The over-all research focus of the Ellis laboratory is the study of genomic instability and its relationship to cancer susceptibility. This focus includes the study of both high-penetrance and low-penetrance cancer-causing genes, population genetics of human cancer susceptibility alleles, and the molecular and cellular biology of the cancer susceptibility genes themselves.

The laboratory focuses on the Bloom’s syndrome (BS) protein BLM and the mechanisms by which BLM maintains genomic integrity. Normally BLM is localized to discrete structure PML nuclear bodies, which are thought to be factor repositories. In response to DNA damage, BLM migrates from the PML-NBs and concentrates focally in DNA damage induced foci. BLM is modified by the small ubiquitin-like modifier SUMO. We have evidence that SUMO modification targets BLM to the PML nuclear bodies. In addition, BLM molecules with experimentally introduced SUMO acceptor site mutations accumulate in DNA damage induced foci, suggesting that SUMO modification regulates BLM’s trafficking from the DNA damage induced foci to the PML nuclear bodies. We are currently testing this model in order to gain further insight into the role of SUMO modification in BLM nuclear trafficking.

The laboratory is interested in the identification of novel genes that cause susceptibility to colorectal cancer (CRC). Assuming that the remaining genetic variance underlying CRC susceptibility is caused by a continuum of susceptibility alleles, from high to low frequency with a range of effect sizes, we are carrying out association studies of biologically relevant candidate genes and genome-wide association analyses. We are screening candidate genes in high-risk families to identify novel CRC-susceptibility alleles. Because DNA repair has been shown to be important in CRC susceptibility, we are screening candidate genes from the mismatch repair and base excision repair pathways. We are also screening the Ras and Wnt signaling pathways. We will better quantify potential susceptibility alleles in large consecutive case-control studies. We are particularly interested in the study of CRC-causing genes in African Americans.

Selected Papers

Ellis NA, Lennon DJ, Proytcheva M, Alhadeff B, Henderson EE, German J. (1995). Somatic Intragenic recombination within the mutated locus BLM can restore to normal the high-SCE phenotype of Bloom syndrome cells. Am J Hum Genet 57:1019-1027.

Ellis* NA, Groden* J, Ye T-Z, Straughen J, Ciocci S, Lennon DJ, Proytcheva M, Alhadeff B, German J. (1995). The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 83: 655-666. [*these authors made an equal contribution]

Tippett P, Ellis NA. (1998). The Xg blood group system: A review. Transfusion Medicine Rev 12:233-257.

Li L, Eng C, Desnick B, German J, Ellis NA. (1998). Carrier frequency of the Bloom syndrome blm^Ash mutation in the Ashkenazi Jewish population. Mol Genet Metab 64:286-290.

Ellis NA, Ciocci S, Proytcheva M, Lennon D, Groden J, German J. (1998). The Ashkenazic Jewish Bloom syndrome mutation blm^Ash is present in nonJewish Americans of Spanish ancestry. Am J Hum Genet 63:1685-1693.

Ellis NA, Proytcheva M, Sanz M, Ye TZ, German, J. (1999). Transfection of BLM into cultured Bloom syndrome cells reduces the SCE rate toward normal. Am J Hum Genet 65:1368-1374.

Beresten SF, Stan R, van Brabant A, Tian Y, Naureckiene S, Ellis NA. (1999). Purification of overexpressed hexa-histidine tagged BLM N431 as oligomeric complexes. Prot Express Purif 17:239-248.

Ellis NA, Ciocci S, German J. (2001). Back mutation can produce phenotype reversion in Bloom syndrome somatic cells. Hum Genet 108:167-173.

Hu P, Beresten S, van Brabant A, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA. (2001). Evidence for BLM and Topoisomerase IIIa interaction in genomic stability. Hum Mol Genet 10:1287-1298.

Gruber* SB, Ellis* NA, Scott KK, Almog R, Kolachana P, Bonner JD, Kirchhoff T, Tomsho LP, Nafa K, Pierce H, Low M, Satagopan J, Rennert H, Huang H, Greenson JK, Groden J, Rapaport B, Shia J, Johnson S, Gregersen PK, Harris CC, Boyd J., Rennert G, Offit K. (2002). BLM heterozygosity and the risk of colorectal cancer. Science 297:2013. [*these authors made an equal contribution]

Foulkes WD, Thiffault I, Gruber SB, Horwitz M, Hamel N, Lee C, Shia J, Markowitz A, Figer A, Friedman E, Farber D, Greenwood CM, Bonner JD, Nafa K, Walsh T, Marcus V, Tomsho L, Gebert J, Macrae FA, Gaff CL, Paillerets BB, Gregersen PK, Weitzel JN, Gordon PH, MacNamara E, King MC, Hampel H, De La Chapelle A, Boyd J, Offit K, Rennert G, Chong G, Ellis NA. (2002). The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am J Hum Genet 71:1395-1412.

Offit K, Pierce H, Kirchhoff T, Kolachana P, Rapaport B, Gregersen P, Johnson S, Yossepowitch O, Huang H, Satagopan J, Robson M, Scheuer L, Nafa K, Ellis N. (2003). Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4:1-4.

Peterlongo P, Nafa K, Lerman GS, Glogowski E, Shia J, Markowitz AJ, Guillem JG, Kolachana P, Boyd JA, Offit K, Ellis NA. (2003). MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 107:571-579

MitraN, YeTZ, SmithA, ChuaiS, KirchhoffT, PeterlongoP, NafaK, PhillipsMS, OffitK, EllisNA. (2004). Localization of cancer susceptibility genes by genome-wide SNP linkage disequilibrium mapping. Can Res 64:8116-8125

Guillem JG, MooreHG, Palmer C, Glogowski E, Finch R, Nafa K, Markowitz A, Offit K, Ellis NA. (2004). A636P testing in Ashkenazi Jews. Familial Cancer 3:223-227

Peterlongo P, Mitra N, Chuai S, Kirchhoff T, Palmer C, Huang H, Nafa K, Offit K, Ellis NA. (2005). Frequency of MYH mutations in Caucasian and Jewish colorectal cancer cases and controls. Int J Cancer 114:505-507

Shia J, Klimstra DS, Nafa K, Offit K, Guillem JG, Markowitz AJ, Gerald WL, Ellis NA. (2005). Value of immunohistochemical detection of DNA mismatch repair gene proteins in predicting germline mutation status in familial colorectal neoplasms. Am J Surg Path 29:96-104

PeterlongoP, RadiceP, SalaP, HongYJ, HongSI, MitraN, OffitK, EllisNA. (2005). Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer. Hum Mut 25:498-200

Eladad, S, Ye TZ, Hu P, Leversha M, Beresten SF, Matunis M, Ellis NA. (2005). Intra-nuclear trafficking of the BLM helicase to DNA damage induced foci is regulated by SUMO-1. Hum Mol Genet 14:1351-1365

Ellis NA, KirchhoffT, MitraN, YeTZ, Chuai S, Huang H, NafaK, Norton L, Neuhausen S, Struewing JP, Narod S, OffitK. (2006). Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping. Genetic Epidemiology 30:48-61

Peterlongo P, Mitra N, Sanchez A, de la Hoya M, Bassi C, Bertario L, Radice P, Glogowski E, Nafa K, Caldez T, OffitK, Ellis NA. Disease-causing mutations of MYH are at increased frequency in colon cancer families. Carcinogenesis (in press; epub)

Guillem JG, Moore HG, Nafa K, Palmer C, Glogowski E, Finch R, Markowitz AJ, Shia J, Offit K, Ellis NA. Prospective single-amplicon MSH2 A636P mutation testing in Ashkenazi Jewish cancer families: experience and recommendations. Annals of Surgery (in press)

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