities. Colorectal cancer in African Americans is more often right-sided and more often diagnosed at an earlier age compared to white populations (27). This new research strand—rich in bioinformatics analyses—is uncovering intriguing new cancer driver genes and raising important questions regarding the somatic mutational mechanisms at play in carcinogenesis. Although the well characterized cancer driver genes in CRC (APC, TP53, KRAS, SMAD4) occur at similar rates in African Americans and whites, the less frequently mutated cancer driver genes are less frequently mutated and novel driver genes appear, findings similar to the work reported by Markowitz and Willis group. These results are raising afresh questions regarding the interplay of genetic ancestry and environmental influences in colorectal carcinogenesis. The challenge is to synthesize germline risk factors, the cancer genome, environmental data from dietary exposures and microbial influences, and data from different ethnic groups to create a fully integrate understanding of cancer risk and development.
1. Ellis et al. Nature 337:81 (1989) http://www.ncbi.nlm.nih.gov/pubmed/2594087
2. Ellis et al. Nature 344:663 (1990) http://www.ncbi.nlm.nih.gov/pubmed/2325773
3. Ellis et al. Cell 63: 977 (1990) http://www.ncbi.nlm.nih.gov/pubmed/2124175
4. Ellis et al. Nat Genet 6:394 (1994) http://www.ncbi.nlm.nih.gov/pubmed/8054981
5. Ellis et al. Nat Genet 8:285 (1994) http://www.ncbi.nlm.nih.gov/pubmed/7533029
6. Tippett and Ellis, Transfusion Med Rev 12:233 (1998) http://www.ncbi.nlm.nih.gov/pubmed/9798268
7. German et al. Proc Natl Acad Sci USA 91:6669 (1994) http://www.ncbi.nlm.nih.gov/pubmed/8022833
8. Ellis et al. Am J Hum Genet. 55:453 (1994) http://www.ncbi.nlm.nih.gov/pubmed/8079989
9. Ellis et al. Am J Hum Genet 57:1019 (1995) http://www.ncbi.nlm.nih.gov/pubmed/7485150
10. Ellis et al. Hum Genet 108: 167 (2001) http://www.ncbi.nlm.nih.gov/pubmed/11281456
11. Ellis et al. Cell 83: 655 (1995) http://www.ncbi.nlm.nih.gov/pubmed/7585968
11. Neff et al. Mol Biol Cell 10:665 (1999) http://www.ncbi.nlm.nih.gov/pubmed/10069810
12. Ellis et al. Am J Hum Genet 65:1368 (1999) http://www.ncbi.nlm.nih.gov/pubmed/10521302
13. Ellis et al. Am J Hum Genet 63: 1685 (1998) http://www.ncbi.nlm.nih.gov/pubmed/9837821
14. Gruber et al. Science 297:2013 (2002) http://www.ncbi.nlm.nih.gov/pubmed/12242432
15. Ellis and Offit, PLoS Genet 9:e1003008 (2012) http://www.ncbi.nlm.nih.gov/pubmed/23028381
16. Foulkes et al. Am J Hum Genet 71: 1395 (2002) http://www.ncbi.nlm.nih.gov/pubmed/12454801
17. Offit et al. BMC Med Genet 4:1 (2003) http://www.ncbi.nlm.nih.gov/pubmed/12529183
18. Kirchoff et al. JNCI 96:68 (2004) http://www.ncbi.nlm.nih.gov/pubmed/14709740
19. Kirchoff et al. Clin Cancer Res 10:2918 (2004) http://www.ncbi.nlm.nih.gov/pubmed/15131025
20. Shaag et al. Hum Mol Genet 14:555 (2005) http://www.ncbi.nlm.nih.gov/pubmed/15649950
21. Mitra et al. Can Res 64: 8116 (2004) http://www.ncbi.nlm.nih.gov/pubmed/15520224
22. Ellis et al. Genet Epidem 30:48 (2006) http://www.ncbi.nlm.nih.gov/pubmed/16206141
23. Gold et al. Proc Natl Acad Sci 105:4340 (2008) http://www.ncbi.nlm.nih.gov/pubmed/18326623
24. German et al. Hum Mutation 28:743 (2007) http://www.ncbi.nlm.nih.gov/pubmed/17407155
25. Kupfer et al. Gasteroenterology 139:1677 (2010) http://www.ncbi.nlm.nih.gov/pubmed/20659471
26. Kupfer et al. Carcinogenesis April 21 (2014) http://www.ncbi.nlm.nih.gov/pubmed/24753543
27. Xicola et al. Clin Cancer Res 20:4960 (2014) http://www.ncbi.nlm.nih.gov/pubmed/25766683
- Ph.D. Genetics
- University of Washington, Seattle, Washington, United States
- Genetic and molecular analysis of the relationship of methylation to the reactivation of the human inactive X chromosome
- B.A. Liberal Arts
- St. John's College, Annapolis, Maryland, United States
- University of Arizona, Tucson, Arizona (2014 - Ongoing)
- University of Illinois at Chicago, Chicago, Illinois (2010 - 2014)
- University of Chicago, Chicago, Illinois (2005 - 2010)
- Memorial Sloan-Kettering Cancer Center (1997 - 2005)
- New York Blood Center (1990 - 1997)
- Imperial Cancer Research Fund (1987 - 1990)
Teaching in cancer biology survey course and in Advanced Topics in Cancer Biology in the CBIO GIDP. Create and maintain venues for communication and collaboration through the UACC Cancer Biology Program and the Center for Applied Genetics and Genomic Medicine. An example is the Genetic and Epigenetic Instability in Cancer OMG (GEICO) conference that takes place weekly.Development of a core curriculum in the Genetics GIDP. Revamp and revivify this decaying program.
The Ellis laboratory is dedicated to investigation of the relationship between genomic instability and cancer susceptibility. Genomic instability is a dominant feature of cancer cells, and it is the central phenotype of a large group of clinical entities in which cancer development is the main and often fatal consequence.
Cancer BiologyCBIO 552 (Fall 2020)
Fundamental Genetic MechanismsCMM 518 (Fall 2020)
Recent Advances GeneticsGENE 670 (Fall 2020)
ResearchGENE 900 (Fall 2020)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2020)
Lab Research RotationGENE 795A (Spring 2020)
Recent Advances GeneticsGENE 670 (Spring 2020)
Cancer BiologyCBIO 552 (Fall 2019)
Fundamental Genetic MechanismsCMM 518 (Fall 2019)
Independent StudyGENE 699 (Fall 2019)
Introduction to ResearchMCB 795A (Fall 2019)
Lab Research RotationGENE 795A (Fall 2019)
Recent Advances GeneticsECOL 670 (Fall 2019)
Recent Advances GeneticsGENE 670 (Fall 2019)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2019)
DissertationCBIO 920 (Spring 2019)
DissertationCMM 920 (Spring 2019)
Recent Advances GeneticsGENE 670 (Spring 2019)
Research ConferenceCBIO 695A (Spring 2019)
ThesisMCB 910 (Spring 2019)
Cancer BiologyCBIO 552 (Fall 2018)
DissertationCBIO 920 (Fall 2018)
DissertationCMM 920 (Fall 2018)
Introduction to ResearchMCB 795A (Fall 2018)
Lab Research RotationGENE 795A (Fall 2018)
Modern GeneticsCMM 518 (Fall 2018)
Recent Advances GeneticsECOL 670 (Fall 2018)
Recent Advances GeneticsGENE 670 (Fall 2018)
ResearchMCB 900 (Fall 2018)
Research ConferenceCBIO 695A (Fall 2018)
ThesisMCB 910 (Fall 2018)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2018)
DissertationCBIO 920 (Spring 2018)
DissertationCMM 920 (Spring 2018)
Honors ThesisMCB 498H (Spring 2018)
ResearchMCB 900 (Spring 2018)
Research ConferenceCBIO 695A (Spring 2018)
ThesisMCB 910 (Spring 2018)
Cancer BiologyCBIO 552 (Fall 2017)
DissertationCMM 920 (Fall 2017)
Honors ThesisMCB 498H (Fall 2017)
Introduction to ResearchMCB 795A (Fall 2017)
ResearchCBIO 900 (Fall 2017)
ResearchMCB 900 (Fall 2017)
Research ConferenceCBIO 695A (Fall 2017)
ThesisMCB 910 (Fall 2017)
Adv Topics in Cancer BiologyCBIO 553 (Spring 2017)
Directed RsrchMCB 492 (Spring 2017)
DissertationCMM 920 (Spring 2017)
ResearchCBIO 900 (Spring 2017)
Research ConferenceCBIO 695A (Spring 2017)
Cancer BiologyCBIO 552 (Fall 2016)
Directed RsrchMCB 492 (Fall 2016)
DissertationCMM 920 (Fall 2016)
Introduction to ResearchMCB 795A (Fall 2016)
ResearchCBIO 900 (Fall 2016)
Research ConferenceCBIO 695A (Fall 2016)
Directed RsrchMCB 492 (Spring 2016)
ResearchCBIO 900 (Spring 2016)
ResearchCMM 900 (Spring 2016)
Research ConferenceCBIO 695A (Spring 2016)
- Kupfer, S. S., & Ellis, N. A. (2016). Hereditary Colorectal Cancer. In Molecular Basis of Human Cancer(pp 381-400). New York: Springer. doi:10.1007/978-1-59745-458-2_25
- Jacobs, E. T., Lance, P., Mandarino, L. J., Ellis, N. A., Chow, H. S., Foote, J., Martinez, J. A., Hsu, C. P., Batai, K., Saboda, K., & Thompson, P. A. (2019). Selenium supplementation and insulin resistance in a randomized, clinical trial. BMJ open diabetes research & care, 7(1), e000613.More infoWhile controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic β-cell function and insulin sensitivity.
- Pond, K. W., & Ellis, N. A. (2019). Quantification of Double-Strand Breaks in Mammalian Cells Using Pulsed-Field Gel Electrophoresis. Methods in molecular biology (Clifton, N.J.), 1999, 75-85.More infoThe double-strand break (DSB) is the most cytotoxic type of DNA damage and measurement of DSBs in cells is essential to understand their induction and repair. Pulsed-field gel electrophoresis (PFGE) allows for quantitative measurement of DSBs in a cell population generated by DNA damaging agents. PFGE has the capacity to separate DNA molecules from several hundred base pairs to over six million base pairs. In the method described here, molecules from five hundred thousand to three million base pairs are consolidated into a single band on the gel that is readily analyzed.
- Pond, K. W., de Renty, C., Yagle, M. K., & Ellis, N. A. (2019). Rescue of collapsed replication forks is dependent on NSMCE2 to prevent mitotic DNA damage. PLoS genetics, 15(2), e1007942.More infoNSMCE2 is an E3 SUMO ligase and a subunit of the SMC5/6 complex that associates with the replication fork and protects against genomic instability. Here, we study the fate of collapsed replication forks generated by prolonged hydroxyurea treatment in human NSMCE2-deficient cells. Double strand breaks accumulate during rescue by converging forks in normal cells but not in NSMCE2-deficient cells. Un-rescued forks persist into mitosis, leading to increased mitotic DNA damage. Excess RAD51 accumulates and persists at collapsed forks in NSMCE2-deficient cells, possibly due to lack of BLM recruitment to stalled forks. Despite failure of BLM to accumulate at stalled forks, NSMCE2-deficient cells exhibit lower levels of hydroxyurea-induced sister chromatid exchange. In cells deficient in both NSMCE2 and BLM, hydroxyurea-induced double strand breaks and sister chromatid exchange resembled levels found in NSCME2-deficient cells. We conclude that the rescue of collapsed forks by converging forks is dependent on NSMCE2.
- Taylor, A. M., Rothblum-Oviatt, C., Ellis, N. A., Hickson, I. D., Meyer, S., Crawford, T. O., Smogorzewska, A., Pietrucha, B., Weemaes, C., & Stewart, G. S. (2019). Chromosome instability syndromes. Nature reviews. Disease primers, 5(1), 64.More infoFanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.
- Xicola, R. M., Clark, J. R., Carroll, T., Alvikas, J., Marwaha, P., Regan, M. R., Lopez-Giraldez, F., Choi, J., Emmadi, R., Alagiozian-Angelova, V., Kupfer, S. S., Ellis, N. A., & Llor, X. (2019). Implication of DNA repair genes in Lynch-like syndrome. Familial cancer, 18(3), 331-342.More infoMany colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.
- Zhou, J., Jenkins, T. G., Jung, A. M., Jeong, K. S., Zhai, J., Jacobs, E. T., Griffin, S. C., Dearmon-Moore, D., Littau, S. R., Peate, W. F., Ellis, N. A., Lance, P., Chen, Y., & Burgess, J. L. (2019). DNA methylation among firefighters. PloS one, 14(3), e0214282.More infoFirefighters are exposed to carcinogens and have elevated cancer rates. We hypothesized that occupational exposures in firefighters would lead to DNA methylation changes associated with activation of cancer pathways and increased cancer risk. To address this hypothesis, we collected peripheral blood samples from 45 incumbent and 41 new recruit non-smoking male firefighters and analyzed the samples for DNA methylation using an Illumina Methylation EPIC 850k chip. Adjusting for age and ethnicity, we performed: 1) genome-wide differential methylation analysis; 2) genome-wide prediction for firefighter status (incumbent or new recruit) and years of service; and 3) Ingenuity Pathway Analysis (IPA). Four CpGs, including three in the YIPF6, MPST, and PCED1B genes, demonstrated above 1.5-fold statistically significant differential methylation after Bonferroni correction. Genome-wide methylation predicted with high accuracy incumbent and new recruit status as well as years of service among incumbent firefighters. Using IPA, the top pathways with more than 5 gene members annotated from differentially methylated probes included Sirtuin signaling pathway, p53 signaling, and 5' AMP-activated protein kinase (AMPK) signaling. These DNA methylation findings suggest potential cellular mechanisms associated with increased cancer risk in firefighters.
- Augustus, G. J., & Ellis, N. A. (2018). Colorectal Cancer Disparity in African Americans: Risk Factors and Carcinogenic Mechanisms. The American journal of pathology, 188(2), 291-303.More infoAfrican Americans have the highest incidence and mortality rates of colorectal cancer (CRC) of any ethnic group in the United States. Although some of these disparities can be explained by differences in access to care, cancer screening, and other socioeconomic factors, disparities remain after adjustment for these factors. Consequently, an examination of recent advances in the understanding of ethnicity-specific factors, including genetic and environmental factors relating to risk of CRC, the biology of CRC progression, and the changes in screening and mortality, is important for evaluating our progress toward eliminating the disparities. An overarching limitation in this field is the number and sample size of studies performed to characterize the etiological bases of CRC incidence and mortality in African Americans. Despite this limitation, significant differences in etiology are manifest in many studies. These differences need validation, and their impacts on disparities need more detailed investigation. Perhaps most heartening, improvements in CRC screening can be attributed to the smallest difference in CRC incidence between African Americans and whites since the late 1980s. Cancer mortality, however, remains a persistent difference.
- Augustus, G. J., Roe, D. J., Jacobs, E. T., Lance, P., & Ellis, N. A. (2018). Is increased colorectal screening effective in preventing distant disease?. PloS one, 13(7), e0200462.More infoScreening in the average risk population for colorectal cancer (CRC) is expected to reduce the incidence of distant (i.e., metastatic) CRCs at least as much as less advanced CRCs. Indeed, since 2000, during which time colonoscopy became widely used as a screening tool, the overall incidence of CRC has been reduced by 29%.
- Batai, K., Bergersen, A., Price, E., Hynes, K., Ellis, N. A., & Lee, B. R. (2018). Clinical and Molecular Characteristics and Burden of Kidney Cancer Among Hispanics and Native Americans: Steps Toward Precision Medicine. Clinical genitourinary cancer, 16(3), e535-e541.More infoCancer disparities in Native Americans (NAs) and Hispanic Americans (HAs) vary significantly in terms of cancer incidence and mortality rates across geographic regions. This review reports that kidney and renal pelvis cancers are unevenly affecting HAs and NAs compared to European Americans of non-Hispanic origin, and that currently there is significant need for improved data and reporting to be able to advance toward genomic-based precision medicine for the assessment of such cancers in these medically underserved populations. More specifically, in states along the US-Mexico border, HAs and NAs have higher kidney cancer incidence rates as well as a higher prevalence of kidney cancer risk factors, including obesity and chronic kidney disease. They are also more likely to receive suboptimal care compared to European Americans. Furthermore, they are underrepresented in epidemiologic, clinical, and molecular genomic studies of kidney cancer. Therefore, we maintain that progress in precision medicine for kidney cancer care requires an understanding of various factors among HAs and NAs, including the real kidney cancer burden, variations in clinical care, issues related to access to care, and specific clinical and molecular characteristics.
- Batai, K., Imler, E., Pangilinan, J., Bell, R., Lwin, A., Price, E., Milinic, T., Arora, A., Ellis, N. A., Bracamonte, E., Seligmann, B., & Lee, B. R. (2018). Whole-transcriptome sequencing identified gene expression signatures associated with aggressive clear cell renal cell carcinoma. Genes & cancer, 9(5-6), 247-256.More infoClear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, yet molecular biomarkers have not been used for the prognosis of ccRCC to aide clinical decision making. This study aimed to identify genes associated with ccRCC aggressiveness and overall survival (OS). Samples of ccRCC tumor tissue were obtained from 33 patients who underwent nephrectomy. Gene expression was determined using whole-transcriptome sequencing. The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) RNA-seq data was used to test association with OS. 290 genes were differentially expressed between tumors with high and low stage, size, grade, and necrosis (SSIGN) score (≥7 . ≤3) with
- Cunniff, C., Djavid, A. R., Carrubba, S., Cohen, B., Ellis, N. A., Levy, C. F., Jeong, S., Lederman, H. M., Vogiatzi, M., Walsh, M. F., & Zauber, A. G. (2018). Health supervision for people with Bloom syndrome. American journal of medical genetics. Part A, 176(9), 1872-1881.More infoBloom Syndrome (BSyn) is an autosomal recessive disorder that causes growth deficiency, endocrine abnormalities, photosensitive skin rash, immune abnormalities, and predisposition to early-onset cancer. The available treatments for BSyn are symptomatic, and early identification of complications has the potential to improve outcomes. To accomplish this, standardized recommendations for health supervision are needed for early diagnosis and treatment. The purpose of this report is to use information from the BSyn Registry, published literature, and expertise from clinicians and researchers with experience in BSyn to develop recommendations for diagnosis, screening, and treatment of the clinical manifestations in people with BSyn. These health supervision recommendations can be incorporated into the routine clinical care of people with BSyn and can be revised as more knowledge is gained regarding their clinical utility.
- Kohler, L. N., Foote, J., Kelley, C. P., Florea, A., Shelly, C., Chow, H. S., Hsu, P., Batai, K., Ellis, N., Saboda, K., Lance, P., & Jacobs, E. T. (2018). Selenium and Type 2 Diabetes: Systematic Review. Nutrients, 10(12).More infoSeveral studies have investigated the potential role of selenium (Se) in the development of type 2 diabetes (T2D) with disparate findings. We conducted a systematic review and meta-analysis to synthesize the evidence of any association between Se and T2D. PubMed, Embase, and Scopus were searched following the Preferred Reporting Items for Systematic Reviews and Meta-analysis Approach (PRISMA). Sixteen studies from 15 papers met inclusion criteria defined for this review. Of the 13 observational studies included, 8 demonstrated a statistically significant positive association between concentrations of Se and odds for T2D, with odds ratios (95% confidence intervals) ranging from 1.52 (1.01⁻2.28) to 7.64 (3.34⁻17.46), and a summary odds ratio (OR) (95% confidence interval (CI)) of 2.03 (1.51⁻2.72). In contrast, among randomized clinical trials (RCTs) of Se, a higher risk of T2D was not observed for those who received Se compared to a placebo (OR = 1.18, 95% CI 0.95⁻1.47). Taken together, the results for the relationship between Se and T2D differ between observational studies and randomized clinical trials (RCTs). It remains unclear whether these differences are the result of uncontrolled confounding in the observational studies, or whether there is a modest effect of Se on the risk for T2D that may vary by duration of exposure. Further investigations on the effects of Se on glucose metabolism are needed.
- Lynn, H., Sun, X., Ayshiev, D., Siegler, J. H., Rizzo, A. N., Karnes, J. H., Gonzales Garay, M., Wang, T., Casanova, N., Camp, S. M., Ellis, N. A., & Garcia, J. G. (2018). Single nucleotide polymorphisms in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PloS one, 13(8), e0200916.More infoPseudogenes are paralogues of functional genes historically viewed as defunct due to either the lack of regulatory elements or the presence of frameshift mutations. Recent evidence, however, suggests that pseudogenes may regulate gene expression, although the functional role of pseudogenes remains largely unknown. We previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk.
- Xicola, R. M., Manojlovic, Z., Augustus, G. J., Kupfer, S. S., Emmadi, R., Alagiozian-Angelova, V., Triche, T., Salhia, B., Carpten, J., Llor, X., & Ellis, N. A. (2018). Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans. Carcinogenesis, 39(11), 1331-1341.More infoAfrican Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (TCGA). Two of the 45 tumors contained POLE mutations. In the remaining 43 tumors, only 27 (63%) contained loss-of-function mutations in APC compared with 80% of TCGA NHW CRCs. APC-mutation-negative CRCs were associated with an earlier onset of CRC (P = 0.01). They were also associated with lower overall mutation burden, fewer copy number variants and a DNA methylation signature that was distinct from the CpG island methylator phenotype characterized in microsatellite unstable disease. Three of the APC-mutation-negative CRCs had loss-of-function mutations in BCL9L. Mutations in driver genes identified by TCGA exome analysis were less frequent in AA CRC cases than TCGA NHWs. Genes that regulate the WNT signaling pathway, including SOX9, GATA6, TET1, GLIS1 and FAT1, were differentially hypermethylated in APC-mutation-negative CRCs, suggesting a novel mechanism for cancer development in these tumors. In summary, we have identified a subtype of CRC that is associated with younger age of diagnosis, lack of APC mutation, microsatellite and chromosome stability, lower mutation burden and distinctive methylation changes.
- Cunniff, C., Bassetti, J. A., & Ellis, N. A. (2017). Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition. Molecular syndromology, 8(1), 4-23.More infoBloom's syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early onset of cancer and for the development of multiple cancers. Loss-of-function mutations of , which codes for a RecQ helicase, cause Bloom's syndrome. The absence of a functional BLM protein causes chromosome instability, excessive homologous recombination, and a greatly increased number of sister chromatid exchanges that are pathognomonic of the syndrome. A common founder mutation designated is present in about 1 in 100 persons of Eastern European Jewish ancestry, and there are additional recurrent founder mutations among other populations. Missense, nonsense, and frameshift mutations as well as multiexonic deletions have all been observed. Bloom's syndrome is a prototypical chromosomal instability syndrome, and the somatic mutations that occur as a result of that instability are responsible for the increased cancer risk. Although there is currently no treatment aimed at the underlying genetic abnormality, persons with Bloom's syndrome benefit from sun protection, aggressive treatment of infections, surveillance for insulin resistance, and early identification of cancer.
- Yazici, C., Wolf, P. G., Kim, H., Cross, T. L., Vermillion, K., Carroll, T., Augustus, G. J., Mutlu, E., Tussing-Humphreys, L., Braunschweig, C., Xicola, R. M., Jung, B., Llor, X., Ellis, N. A., & Gaskins, H. R. (2017). Race-dependent association of sulfidogenic bacteria with colorectal cancer. Gut, 66(11), 1983-1994.More infoColorectal cancer (CRC) incidence is higher in African Americans (AAs) compared with non-Hispanic whites (NHWs). A diet high in animal protein and fat is an environmental risk factor for CRC development. The intestinal microbiota is postulated to modulate the effects of diet in promoting or preventing CRC. Hydrogen sulfide, produced by autochthonous sulfidogenic bacteria, triggers proinflammatory pathways and hyperproliferation, and is genotoxic. We hypothesised that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHW.
- Ashktorab, H., Ahuja, S., Kannan, L., Llor, X., Ellis, N. A., Xicola, R. M., Laiyemo, A. O., Carethers, J. M., Brim, H., & Nouraie, M. (2016). A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget, 7(23), 34546-57.More infoAfrican Americans (AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in this population while others report lower frequency compared to Caucasians.
- Grimm, W. A., Messer, J. S., Murphy, S. F., Nero, T., Lodolce, J. P., Weber, C. R., Logsdon, M. F., Bartulis, S., Sylvester, B. E., Springer, A., Dougherty, U., Niewold, T. B., Kupfer, S. S., Ellis, N., Huo, D., Bissonnette, M., & Boone, D. L. (2016). The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut, 65(3), 456-64.More infoATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells.
- Markowitz, S. D., Nock, N. L., Schmit, S. L., Stadler, Z. K., Joseph, V., Zhang, L., Willis, J. E., Scacheri, P., Veigl, M., Adams, M. D., Raskin, L., Sullivan, J. F., Stratton, K., Shia, J., Ellis, N., Rennert, H. S., Manschreck, C., Li, L., Offit, K., , Elston, R. C., et al. (2016). A Germline Variant on Chromosome 4q31.1 Associates with Susceptibility to Developing Colon Cancer Metastasis. PloS one, 11(1), e0146435.More infoWe tested for germline variants showing association to colon cancer metastasis using a genome-wide association study that compared Ashkenazi Jewish individuals with stage IV metastatic colon cancers versus those with stage I or II non-metastatic colon cancers. In a two-stage study design, we demonstrated significant association to developing metastatic disease for rs60745952, that in Ashkenazi discovery and validation cohorts, respectively, showed an odds ratio (OR) = 2.3 (P = 2.73E-06) and OR = 1.89 (P = 8.05E-04) (exceeding validation threshold of 0.0044). Significant association to metastatic colon cancer was further confirmed by a meta-analysis of rs60745952 in these datasets plus an additional Ashkenazi validation cohort (OR = 1.92; 95% CI: 1.28-2.87), and by a permutation test that demonstrated a significantly longer haplotype surrounding rs60745952 in the stage IV samples. rs60745952, located in an intergenic region on chromosome 4q31.1, and not previously associated with cancer, is, thus, a germline genetic marker for susceptibility to developing colon cancer metastases among Ashkenazi Jews.
- Xicola, R. M., Bontu, S., Doyle, B. J., Rawson, J., Garre, P., Lee, E., de la Hoya, M., Bessa, X., Clofent, J., Bujanda, L., Balaguer, F., Castellví-Bel, S., Alenda, C., Jover, R., Ruiz-Ponte, C., Syngal, S., Andreu, M., Carracedo, A., Castells, A., , Newcomb, P. A., et al. (2016). Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC). Carcinogenesis, 37(8), 751-8.More infoThe purpose of this study was to identify novel colorectal cancer (CRC)-causing alleles in unexplained familial CRC cases. In order to do so, coding regions in five candidate genes (MGMT, AXIN2, CTNNB1, TGFBR1 and TGFBR2) were sequenced in 11 unrelated microsatellite-stable hereditary non-polyposis CRC (MSS HNPCC) cases. Selected genetic variants were genotyped in a discovery set of 27 MSS HNPCC cases and 85 controls. One genetic variant, rs67687202, in TGFBR1 emerged as significant (P = 0.002), and it was genotyped in a replication set of 87 additional MSS HNPCC-like cases and 338 controls where it was also significantly associated with MSS HNPCC cases (P = 0.041). In the combined genotype data, rs67687202 was associated with a moderate increase in CRC risk (OR = 1.68; 95% CI = 1.13-2.50; P = 0.010). We tested a highly correlated SNP rs868 in 723 non-familial CRC cases compared with 629 controls, and it was not significantly associated with CRC risk (P = 0.370). rs868 is contained in a let-7 miRNA binding site in the 3'UTR of TGFBR1, which might provide a functional basis for the association in MSS HNPCC. In luciferase assays, the risk-associated allele for rs868 was associated with half the luciferase expression in the presence of miRNA let-7b-5p compared with protective allele, suggesting more binding of let-7b-5p and less TGFBR1 expression. Thus, rs868 potentially is a CRC risk-causing allele. Our results support the concept that rs868 is associated with lower TGFBR1 expression thereby increasing CRC risk.
- Hulur, I., Gamazon, E. R., Skol, A. D., Xicola, R. M., Llor, X., Onel, K., Ellis, N. A., & Kupfer, S. S. (2015). Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci. BMC genomics, 16, 138.More infoGenome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). However, the functional role of many of these SNPs is largely unknown and tissue-specific resources are lacking. Expression quantitative trait loci (eQTL) mapping identifies target genes of disease-associated SNPs. This study provides a comprehensive eQTL map of distal colonic samples obtained from 40 healthy African Americans and demonstrates their relevance for GWAS of colonic diseases.
- Kupfer, S. S., Skol, A. D., Hong, E., Ludvik, A., Kittles, R. A., Keku, T. O., Sandler, R. S., & Ellis, N. A. (2014). Shared and independent colorectal cancer risk alleles in TGFβ-related genes in African and European Americans. Carcinogenesis, 35(9), 2025-30.More infoGenome-wide association studies (GWAS) in colorectal cancer (CRC) identified five regions near transforming growth factor β-related genes BMP4, GREM1, CDH1, SMAD7 and RPHN2. The true risk alleles remain to be identified in these regions, and their role in CRC risk in non-European populations has been understudied. Our previous work noted significant genetic heterogeneity between African Americans (AAs) and European Americans (EAs) for single nucleotide polymorphisms (SNPs) identified in GWAS. We hypothesized that associations may not have been replicated in AAs due to differential or independent genetic structures. In order to test this hypothesis, we genotyped 195 tagging SNPs across these five gene regions in 1194 CRC cases (795 AAs and 399 EAs) and 1352 controls (985 AAs and 367 EAs). Imputation was performed, and association testing of genotyped and imputed SNPs included ancestry, age and sex as covariates. In two of the five genes originally associated with CRC, we found evidence for association in AAs including rs1862748 in CDH1 (OR(Add) = 0.82, P = 0.02) and in GREM1 the SNPs rs10318 (OR(Rec) = 60.1, P = 0.01), rs11632715 (OR(Rec) = 2.36; P = 0.004) and rs12902616 (OR(Rec) = 1.28, P = 0.005), the latter which is in linkage disequilibrium with the previously identified SNP rs4779584. Testing more broadly for associations in these gene regions in AAs, we noted three statistically significant association peaks in GREM1 and RHPN2 that were not identified in EAs. We conclude that some CRC risk alleles are shared between EAs and AAs and others are population specific.
- Pibiri, F., Kittles, R. A., Sandler, R. S., Keku, T. O., Kupfer, S. S., Xicola, R. M., Llor, X., & Ellis, N. A. (2014). Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer causes & control : CCC, 25(5), 561-70.More infoDisparities in both colorectal cancer (CRC) incidence and survival impact African Americans (AAs) more than other US ethnic groups. Because vitamin D is thought to protect against CRC and AAs have lower serum vitamin D levels, genetic variants that modulate the levels of active hormone in the tissues could explain some of the cancer health disparity. Consequently, we hypothesized that genetic variants in vitamin D-related genes are associated with CRC risk.
- Xicola, R. M., Gagnon, M., Clark, J. R., Carroll, T., Gao, W., Fernandez, C., Mijic, D., Rawson, J. B., Janoski, A., Pusatcioglu, C. K., Rajaram, P., Gluskin, A. B., Regan, M., Chaudhry, V., Abcarian, H., Blumetti, J., Cintron, J., Melson, J., Xie, H., , Guzman, G., et al. (2014). Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. Clinical cancer research : an official journal of the American Association for Cancer Research, 20(18), 4962-70.More infoAfrican Americans (AA) have the highest incidence of colorectal cancer compared with other U.S. populations and more proximal colorectal cancers. The objective is to elucidate the basis of these cancer disparities.
- Cunniff, C., Bassetti, J. A., & Ellis, N. A. (2017. Bloom's syndrome: Clinical spectrum, molecular pathogenesis, and cancer predisposition(pp 4-23).
- de Renty, C., & Ellis, N. A. (2017. Bloom's syndrome: Why not premature aging?: A comparison of the BLM and WRN helicases(pp 36-51).More infoGenomic instability is a hallmark of cancer and aging. Premature aging (progeroid) syndromes are often caused by mutations in genes whose function is to ensure genomic integrity. The RecQ family of DNA helicases is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes - BLM, WRN, and RECQL4 - give rise to Bloom's syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS), respectively. WS is a prototypic premature aging disorder; however, the clinical features present in BS and RTS do not indicate accelerated aging. The BLM helicase has pivotal functions at the crossroads of DNA replication, recombination, and repair. BS cells exhibit a characteristic form of genomic instability that includes excessive homologous recombination. The excessive homologous recombination drives the development in BS of the many types of cancers that affect persons in the normal population. Replication delay and slower cell turnover rates have been proposed to explain many features of BS, such as short stature. More recently, aberrant transcriptional regulation of growth and survival genes has been proposed as a hypothesis to explain features of BS.