Michael L. Nickerson, Ph.D.
Michael L. Nickerson, Ph.D.
Staff Scientist

Center for Cancer Research
National Cancer Institute

Building 560, Room 21-21
Frederick, MD 21702-1201
301-846-6973

My goal is to comprehensively identify clinically relevant variations that are associated with the cancer genome and develop clinical biomarkers that improve the diagnosis and treatment of cancer. I am working to define the clinical cancer genome (i.e., the genetic basis of sporadic and inherited cancer) that applies to the largest numbers of patients and the most severe disease. The molecular genetics assays I have developed have been used in research studies and clinical trials. By defining clear associations between genetic variation, a specific aspect of the disease phenotype, and patient treatment, we identify high-value biomarkers for rigorous translational development.

Areas of Expertise
1) cancer genes, 2) clinical cancer genomics, 3) urologic cancer, 4) GWAS and clinical trials, 5) translational biochemistry

Molecular Genetics Characterization of Cancer Genes

Studies of cancer families

My current primary focus is to study the molecular genetics of cancer genes to identify clinical biomarkers of disease and response to therapy. This is derived, in part, from my training that includes studies of familial cancer to discover new cancer genes using positional cloning. These were conducted in the laboratory of Dr. Berton Zbar, National Cancer Institute (NCI) (1998 – 2004). My studies emphasized somatic cancer gene alterations from 2004 to the present, including characterizing associations between mutations and clinical biomarkers, tumor pathology, environmental exposure, and therapeutic response in clinical trials. Studies of families with inherited cancer were successful and allowed me to discover and characterize novel cancer genes, including the Birt-Hogg-Dubé (BHD), fumarate hydratase, and MET genes in kidney cancer; and the Dead-end gene in testicular cancer. I led positional cloning efforts to identify mutations in the Ubi A-domain 1 (UBIAD1) gene in families with Schnyder cornea dystrophy (SCD). Working with Dr. Jayne Weis, Louisiana State University, we have identified 23 different UBIAD1 mutations in over 50 SCD families in seven publications (2007 – 2013). In all these studies, I developed the PCR and sequencing methods to thoroughly examine these genes.

Translational research subsequent to these cancer gene discoveries has identified inherited cancer gene mutations in animals, which are currently being developed as animal models for the treatment of testicular germ cell cancer and chromophobe kidney cancer. We identified the binding partners and signaling pathways of cancer proteins in SCD and chromophobe kidney cancer. For example, with collaborators from Myriad Genetics and Leidos, I led efforts to demonstrate an interaction between UBIAD1 and HMGCR, the rate-limiting enzyme in cholesterol synthesis. Molecular modeling studies of phenolic ligands that were conducted with researchers in Germany predicted cholesterol binding to UBIAD1 and suggested HMGCR inhibitors, such as statins, might be effective to treat SCD. Canines with an SCD-like condition are currently being analyzed by genome sequencing as potential animal models.

Studies of somatic alterations in tumors

My focus shifted to characterizing somatic cancer gene mutations in 2004 when I became the Director of a commercial molecular genetics laboratory at Transgenomic, Inc. My international efforts were to work with large biopharmaceutical companies to apply molecular genetics to analyze patient samples in clinical trials. In part, my efforts resulted in two large contracts of almost $1 million to characterize somatic alterations in the EGFR and KRAS genes in patient tumors from Genentech-sponsored clinical trials of targeted therapeutics in non-small cell lung cancer. The mutations were used to stratify patients and identify clinical biomarkers associated with a favorable response to the therapy.

I led studies to characterize somatic mutations in the von Hippel-Lindau (VHL) gene in >300 primary clear cell kidney cancer (ccRCC) tumors in 2008. Using highly sensitive methods that I developed (and approximately twice the effort!), DCEG collaborator, Dr. Lee Moore, and I detected sequence alterations in 84% of tumors. This study provided seminal insight on the high degree of genetic heterogeneity since confirmed in these tumors. We were the first to show that tumors with somatic VHL sequence alterations were distinct from tumors displaying hypermethylation of the VHL gene promoter, an observation that has been subsequently confirmed by multiple studies.

I have recently applied next generation sequencing (NGS) to characterize urologic cancer genes and have authored or co-authored 10 NGS studies (2011 – 2014) of bladder (BCa), prostate (PCa), and kidney cancer (RCC) with collaborators from the Division of Cancer Epidemiology and Genetics (DCEG), NCI; Urologic Oncology Branch (UOB), NCI; Johns Hopkins University (JHU); University of Colorado (UC); Louisiana State University; and the Beijing Genomics Institute (BGI). These studies resulted in publications in Nature Genetics (two studies), the Journal of the National Cancer Institute, Oncogenesis, PLoS Genetics, Clinical Cancer Research, and Genome Biology

Building on experience gained by working in industry, I catalyzed collaboration between NCI, UC, and BGI and we were the first to identify frequent somatic mutations in STAG2 and BAP1 in BCa. We identified novel genetic alterations associated with BCa phenotypes, such as chromosomal alterations due, in part, to defective sister chromatid separation in STAG2-mutant tumors. Somatic BAP1 alterations correlated with papillary tumor histology and contributed to a high frequency of BRCA pathway alterations. We were first to report an unexpected number and distribution of 20 (19 were novel) germline TERT promoter variants in addition to somatic TERT promoter variants in 69% of 54 BCa tumors, and we identified TERT as the most frequently altered BCa gene.

In an NGS study of PCa with collaborators at the Johns Hopkins University and the NCI Urologic Oncology Branch, I investigated the accumulation of somatic alterations that arose during progression of PCa in a first index patient, and this study uncovered germline and somatic cancer gene alterations contributing to PCa. We discovered six alterations in four cancer genes that arose at different times during the course of disease. The patient inherited a deleterious, germline BRCA1 allele known to be associated with cancer, p.E23Rfs (rs11571833). Significantly, the remaining wild-type allele was lost in all of the metastatic tumors, and metastatic PCa cells were homozygous for the mutation and BRCA1-null. Copy number analysis of NGS allowed us to detect a somatic deletion that resulted in the expression of a TMPRSS2-ERG fusion protein in the primary tumors. Finally, somatic variants introduced missense mutations in genes encoding two chromatin- and epigenetic-associated proteins, polybromo 1 (PBRM1) and the ten-eleven translocation 2 (TET2). The somatic PBRM1 alteration was detected in the primary tumor and all metastatic tumors. The somatic TET2 mutation was of interest as it was absent from the primary tumor yet was observed in all metastatic tumors (n = 11), indicating the alteration coincided with early stages of metastatic disease. We sequenced PBRM1 and TET2 using metastatic PCa tumor DNA from 29 additional patients and observed additional somatic alterations only in TET2. TET2 was altered by three somatic sequence variants introducing missense substitutions (3/30, 10%), including a catalytic domain alteration; by somatic copy number loss in 41% of tumors (array CGH confirmed by homozygosity in SNP arrays); and by 21 different combinations of 15 germline variants causing missense substitutions and altering a splice junction. Translational studies of TET2 function are currently underway and, with researchers from the Leidos, NCI DCEG, and the NCI Cancer and Inflammation Program, we have identified binding partners indicating TET2 has a key role in regulating gene expression stimulated by androgen signaling through the androgen receptor.

Translational genetics studies of cancer genes

The cancer gene discoveries described above have immediate translational value and I have begun to work with collaborators to develop clinical biomarkers. We have identified frequently altered cancer genes in various tissues of interest, including kidney, prostate, bladder, and colon, from my own and published NGS studies of tumors. I have designed multiplexed PCR panels that will amplify the coding regions, splice junctions, and noncoding regulatory regions of these genes for NGS. Drs. Lee Moore, Meredith Yeager, and I have analyzed >300 ccRCC tumors with a 10 gene panel that includes VHL, BAP1, and PBRM1.   We have confirmed the ten genes are frequently altered in ccRCC and are examining gene-gene interactions and associations of gene alterations with pathologic, exposure, response to therapey, and survival data. I designed a larger colon cancer ~40 gene panel that includes 10 microsatellite markers. We recently developed a program to analyze NGS data for microsatellite instability and have successfully analyzed 92 NCI DCEG tumor-normal pairs and a tumor-normal sample panel from the Howard University Cancer Center. These studies will identify altered genes in Caucasian and African American colon cancer that drive specific aspects of the complex cancer phenotype and these genes will be analyzed in even larger studies to confirm their significant roles in cancer and the clinic. 

Clinical trials incorporating molecular cancer genetics

The ultimate translational outcome of the cancer gene discoveries that are described above is to identify genetic biomarkers that can be developed as companion biomarkers for use in clinical trials. In collaboration with many clinicians and researchers, I have developed molecular genetics assays that have been/are being used in three clinical trials. The goals of these studies are to show that high sensitivity characterization of altered cancer genes will identify lethal and benign subtypes of disease, and patients that respond or do not respond to a specific therapy.

1) A Study to Evaluate the Efficacy of Bevacizumab in Combination With Tarceva for Advanced Non-Small Cell Lung Cancer. Study Director: Paula O'Connor, M.D., Genentech.

Molecular genetics analysis in a Genentech-sponsored clinical trial, protocol OSI3364g. Mutation detection in EGFR and KRAS in ~550 non-small cell lung cancer tumors from patients treated with bevacizumab (Avastin) or tarceva (Erlotinib). ClinicalTrials.gov Identifier: NCT00130728

2) A Study Comparing Bevacizumab Therapy With or Without Erlotinib for First-Line Treatment of Non-Small Cell Lung Cancer (ATLAS). Study Director: Donald Strickland, M.D., Genentech.

Molecular genetics analysis in a Genentech-sponsored clinical trial, protocol AVF3671g. Mutation detection in EGFR and KRAS in ~650 non-small cell lung cancer tumors from patients treated with Avastin or Erlotinib. ClinicalTrials.gov Identifier: NCT00257608

3) Molecular genetics analysis of 10 kidney cancer genes in ~350 ccRCC tumors from patients treated with Avastin, in collaboration with the NCI DCEG, Cancer and Leukemia Group B, and Dr. Phil Febbo, M.D., University of California San Francisco, Chief Scientific Officer, Genomic Health.

 

Scientific Focus Areas:
Cancer Biology, Cell Biology, Chromosome Biology, Genetics and Genomics, Molecular Biology and Biochemistry
Selected Publications
  1. Nickerson ML, Dancik GM, Im KM, Edwards MG, Turan S, Brown J, Ruiz-Rodriguez C, Owens C, Costello JC, Guo G, Tsang SX, Li Y, Zhou Q, Cai Z, Moore LE, Lucia MS, Dean M, Theodorescu D.
    Clin Cancer Res. 20(18): 4935-48, 2014. [ Journal Article ]
  2. Ashktorab H, Daremipouran M, Devaney J, Varma S, Rahi H, Lee E, Shokrani B, Schwartz R, Nickerson ML, Brim H.
    Cancer. [Epub ahead of print], 2014. [ Journal Article ]
  3. Nickerson ML, Im KM, Misner KJ, Tan W, Lou H, Gold B, Wells DW, Bravo HC, Fredrikson KM, Harkins TT, Milos P, Zbar B, Linehan WM, Yeager M, Andresson T, Dean M, Bova GS.
    Hum Mutat. 34(9): 1231-41, 2013. [ Journal Article ]
  4. Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, 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, Dean M, Zou X, Hu X, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai, Z.
    Nat Genet. 45(12): 1459-63, 2013. [ Journal Article ]
  5. Nickerson ML, Bosley AD, Weiss JS, Kostiha BN, Hirota Y, Brandt W, Esposito D, Kinoshita S, Wessjohann L, Morham SG, Andresson T, Kruth HS, Okano T, Dean M.
    Hum Mutat. 34: 317-29, 2013. [ Journal Article ]

Dr. Nickerson obtained a Bachelor’s degree in biology from the St. Mary’s College of Maryland, a Master’s degree in biochemistry from the State University of New York at Stony Brook, and a Ph.D. in molecular medicine from the George Washington University, one of the top medical schools in the U.S. He received training in cancer genetics and cancer gene discovery through studies of families with inherited clear cell, papillary, and chromophobe kidney cancer in the laboratory of Dr. Berton Zbar, M.D., at the National Cancer Institute in Frederick, MD. He gained critical experience in the biotech industry as Director of the Genome Research Division at Transgenomic, Inc., a commercial clinical cancer genetics testing laboratory. Dr. Nickerson is currently a staff scientist in the laboratory of Dr. Michael Dean in the Cancer and Inflammation Program at the National Cancer Institute in Frederick, MD. 

Dr. Nickerson has made significant contributions to the identification and characterization of disease genes. He is first author of a seminal paper that identifies mutations in the Birt-Hogg-Dubé (BHD) gene in patients with Birt-Hogg-Dubé Syndrome. The altered BHD gene has been implicated in families with inherited pneumothorax, chromophobe kidney cancer, and fibrofolliculomas, which are benign growths of hair follicles. Dr. Nickerson co-authored papers describing BHD mutations in important animal models of disease, Nihon rats with kidney cancer and canines with renal cystadenoma and nodular dermatofibrosis. He co-authored discoveries describing mutations in the dead-end gene in the ‘Ter’ (teratoma) mouse model of testicular cancer, and mutations in the fumarate hydratase gene in leiomyomatosis and papillary kidney cancer. Using positional cloning, he identified mutations in the UBIAD1 gene in patients with Schnyder Corneal Dystrophy (SCD) and published a series of seven translational papers describing mutations in over 50 SCD families, UBIAD1 protein structure and function, and UBIAD1 binding partners. 

Key to these discoveries was the development of high throughput and sensitive mutation detection methods. In addition to applying these methods to studies of families with inherited disease, Dr. Nickerson has successfully refined them to characterize somatic alterations in the von Hippel-Lindau gene in kidney tumors as part of an international epidemiology study, and to characterize KRAS and EGFR mutations in lung tumors from patients in clinical trials. Mutations in KRAS and EGFR were correlated with a significant response to a targeted therapy, Avastin, in phase III clinical trials sponsored by Genentech.  He was an early adopter of Next Generation Sequencing and Dr. Nickerson has performed whole genome, transcriptome, and exome sequencing of urologic tumors using Illumina, 454, SOLiD, Helicos, PacBio, and Ion Torrent platforms.  These studies have resulted in the identification of frequently mutated cancer genes in prostate (TET2), bladder (BAP1, TERT, and BRCA pathway genes), and kidney cancers that are involved in creating, sensing, and erasing DNA and chromatin epigenetic modifications.  Current efforts include correlating somatic mutations with patient lifestyle and exposure, clinical measures of disease, gene-gene interactions, and response to therapy. These efforts aim to improve our understanding and treatment of cancer, and link cancer gene mutations to patient response to treatment.

Summary

My goal is to comprehensively identify clinically relevant variations that are associated with the cancer genome and develop clinical biomarkers that improve the diagnosis and treatment of cancer. I am working to define the clinical cancer genome (i.e., the genetic basis of sporadic and inherited cancer) that applies to the largest numbers of patients and the most severe disease. The molecular genetics assays I have developed have been used in research studies and clinical trials. By defining clear associations between genetic variation, a specific aspect of the disease phenotype, and patient treatment, we identify high-value biomarkers for rigorous translational development.

Areas of Expertise
1) cancer genes, 2) clinical cancer genomics, 3) urologic cancer, 4) GWAS and clinical trials, 5) translational biochemistry

Research

Molecular Genetics Characterization of Cancer Genes

Studies of cancer families

My current primary focus is to study the molecular genetics of cancer genes to identify clinical biomarkers of disease and response to therapy. This is derived, in part, from my training that includes studies of familial cancer to discover new cancer genes using positional cloning. These were conducted in the laboratory of Dr. Berton Zbar, National Cancer Institute (NCI) (1998 – 2004). My studies emphasized somatic cancer gene alterations from 2004 to the present, including characterizing associations between mutations and clinical biomarkers, tumor pathology, environmental exposure, and therapeutic response in clinical trials. Studies of families with inherited cancer were successful and allowed me to discover and characterize novel cancer genes, including the Birt-Hogg-Dubé (BHD), fumarate hydratase, and MET genes in kidney cancer; and the Dead-end gene in testicular cancer. I led positional cloning efforts to identify mutations in the Ubi A-domain 1 (UBIAD1) gene in families with Schnyder cornea dystrophy (SCD). Working with Dr. Jayne Weis, Louisiana State University, we have identified 23 different UBIAD1 mutations in over 50 SCD families in seven publications (2007 – 2013). In all these studies, I developed the PCR and sequencing methods to thoroughly examine these genes.

Translational research subsequent to these cancer gene discoveries has identified inherited cancer gene mutations in animals, which are currently being developed as animal models for the treatment of testicular germ cell cancer and chromophobe kidney cancer. We identified the binding partners and signaling pathways of cancer proteins in SCD and chromophobe kidney cancer. For example, with collaborators from Myriad Genetics and Leidos, I led efforts to demonstrate an interaction between UBIAD1 and HMGCR, the rate-limiting enzyme in cholesterol synthesis. Molecular modeling studies of phenolic ligands that were conducted with researchers in Germany predicted cholesterol binding to UBIAD1 and suggested HMGCR inhibitors, such as statins, might be effective to treat SCD. Canines with an SCD-like condition are currently being analyzed by genome sequencing as potential animal models.

Studies of somatic alterations in tumors

My focus shifted to characterizing somatic cancer gene mutations in 2004 when I became the Director of a commercial molecular genetics laboratory at Transgenomic, Inc. My international efforts were to work with large biopharmaceutical companies to apply molecular genetics to analyze patient samples in clinical trials. In part, my efforts resulted in two large contracts of almost $1 million to characterize somatic alterations in the EGFR and KRAS genes in patient tumors from Genentech-sponsored clinical trials of targeted therapeutics in non-small cell lung cancer. The mutations were used to stratify patients and identify clinical biomarkers associated with a favorable response to the therapy.

I led studies to characterize somatic mutations in the von Hippel-Lindau (VHL) gene in >300 primary clear cell kidney cancer (ccRCC) tumors in 2008. Using highly sensitive methods that I developed (and approximately twice the effort!), DCEG collaborator, Dr. Lee Moore, and I detected sequence alterations in 84% of tumors. This study provided seminal insight on the high degree of genetic heterogeneity since confirmed in these tumors. We were the first to show that tumors with somatic VHL sequence alterations were distinct from tumors displaying hypermethylation of the VHL gene promoter, an observation that has been subsequently confirmed by multiple studies.

I have recently applied next generation sequencing (NGS) to characterize urologic cancer genes and have authored or co-authored 10 NGS studies (2011 – 2014) of bladder (BCa), prostate (PCa), and kidney cancer (RCC) with collaborators from the Division of Cancer Epidemiology and Genetics (DCEG), NCI; Urologic Oncology Branch (UOB), NCI; Johns Hopkins University (JHU); University of Colorado (UC); Louisiana State University; and the Beijing Genomics Institute (BGI). These studies resulted in publications in Nature Genetics (two studies), the Journal of the National Cancer Institute, Oncogenesis, PLoS Genetics, Clinical Cancer Research, and Genome Biology

Building on experience gained by working in industry, I catalyzed collaboration between NCI, UC, and BGI and we were the first to identify frequent somatic mutations in STAG2 and BAP1 in BCa. We identified novel genetic alterations associated with BCa phenotypes, such as chromosomal alterations due, in part, to defective sister chromatid separation in STAG2-mutant tumors. Somatic BAP1 alterations correlated with papillary tumor histology and contributed to a high frequency of BRCA pathway alterations. We were first to report an unexpected number and distribution of 20 (19 were novel) germline TERT promoter variants in addition to somatic TERT promoter variants in 69% of 54 BCa tumors, and we identified TERT as the most frequently altered BCa gene.

In an NGS study of PCa with collaborators at the Johns Hopkins University and the NCI Urologic Oncology Branch, I investigated the accumulation of somatic alterations that arose during progression of PCa in a first index patient, and this study uncovered germline and somatic cancer gene alterations contributing to PCa. We discovered six alterations in four cancer genes that arose at different times during the course of disease. The patient inherited a deleterious, germline BRCA1 allele known to be associated with cancer, p.E23Rfs (rs11571833). Significantly, the remaining wild-type allele was lost in all of the metastatic tumors, and metastatic PCa cells were homozygous for the mutation and BRCA1-null. Copy number analysis of NGS allowed us to detect a somatic deletion that resulted in the expression of a TMPRSS2-ERG fusion protein in the primary tumors. Finally, somatic variants introduced missense mutations in genes encoding two chromatin- and epigenetic-associated proteins, polybromo 1 (PBRM1) and the ten-eleven translocation 2 (TET2). The somatic PBRM1 alteration was detected in the primary tumor and all metastatic tumors. The somatic TET2 mutation was of interest as it was absent from the primary tumor yet was observed in all metastatic tumors (n = 11), indicating the alteration coincided with early stages of metastatic disease. We sequenced PBRM1 and TET2 using metastatic PCa tumor DNA from 29 additional patients and observed additional somatic alterations only in TET2. TET2 was altered by three somatic sequence variants introducing missense substitutions (3/30, 10%), including a catalytic domain alteration; by somatic copy number loss in 41% of tumors (array CGH confirmed by homozygosity in SNP arrays); and by 21 different combinations of 15 germline variants causing missense substitutions and altering a splice junction. Translational studies of TET2 function are currently underway and, with researchers from the Leidos, NCI DCEG, and the NCI Cancer and Inflammation Program, we have identified binding partners indicating TET2 has a key role in regulating gene expression stimulated by androgen signaling through the androgen receptor.

Translational genetics studies of cancer genes

The cancer gene discoveries described above have immediate translational value and I have begun to work with collaborators to develop clinical biomarkers. We have identified frequently altered cancer genes in various tissues of interest, including kidney, prostate, bladder, and colon, from my own and published NGS studies of tumors. I have designed multiplexed PCR panels that will amplify the coding regions, splice junctions, and noncoding regulatory regions of these genes for NGS. Drs. Lee Moore, Meredith Yeager, and I have analyzed >300 ccRCC tumors with a 10 gene panel that includes VHL, BAP1, and PBRM1.   We have confirmed the ten genes are frequently altered in ccRCC and are examining gene-gene interactions and associations of gene alterations with pathologic, exposure, response to therapey, and survival data. I designed a larger colon cancer ~40 gene panel that includes 10 microsatellite markers. We recently developed a program to analyze NGS data for microsatellite instability and have successfully analyzed 92 NCI DCEG tumor-normal pairs and a tumor-normal sample panel from the Howard University Cancer Center. These studies will identify altered genes in Caucasian and African American colon cancer that drive specific aspects of the complex cancer phenotype and these genes will be analyzed in even larger studies to confirm their significant roles in cancer and the clinic. 

Clinical trials incorporating molecular cancer genetics

The ultimate translational outcome of the cancer gene discoveries that are described above is to identify genetic biomarkers that can be developed as companion biomarkers for use in clinical trials. In collaboration with many clinicians and researchers, I have developed molecular genetics assays that have been/are being used in three clinical trials. The goals of these studies are to show that high sensitivity characterization of altered cancer genes will identify lethal and benign subtypes of disease, and patients that respond or do not respond to a specific therapy.

1) A Study to Evaluate the Efficacy of Bevacizumab in Combination With Tarceva for Advanced Non-Small Cell Lung Cancer. Study Director: Paula O'Connor, M.D., Genentech.

Molecular genetics analysis in a Genentech-sponsored clinical trial, protocol OSI3364g. Mutation detection in EGFR and KRAS in ~550 non-small cell lung cancer tumors from patients treated with bevacizumab (Avastin) or tarceva (Erlotinib). ClinicalTrials.gov Identifier: NCT00130728

2) A Study Comparing Bevacizumab Therapy With or Without Erlotinib for First-Line Treatment of Non-Small Cell Lung Cancer (ATLAS). Study Director: Donald Strickland, M.D., Genentech.

Molecular genetics analysis in a Genentech-sponsored clinical trial, protocol AVF3671g. Mutation detection in EGFR and KRAS in ~650 non-small cell lung cancer tumors from patients treated with Avastin or Erlotinib. ClinicalTrials.gov Identifier: NCT00257608

3) Molecular genetics analysis of 10 kidney cancer genes in ~350 ccRCC tumors from patients treated with Avastin, in collaboration with the NCI DCEG, Cancer and Leukemia Group B, and Dr. Phil Febbo, M.D., University of California San Francisco, Chief Scientific Officer, Genomic Health.

 

Scientific Focus Areas:
Cancer Biology, Cell Biology, Chromosome Biology, Genetics and Genomics, Molecular Biology and Biochemistry

Publications

Selected Publications
  1. Nickerson ML, Dancik GM, Im KM, Edwards MG, Turan S, Brown J, Ruiz-Rodriguez C, Owens C, Costello JC, Guo G, Tsang SX, Li Y, Zhou Q, Cai Z, Moore LE, Lucia MS, Dean M, Theodorescu D.
    Clin Cancer Res. 20(18): 4935-48, 2014. [ Journal Article ]
  2. Ashktorab H, Daremipouran M, Devaney J, Varma S, Rahi H, Lee E, Shokrani B, Schwartz R, Nickerson ML, Brim H.
    Cancer. [Epub ahead of print], 2014. [ Journal Article ]
  3. Nickerson ML, Im KM, Misner KJ, Tan W, Lou H, Gold B, Wells DW, Bravo HC, Fredrikson KM, Harkins TT, Milos P, Zbar B, Linehan WM, Yeager M, Andresson T, Dean M, Bova GS.
    Hum Mutat. 34(9): 1231-41, 2013. [ Journal Article ]
  4. Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, 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, Dean M, Zou X, Hu X, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai, Z.
    Nat Genet. 45(12): 1459-63, 2013. [ Journal Article ]
  5. Nickerson ML, Bosley AD, Weiss JS, Kostiha BN, Hirota Y, Brandt W, Esposito D, Kinoshita S, Wessjohann L, Morham SG, Andresson T, Kruth HS, Okano T, Dean M.
    Hum Mutat. 34: 317-29, 2013. [ Journal Article ]

Biography

Dr. Nickerson obtained a Bachelor’s degree in biology from the St. Mary’s College of Maryland, a Master’s degree in biochemistry from the State University of New York at Stony Brook, and a Ph.D. in molecular medicine from the George Washington University, one of the top medical schools in the U.S. He received training in cancer genetics and cancer gene discovery through studies of families with inherited clear cell, papillary, and chromophobe kidney cancer in the laboratory of Dr. Berton Zbar, M.D., at the National Cancer Institute in Frederick, MD. He gained critical experience in the biotech industry as Director of the Genome Research Division at Transgenomic, Inc., a commercial clinical cancer genetics testing laboratory. Dr. Nickerson is currently a staff scientist in the laboratory of Dr. Michael Dean in the Cancer and Inflammation Program at the National Cancer Institute in Frederick, MD. 

Dr. Nickerson has made significant contributions to the identification and characterization of disease genes. He is first author of a seminal paper that identifies mutations in the Birt-Hogg-Dubé (BHD) gene in patients with Birt-Hogg-Dubé Syndrome. The altered BHD gene has been implicated in families with inherited pneumothorax, chromophobe kidney cancer, and fibrofolliculomas, which are benign growths of hair follicles. Dr. Nickerson co-authored papers describing BHD mutations in important animal models of disease, Nihon rats with kidney cancer and canines with renal cystadenoma and nodular dermatofibrosis. He co-authored discoveries describing mutations in the dead-end gene in the ‘Ter’ (teratoma) mouse model of testicular cancer, and mutations in the fumarate hydratase gene in leiomyomatosis and papillary kidney cancer. Using positional cloning, he identified mutations in the UBIAD1 gene in patients with Schnyder Corneal Dystrophy (SCD) and published a series of seven translational papers describing mutations in over 50 SCD families, UBIAD1 protein structure and function, and UBIAD1 binding partners. 

Key to these discoveries was the development of high throughput and sensitive mutation detection methods. In addition to applying these methods to studies of families with inherited disease, Dr. Nickerson has successfully refined them to characterize somatic alterations in the von Hippel-Lindau gene in kidney tumors as part of an international epidemiology study, and to characterize KRAS and EGFR mutations in lung tumors from patients in clinical trials. Mutations in KRAS and EGFR were correlated with a significant response to a targeted therapy, Avastin, in phase III clinical trials sponsored by Genentech.  He was an early adopter of Next Generation Sequencing and Dr. Nickerson has performed whole genome, transcriptome, and exome sequencing of urologic tumors using Illumina, 454, SOLiD, Helicos, PacBio, and Ion Torrent platforms.  These studies have resulted in the identification of frequently mutated cancer genes in prostate (TET2), bladder (BAP1, TERT, and BRCA pathway genes), and kidney cancers that are involved in creating, sensing, and erasing DNA and chromatin epigenetic modifications.  Current efforts include correlating somatic mutations with patient lifestyle and exposure, clinical measures of disease, gene-gene interactions, and response to therapy. These efforts aim to improve our understanding and treatment of cancer, and link cancer gene mutations to patient response to treatment.