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THE FOLLOWING IS A REVIEW OF THE INNOVATIVE CLINICAL AND LABORATORY GENETIC RESEARCH BY DR. KENNETH OFFIT AND HIS RESEARCH COLLEAGUES SUPPORTED IN PART BY LYMPHOMA FOUNDATION GRANTS
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2010 UPDATE BY KENNETH OFFIT, M.D. TO THE LYMPHOMA FOUNDATION
Kenneth Offit, M.D., M.P.H.
Director,
Clinical Genetics Service The first of these is a major publication appearing in the high impact journal, PLoS Genetics. This paper was recently accepted for publication. It is the result of three years of work, bringing together DNA samples from thousands of women around the world who provided these samples to our international consortia. The goal of the project was to identify genetic factors associating with resistance to breast cancer among the elderly. This project had initial early support from The Lymphoma Foundation. The aim of the project was to look at the genetic profiles of older individuals who did not experience a diagnosis of breast cancer over the course of their lifetime, despite having a very high risk genetic profile. These women were compared to younger women who did develop breast cancer at a very early age, and who also carried the same predisposing genetic mutations of BRCA genes. The result of a whole genome analysis conducted in collaboration with colleagues at Harvard and MIT, at The Broad Institute, revealed one particular marker, which was associated with a breast cancer risk or, inversely, with a resistance to breast cancer, in this population. This marker was comprised of single-nucleotide polymorphisms around the gene ZNF365. ZNF365 is a zinc finger gene, a member of the class of tyrosine kinase signaling pathways that have been found to be over expressed in breast cancers, as well as a number of other cancers, including solid tumors and lymphomas. Interestingly, genetic variants in this same gene were independently found to be associated with sporadic breast cancer risk in a study published at about the same time by colleagues at the University of Cambridge, and very recently (March 2012) this same gene has been implicated in breast density on mammography. While these findings are of interest, the relative protective effect of these variants was quite small, as in other genome-wide variants discovered to date. This paper marks just the first stages of the analysis, with a more detailed analysis of the genomic scan data now in progress. This additional work is being carried out at Genome Quebec. As indicated by the size of the author list on the PLoS Genetics publication, this was an enormous international collaboration headed by the Memorial Sloan KetterinCancer Center (MSKCC) group. We are indebted to The Lymphoma Foundation for providing the seed funds that allowed over $2M of grant funding to be secured, resulting ultimately in this high impact publication. The second paper to be cited underscores some of the comments above regarding findings of genomewide association studies in cancer. That paper, published in the Journal of Clinical Oncology, provides the first analytic overview of this body of genomic research. In this paper, written by a junior faculty member of the Clinical Genetics Service, the range of risks associated with genetic variants for cancer types is presented in an analytic framework. This paper serves as a useful resource for clinicians seeking to understand the emerging literature of inherited cancer genomics. Among the points raised in the paper is the observation that one of the highest risk genomic variants associated with cancer was reported for myeloproliferative disorders (including polycythemia vera and essential thrombocytosis). The third paper bearing support of The Lymphoma Foundation, recently published, relates to prostate cancer. In this paper, published in the journal of the American Association of Cancer Research, Clinical Cancer Research, our group defined for the first time the adverse outcome of prostate cancer occurring in the setting of an inherited mutation of the BRCA genes. This observation was conducted in Ashkenazi Jewish individuals, but should be valid across all ethnic and population subgroups. The finding that men with prostate cancer carrying BRCA mutations have a higher Gleason grade and also a much more aggressive course of disease has important clinical implications. This is because there is now a targeted therapy, consisting of PARP inhibitors, that has been shown to have activity in women with breast and ovarian cancer and BRCA mutations. We postulate in this article that a subset of men in the general population with poor prognosis prostate cancer could also benefit from this targeted therapy that has heretofore been utilized only in women with BRCA mutations. We calculate that approximately 3,000 cases of prostate cancer each year in The United States would benefit from this potential new therapeutic approach…” September 9, 2009 TO: Mortimer Lacher, MD, FACP President, The Lymphoma Foundation
This letter constitutes our annual update of research activities supported by The Lymphoma Foundation. We will begin with the review of articles and then data that is not yet published or that is still in progress.
Review of Articles As indicated to you last year, we are increasing our emphasis on lymphoma genetics. Although our major paper is still in the works for this year, we did have an interesting collaborative publication in the past year. This paper, entitled, "Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells," was published in the prestigious Proceedings of the National Academy of Sciences. It was a collaboration with our colleague Marshall Horwitz in the Division of Medical Genetics at the University of Washington School of Medicine in Seattle. Marshall identified a translocation in a family with Hodgkin’s disease. We were very interested in candidate genes at this translocation junction and explored SNPs in this and other regions in our familial lymphomas. This translocation involved chromosomes 2 and 3. It was found to disrupt a gene KLHDC8B, which had previously been uncharacterized. Interestingly, loss if heterozygosity was noted in the Reed-Steinberg cells of one of the cases of Hodgkin’s disease, but not in the reactive T lymphocytes. This is a very interesting finding and is somewhat reminiscent of the observation whereby the gene BRCA2 was identified by loss of heterozygosity in a pancreatic cancer. As you will recall, BRCA2 was later shown to be a major predisposing gene for breast cancer. While we played really a supportive role in this paper by Dr. Horwitz, our contribution at the early stages was critical and we will be continuing our collaborations with his group. He has also offered to provide DNA from his familial cases for our family studies to be described shortly. As noted, support of The Lymphoma Foundation was cited in this paper.
A second paper that identified support of The Lymphoma Foundation was
published recently in Locus and Breast Cancer Susceptibility." In this paper, we expanded on our discovery of the chromosome 6 locus for cancer susceptibility reported last year in the Proceedings of the National Academy of Sciences and described in last year’s report to the Foundation. In the current study, we have confirmed the significance of this locus, not only in Jewish families with breast cancer, but also in non-Jewish families. Again, the major significance of these findings relates to their stimulating further biologic inquiry into the mechanisms of the particular genes disrupted. Potentially, these genes could serve as targets for cancer prevention.
A third paper that I am including here is a technical paper entitled, "A Rapid and Reliable Test for BRCA1 and BRCA2 Founder Mutation Analysis in Paraffin Tissue Using Pyrosequencing." This paper recognizes the support of the Dannheiser Foundation [contributed via the Lymphoma Foundation] and the Edward Spiegel Memorial Fund [of the Lymphoma Foundation].
This is a technical genetics paper that describes a new method of finding genetic mutations in material embedded in paraffin tissue. As you know, most biopsy specimens from patients taken by pathology departments, is embedded in beeswax (paraffin). In this paper, we have shown that we are able to recover DNA from this material and use it for diagnostic testing. While this paper addresses the use of this technique for determining mutations in the BRCA genes, the method could, in theory, be used for detection of other genetic abnormalities, as well.
Research Findings Not Yet Published As an update to last year’s report, at that time we were very excited about an extremely high association with a particular gene in the TGF signaling pathway. When we repeated the genotyping on an expanded dataset, the findings were considerably weaker, but still significant. This was somewhat disappointing, but such are the realities of scientific research.
On a more promising front, this past summer we have completed our whole genome association study of non-Hodgkin’s lymphoma. This study now involves over two hundred and fifty families, including approximately one-third from our colleague at the Dana-Farber Cancer Institute. These families all have two individuals with a lymphoid cancer in them, either non-Hodgkin’s lymphoma, Hodgkin’s disease, CLL or a plasma cell neoplasm. The genotyping has been completed here in New York and at the Coriell Institute and we are in the process of analyzing that data at the present time. The preliminary findings in these families will be confirmed in a series of fifteen-hundred lymphoma cases and fifteen-hundred normal controls. The pathology specimens for these have been independently reviewed by the Research Assistant working with Dr. Andrew Zelenetz, Chief of the Lymphoma Service, at Memorial SIoan-Kettering Cancer Center. Dr. ZeIenetz will be a collaborator in this study. Once this data is analyzed, it will be submitted this fall to a high impact journal and will constitute one of the first whole genome association studies of non-Hodgkin’s lymphoma. We are very excited about this project, which has been the recipient of considerable funding support from The Lymphoma Foundation, as well as other sources. An effort will also be made over the course of the fall to submit several grants in addition, to generate the approximately $150,000 cost of the second phase replication study of the fifteen-hundred cases and controls mentioned above:
Conclusion The above constitutes a review of activities, papers and projects underway with the support of The Lymphoma Foundation. We continue to be grateful for this ongoing support, which is vital to move research forward in the area of the genetics of lymphoma, as well as the genetics of other malignancies. A key aspect of our work is that any individual cancer, whether lymphoma or breast cancer, offers the genetic clues that will allow the targeted prevention and treatment of all cancers.
Submitted by Chief, Clinical Genetics Service Vice Chairman, Academic Affairs, Department of Medicine, Vice Chairman, Program in Cancer Prevention and Population Research, Memorial SIoan-Kettering Cancer Center; Member, Cancer Biology and Genetics Program (joint), SIoan-Kettering Institute; Professor of Medicine and Public Health, Weill College of Medicine, Cornell University THE FOLLOWING PUBLICATIONS BY DR. KENNETH OFFIT and his research colleagues (2002-2006) ARE A RECORD OF ADDITIONAL INNOVATIVE CLINICAL AND LABORATORY GENETIC RESEARCH SUPPORTED IN PART BY LYMPHOMA FOUNDATION GRANTS
CANCER AND LYMPHOMA GENETICS MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner Bond GL, Hirshfield KM, KirchhoffT, Alexe G, Bond EE, Robins H, Basrtel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ.. Cancer Research 2006,66(10):5104-10 Accuracy of BRCAI and BRCA2 founder mutation analysis in formalin-fixed and paraffin-embedded (FFPE) tissue Adank MA, Brogi E, Bogomolniy F, Wadsworth EA, Lafaro KJ, Yee CJ, KirchhoffT, Meijers-Heijboer EJ, KauffNK, Boyd J, Offit K.. Familial Cancer 2006 (in press) Cancer Genetic Testing and Assisted Reproduction. Offit K, Kohut K, Clagett B, Wadsworth E, Cummings S, White M, Sagi M, Bernstein D, Davis JG. Journal of Clinical Oncology 2006. Electronically published online by the Journal of Clinical Oncology in July, 2006 and was formally published in October 2006
2004-2005 The TP53 Mutational spectrum and frequency of CHEK2* 1100delC in Li Fraumeni-like kindreds Siddiqui, R, Onel K, Facio F, Nafa D, Robles-Diaz R, Kauff N, Huang H, Robson M, Ellis N, Offit K Familial Cancer 2005; 4(2):177-81 Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk. Kaklamani VG, Baddi L, Liu J, Rosman D, Phukan S, Bradley C, Hegarty C, McDaniel B, Rademaker A, Oddoux C, Ostrer H, Michel LS, Huang H, Chen Y, Ahsan H, Offit K, Pasche B. Cancer Research 2005; 65(8):3454-61. Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Gold B, Kalush F, Bergeron J, Scott K, Mitra N, Wilson K, Ellis N, Huang H, Chen M, Lippert R, Halldorsson BV, Woodworth B, White T, Clark AG, Parl FF, Broder S, Dean M, Offit K. Cancer Research 2004; 64:8891-900.
Localization of cancer susceptibility genes by genome-wide
single-nucleotide polymorphism linkage-disequilibrium mapping.
Mitra N, Ye
TZ, Smith A, Chuai S, Kirchhoff T, Peterlongo P, Nafa K, Phillips MS,
Offit K, Ellis NA.
Cancer Research
2004; 64: 8116-25. |
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Hereditary ovarian cancer in Ashkenazi Jews. Robles-Diaz L, Goldfrank D, Kauff N, Robson M, Offit K Familial Cancer 2004; 3:259-64
A636P testing in Ashkenazi Jews. Guillem JG, Moore HG, Palmer, C, Glogowski E,
Finch R, Nafa K, Markowitz AJ, Pleomorphic expression of a germline kit mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Robson ME, Glogowski E, Sommer G, Antonescu CR, Khedoudja N, Maki RG, Ellis N, Besmer P, Brennan M, Offit K. Clinical Cancer Research 2004;10:1250-4.
Functional and
genomic approaches reveal an ancient CHEK2 allele associated with breast
cancer in the Ashkenazi Jewish population.
Shaag A, Walsh T,
Renbaum P, Kirchhoff T, Nafa K, Shiovitz S, Mandell JB, Welcsh P, Lee
MK, Ellis N, Offit K, Levy-Lahad E, King MC. Human Molecular Genetics
2005; 14:555-63 |
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2002-2003 Analysis of Mismatch Repair Defects in the Familial Occurrence of Lymphoma and Colorectal Cancer, Teruya-Feldstein, J., Greene, J., Cohen, L., Popplewell, L., Ellis, N.A., Offit, K., Leukemia and Lymphoma, 2002 Vol. 43 (8), pp. 1619-1626.
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2002-2005 Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk. Kaklamani VG, Baddi L, Liu J, Rosman D, Phukan S, Bradley C, Hegarty C, McDaniel B, Rademaker A, Oddoux C, Ostrer H, Michel LS, Huang H, Chen Y, Ahsan H, Offit K, Pasche B. Cancer Research 2005; 65(8):3454-61. Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Gold B, Kalush F, Bergeron J, Scott K, Mitra N, Wilson K, Ellis N, Huang H, Chen M, Lippert R, Halldorsson BV, Woodworth B, White T, Clark AG, Parl FF, Broder S, Dean M, Offit K. Cancer Research 2004; 64:8891-900. Hereditary ovarian cancer in Ashkenazi Jews. Robles-Diaz L, Goldfrank D, Kauff N, Robson M, Offit K Familial Cancer 2004; 3:259-64 Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Shaag A, Walsh T, Renbaum P, Kirchhoff T, Nafa K, Shiovitz S, Mandell JB, Welcsh P, Lee MK, Ellis N, Offit K, Levy-Lahad E, King MC. Human Molecular Genetics 2005; 14:555-63
Localization of Breast Cancer
Susceptibility Loci by Genome-Wide SNP Linkage Disequilibrium Mapping,
N.A. Ellis, T. Kirchhoff, N. Mitra,
T.-Z. Ye, S. Chuai, H. Huang, K. Nafa, L. Norton, S. Neuhausen, J.P.
Struewing, S. Narod, K. Offit, (in preparation).
Risk-Reducing Salpingo-Oophorectomy in Women with a BRCA1 or BRCA2
Mutation,
Kauff, N.D., Satagopan, J.M., Robson, M.E., Scheuer, L., Hensley, M.,
Hudis, C.A., Ellis, N.A., Boyd, J., Borgen, P.I., Barakat, R.R., Norton,
L., Offit, K., N Engl J Med, Vol. 346 , No. 21 May 23, 2002:
pp 1609-1615. Frequency of CHEK2*1100delC in New York breast cancer cases and controls, K. Offit, H. Pierce, T. Kirchhoff, P. Kolachana, B. Rapaport, P. Gregersen, S. Johnson, O. Yossepowitch, H. Huang, J. Satagopan, M. Robson, L. Scheuer, BMC Medical Genetics, 2003, 4, http://www.biomedcentral.com/1471-2350/4/1.
BRCA1 AND BRCA2 Germline Mutations in Lymphoma Patients, O. Yossepowitch, N. Olvera, J. M. Satagopan, H. Huang, S. Jhanwar, B. Rapaport, J. J. Boyd, K. Offit, Leukemia and Lymphoma, 2003 Vol. 44 (1), pp. 127-131 COLON CANCER and OTHER GASTROINTESTINAL GENETICS
2004
2002-2003
2004-2005 The TP53 Mutational spectrum and frequency of CHEK2* 1100delC in Li Fraumeni-like kindreds Siddiqui, R, Onel K, Facio F, Nafa D, Robles-Diaz R, Kauff N, Huang H, Robson M, Ellis N, Offit K Familial Cancer 2005; 4(2):177-81 The FANCD1/BRCA2*6174DELT Mutation is Rare in Sporadic Pediatric Medulloblastoma, K. Onel, T. Kirchhoff, J.C. Allen, E. Jiminez, K. Offit, (in preparation)
**Dr. Kenneth Offit
is
the Director of the Clinical Genetics
Service at the Memorial Sloan Kettering Cancer Center and author of
Clinical Cancer Genetics
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