Michael  Dean, Ph.D.
Michael Dean, Ph.D.
Senior Investigator
Head, Human Genetics Section
CIP Deputy Program Director

Center for Cancer Research
National Cancer Institute

Building 560, Room 21-18
Frederick, MD 21702-1201
301-846-5931

Our laboratory has sequenced the exome of tumors from the bladder, cervical, kidney, prostate, and adrenal gland. This data has identified a large number of somatic mutations of the genes involved in histone modification and chromatin remodeling.

We have established a pediatric cancers in Guatemala and Nicaragua and identified a significant health disparity in the diagnosis and early diagnosis of cancer among the indigenous Mayan people of Guatemala.

Cervical cancer represents one of the most common cancers in Latin America and we are collecting cancer tissue, blood samples, and data on these cases and performing genome sequencing.

Areas of Expertise
1) genetics 2) genomics 3) molecular biology 4) global health

Genetic Analysis of Complex Diseases

Our laboratory's objective is to develop methods for analyzing complex diseases and to apply them to human genetic conditions, cancer, HIV infection, and other diseases. Resistance of tumors to several drugs (multidrug resistance, or MDR) is a major limitation of cancer chemotherapy. In some tumors, MDR is due to the overexpression of the P-glycoprotein (PGP)/MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of the ATP-binding cassette (ABC) family of transporters. We have characterized the complete set of human ABC genes, bringing the total of human ABC genes to 48 (see the ABC Central Genes Portal for links to all sequences).

One of these genes, ABCG2/MXR, is a multidrug transporter important for resistance to mitoxantrone and other drugs. This gene is also expressed in early stem cells and may protect these cells from damage. Several ABC genes are involved in human genetic disease. ABCA4/ABCR is expressed exclusively in the retina, in rod photoreceptor cells. This gene is responsible for the recessive retinal degeneration syndrome Stargardt disease, and is also mutated in some patients with retinitis pigmentosa and cone-rod dystrophy.

Some parents of Stargardt disease patients have age-related macular degeneration (AMD). AMD is the most common cause of vision loss in the elderly, and we have found that a significant portion of AMD patients have mutations in one allele of the ABCA4/ABCR gene, suggesting that this gene can predispose individuals to AMD.

The ABCG5 and ABCG8 genes are expressed in the intestine and liver and are mutated in patients with the recessive disease sitosterolemia. These patients have defective retention of non-cholesterol sterols and resultant xanthomas, arthritis and hypercholesterolemia. The ABCA3 gene is expressed in type II alveolar cells in the lung and is mutated in many neonates with deficiency in lung surfactants. This is a fatal disorder resulting in respiratory distress at birth. Milder mutations in this gene may give rise to later onset pulmonary diseases.

Cancer. Although some cancers are inherited as a genetic disorder, the vast majority of cancers occur from a complex combination of genetic and environmental factors. To understand the role of estrogens in breast cancer we have characterized variation in the estrogen and progesterone receptor genes. These studies indicate that estrogen receptor variation plays a role in breast cancer. Inflammation is thought to be an important factor in the development of cancer.

One of the body's important defense mechanisms against bacteria and fungi are the complement proteins. By studying variants in one of the complement genes, complement factor H (CFH) we have identified this gene as critical to the development of age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly and is estimated to affect as many as 10 million Americans. AMD is a complex disease, with onset typically ocurring after the age of 65, and the known risk factors include smoking, diet, and age. Women are more often affected by this disease, and it is the leading cause of vision loss in the elderly. There is also strong evidence for a genetic contribution to this disease. We previously identified a role of the ABCA4 gene in AMD, but the contribution of this gene is small. Through the analysis of a rare kidney disease caused by mutations in the CFH gene, it was demonstrated that these people also have an early onset form of AMD. By examining the eight genetic variants in the CFH gene, we found a significant association between these variants and the disease. The most common at-risk genotype was found in 50% of AMD patients and only 29% of controls. We also found an accumulation of the CFH protein in ocular drusen, characteristic deposits associated with the early stages of AMD. The research is a major breakthrough in the understanding of AMD. It suggests an infectious agent might be a critical trigger, and that by identifying the pathogen the disease may be prevented or its progression limited. The complement pathway may also be important in the body's response to other pathogens and irritants associated with cancer. Further study of this important component of innate immunity could lead to insight into human disease.

Cancer Stem Cells. The identification of a small population of self-renewing cells in many solid tumors (cancer stem cells) has opened up new approaches to cancer therapy. We previously cloned the PTCH gene as a tumor suppressor. PTCH is the receptor for Hedgehog (HH) proteins and this pathway is critical to normal stem cell development. HH proteins are overexpressed in many tumor types including pancreas, prostate, gastrointestinal (GI) and small cell lung cancer (SCLC). We have developed new peptide reagents against the SMO protein, a critical signaling molecule for PTCH. These peptides block the growth of several cell lines with HH activation and downregulate HH/PTCH gene and protein expression. The ABCG2 protein is also highly expressed in cancer stem cells and we have completed a screen for new drugs that inhibit this transporter.

Collaborators

Collaborators on our research are Z.Q. Chen, and Julie Sawitzke, SAIC-Frederick; Larry Nogee Johns Hopkins Medical School:, Sam Broder, Celera and Ken Offitt, Memorial Sloan-Ketting; Rando Allikmets, Columbia University; and Greg Hageman, University of Iowa.

Scientific Focus Areas:
Epidemiology, Genetics and Genomics, Health Disparities
  1. Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, Dean M, Huang Y, Jia W, Zhou Q, Tang A, Yang Z, Li X, Song P, Zhao X, Ye R, Zhang S, Lin Z, Qi M, Wan S, Xie L, Fan F, Nickerson ML, Zou X, Hu X, Xing L, Lv Z, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Fang X, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Chen H, Chan HC, Tsang S, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai Z.
    Nat. Genet. 45: 1459-63, 2013. [ Journal Article ]
  2. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N.
    Science. 245: 1059-65, 1989. [ Journal Article ]
  3. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ
    Science. 273: 1856-62, 1996. [ Journal Article ]
  4. Dean M, Fojo T, Bates S.
    Nat. Rev. Cancer. 5: 275-84, 2005. [ Journal Article ]
  5. Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M.
    Cancer Res. 58: 5337-9, 1998. [ Journal Article ]

Dr. Dean obtained his Ph.D. from the Biochemistry Department at the Boston University School of Medicine. He performed his postdoctoral studies at the National Cancer Institute on the MET oncogene and cystic fibrosis gene. He is a member of the American Society of Human Genetics, American Association of Cancer Research, Centre Etude du Polymorphisme Humaine (CEPH), the Human Genome Organization (HUGO), and an adjunct faculty member at Hood College.

Name Position
Lisa Garland Research Assistant (Contr)
Bert Gold, Ph.D., FACMG Staff Scientist
Maria Rodriguez Herrera Summer Student
Gabriela Mimendi Special Volunteer
Karobi Moitra Ph.D Guest Researcher
Michael L. Nickerson, Ph.D. Staff Scientist
Julie Sawitzke Research Assistant (Contr)
Shirley Tsang Guest Researcher
Sevilay Turan Postbaccalaureate Fellow

Summary

Our laboratory has sequenced the exome of tumors from the bladder, cervical, kidney, prostate, and adrenal gland. This data has identified a large number of somatic mutations of the genes involved in histone modification and chromatin remodeling.

We have established a pediatric cancers in Guatemala and Nicaragua and identified a significant health disparity in the diagnosis and early diagnosis of cancer among the indigenous Mayan people of Guatemala.

Cervical cancer represents one of the most common cancers in Latin America and we are collecting cancer tissue, blood samples, and data on these cases and performing genome sequencing.

Areas of Expertise
1) genetics 2) genomics 3) molecular biology 4) global health

Research

Genetic Analysis of Complex Diseases

Our laboratory's objective is to develop methods for analyzing complex diseases and to apply them to human genetic conditions, cancer, HIV infection, and other diseases. Resistance of tumors to several drugs (multidrug resistance, or MDR) is a major limitation of cancer chemotherapy. In some tumors, MDR is due to the overexpression of the P-glycoprotein (PGP)/MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of the ATP-binding cassette (ABC) family of transporters. We have characterized the complete set of human ABC genes, bringing the total of human ABC genes to 48 (see the ABC Central Genes Portal for links to all sequences).

One of these genes, ABCG2/MXR, is a multidrug transporter important for resistance to mitoxantrone and other drugs. This gene is also expressed in early stem cells and may protect these cells from damage. Several ABC genes are involved in human genetic disease. ABCA4/ABCR is expressed exclusively in the retina, in rod photoreceptor cells. This gene is responsible for the recessive retinal degeneration syndrome Stargardt disease, and is also mutated in some patients with retinitis pigmentosa and cone-rod dystrophy.

Some parents of Stargardt disease patients have age-related macular degeneration (AMD). AMD is the most common cause of vision loss in the elderly, and we have found that a significant portion of AMD patients have mutations in one allele of the ABCA4/ABCR gene, suggesting that this gene can predispose individuals to AMD.

The ABCG5 and ABCG8 genes are expressed in the intestine and liver and are mutated in patients with the recessive disease sitosterolemia. These patients have defective retention of non-cholesterol sterols and resultant xanthomas, arthritis and hypercholesterolemia. The ABCA3 gene is expressed in type II alveolar cells in the lung and is mutated in many neonates with deficiency in lung surfactants. This is a fatal disorder resulting in respiratory distress at birth. Milder mutations in this gene may give rise to later onset pulmonary diseases.

Cancer. Although some cancers are inherited as a genetic disorder, the vast majority of cancers occur from a complex combination of genetic and environmental factors. To understand the role of estrogens in breast cancer we have characterized variation in the estrogen and progesterone receptor genes. These studies indicate that estrogen receptor variation plays a role in breast cancer. Inflammation is thought to be an important factor in the development of cancer.

One of the body's important defense mechanisms against bacteria and fungi are the complement proteins. By studying variants in one of the complement genes, complement factor H (CFH) we have identified this gene as critical to the development of age-related macular degeneration (AMD). AMD is the leading cause of blindness in the elderly and is estimated to affect as many as 10 million Americans. AMD is a complex disease, with onset typically ocurring after the age of 65, and the known risk factors include smoking, diet, and age. Women are more often affected by this disease, and it is the leading cause of vision loss in the elderly. There is also strong evidence for a genetic contribution to this disease. We previously identified a role of the ABCA4 gene in AMD, but the contribution of this gene is small. Through the analysis of a rare kidney disease caused by mutations in the CFH gene, it was demonstrated that these people also have an early onset form of AMD. By examining the eight genetic variants in the CFH gene, we found a significant association between these variants and the disease. The most common at-risk genotype was found in 50% of AMD patients and only 29% of controls. We also found an accumulation of the CFH protein in ocular drusen, characteristic deposits associated with the early stages of AMD. The research is a major breakthrough in the understanding of AMD. It suggests an infectious agent might be a critical trigger, and that by identifying the pathogen the disease may be prevented or its progression limited. The complement pathway may also be important in the body's response to other pathogens and irritants associated with cancer. Further study of this important component of innate immunity could lead to insight into human disease.

Cancer Stem Cells. The identification of a small population of self-renewing cells in many solid tumors (cancer stem cells) has opened up new approaches to cancer therapy. We previously cloned the PTCH gene as a tumor suppressor. PTCH is the receptor for Hedgehog (HH) proteins and this pathway is critical to normal stem cell development. HH proteins are overexpressed in many tumor types including pancreas, prostate, gastrointestinal (GI) and small cell lung cancer (SCLC). We have developed new peptide reagents against the SMO protein, a critical signaling molecule for PTCH. These peptides block the growth of several cell lines with HH activation and downregulate HH/PTCH gene and protein expression. The ABCG2 protein is also highly expressed in cancer stem cells and we have completed a screen for new drugs that inhibit this transporter.

Collaborators

Collaborators on our research are Z.Q. Chen, and Julie Sawitzke, SAIC-Frederick; Larry Nogee Johns Hopkins Medical School:, Sam Broder, Celera and Ken Offitt, Memorial Sloan-Ketting; Rando Allikmets, Columbia University; and Greg Hageman, University of Iowa.

Scientific Focus Areas:
Epidemiology, Genetics and Genomics, Health Disparities

Publications

  1. Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, Dean M, Huang Y, Jia W, Zhou Q, Tang A, Yang Z, Li X, Song P, Zhao X, Ye R, Zhang S, Lin Z, Qi M, Wan S, Xie L, Fan F, Nickerson ML, Zou X, Hu X, Xing L, Lv Z, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Fang X, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Chen H, Chan HC, Tsang S, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai Z.
    Nat. Genet. 45: 1459-63, 2013. [ Journal Article ]
  2. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N.
    Science. 245: 1059-65, 1989. [ Journal Article ]
  3. Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JJ, Buchbinder SP, Vittinghoff E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah A, Rinaldo C, Detels R, O'Brien SJ
    Science. 273: 1856-62, 1996. [ Journal Article ]
  4. Dean M, Fojo T, Bates S.
    Nat. Rev. Cancer. 5: 275-84, 2005. [ Journal Article ]
  5. Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M.
    Cancer Res. 58: 5337-9, 1998. [ Journal Article ]

Biography

Dr. Dean obtained his Ph.D. from the Biochemistry Department at the Boston University School of Medicine. He performed his postdoctoral studies at the National Cancer Institute on the MET oncogene and cystic fibrosis gene. He is a member of the American Society of Human Genetics, American Association of Cancer Research, Centre Etude du Polymorphisme Humaine (CEPH), the Human Genome Organization (HUGO), and an adjunct faculty member at Hood College.

Team

Name Position
Lisa Garland Research Assistant (Contr)
Bert Gold, Ph.D., FACMG Staff Scientist
Maria Rodriguez Herrera Summer Student
Gabriela Mimendi Special Volunteer
Karobi Moitra Ph.D Guest Researcher
Michael L. Nickerson, Ph.D. Staff Scientist
Julie Sawitzke Research Assistant (Contr)
Shirley Tsang Guest Researcher
Sevilay Turan Postbaccalaureate Fellow