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Articles by M. R Spitz
Total Records ( 4 ) for M. R Spitz
  X Wu , M. R Spitz , J. J Lee , S. M Lippman , Y Ye , H Yang , F. R Khuri , E Kim , J Gu , R Lotan and W. K. Hong
 

This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early-stage head and neck squamous cell carcinoma (HNSCC) patients.

We constructed a custom chip containing a comprehensive panel of 9,645 chromosomal and mitochondrial single nucleotide polymorphisms (SNP) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.

Individually, six chromosomal SNPs and seven mitochondrial SNPs were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed when these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00 x 10–20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables.

This is the first large-scale systematic evaluation of germ-line genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and showed the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germ-line genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.

  M. R Spitz and M. L. Bondy
 

Classical epidemiologic studies have made seminal contributions to identifying the etiology of most common cancers. Molecular epidemiology was conceived of as an extension of traditional epidemiology to incorporate biomarkers with questionnaire data to further our understanding of the mechanisms of carcinogenesis. Early molecular epidemiologic studies employed functional assays. These studies were hampered by the need for sequential and/or prediagnostic samples, viable lymphocytes and the uncertainty of how well these functional data (derived from surrogate lymphocytic tissue) reflected events in the target tissue. The completion of the Human Genome Project and Hapmap Project, together with the unparalleled advances in high-throughput genotyping revolutionized the practice of molecular epidemiology. Early studies had been constrained by existing technology to use the hypothesis-driven candidate gene approach, with disappointing results. Pathway analysis addressed some of the concerns, although the study of interacting and overlapping gene networks remained a challenge. Whole-genome scanning approaches were designed as agnostic studies using a dense set of markers to capture much of the common genome variation to study germ-line genetic variation as risk factors for common complex diseases. It should be possible to exploit the wealth of these data for pharmacogenetic studies to realize the promise of personalized therapy. Going forward, the temptation for epidemiologists to be lured by high-tech ‘omics’ will be immense. Systems Epidemiology, the observational prototype of systems biology, is an extension of classical epidemiology to include powerful new platforms such as the transcriptome, proteome and metabolome. However, there will always be the need for impeccably designed and well-powered epidemiologic studies with rigorous quality control of data, specimen acquisition and statistical analysis.

  X Zhang , H Yang , J. J Lee , E Kim , S. M Lippman , F. R Khuri , M. R Spitz , R Lotan , W. K Hong and X. Wu
 

Second primary tumor (SPT) and/or recurrence negatively impact the prognosis of patients with curatively treated early-stage head and neck cancer. MicroRNAs (miRNAs) play important roles in cancer development. We explored whether the variations of miRNA-related pathway were associated with the risk of SPT/recurrence in patients with early-stage head and neck cancer. This study includes 150 early-stage head and neck cancer patients with SPT/recurrence and 300 patients without SPT/recurrence. Two hundred and thirty-five tagging and potentially functional single-nucleotide polymorphisms (SNPs) were genotyped from eight miRNA biogenesis pathway genes and 135 miRNA-targeted genes. Eighteen miRNA-related SNPs were significantly associated with the risk of SPT/recurrence. The most significant SNP was rs3747238, a miRNA-binding site SNP in SMC1B. The variant homozygous genotype of this SNP was associated with a 1.74-fold increased risk [95% confidence interval (CI) 1.19–2.54; P = 0.004]. Cumulative effect analysis showed joint effects for the number of unfavorable genotype in patients. Survival tree analysis further identified the high-order gene–gene interactions and categorized the study subjects into low-, medium- and high-risk groups. Patients in the high-risk group had a 4.84-fold increased risk (95% CI: 3.11–7.51; P = 2.45 x 10–12) and a shorter event-free median survival time of 37.9 months (log rank P = 2.28 x 10–13). Our results suggested that miRNA-related genetic polymorphisms may be used individually and jointly to predict the risk of SPT/recurrence of early-stage head and neck cancer patients.

  A. N Freedman , L. B Sansbury , W. D Figg , A. L Potosky , S. R Weiss Smith , M. J Khoury , S. A Nelson , R. M Weinshilboum , M. J Ratain , H. L McLeod , R. S Epstein , G. S Ginsburg , R. L Schilsky , G Liu , D. A Flockhart , C. M Ulrich , R. L Davis , L. J Lesko , I Zineh , G Randhawa , C. B Ambrosone , M. V Relling , N Rothman , H Xie , M. R Spitz , R Ballard Barbash , J. H Doroshow and L. M. Minasian
 

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

 
 
 
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