Peter W Laird

Publications (167) View all

• Article: Associations Between Colorectal Cancer Molecular Markers and Pathways with Clinico-Pathologic Features in Older Women.

  N J Samadder, Robert A Vierkant, Lori S Tillmans, Alice H Wang, Daniel J Weisenberger, Peter W Laird, Charles F Lynch, Kristin E Anderson, Amy J French, Robert W Haile, John D Potter, Susan L Slager, Thomas C Smyrk, Stephen N Thibodeau, James R Cerhan, Paul J Limburg
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  ABSTRACT: BACKGROUND & AIMS: Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (IWHS; n=41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. METHODS: We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high (MSI-H) or low (MSI-L), CIMP high (CIMP-H) or low (CIMP-L), CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n=170), alternate (MSS, CIMP-L, BRAF mutation negative, and KRAS mutation positive; n=58), serrated (any MSI, CIMP-H, BRAF mutation positive, and KRAS mutation negative; n=142) or unassigned (n=193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. RESULTS: Patients' mean age (P=.03) and tumors' anatomic subsite (P=.0001) and grade (P=.0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI-L, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n=50 cases; relative risk, 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). CONCLUSION: We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, further studies are needed to determine how these features might influence prognosis.
  Gastroenterology 05/2013; · 11.68 Impact Factor
• Article: Interplay between the Cancer Genome and Epigenome.

  Hui Shen, Peter W Laird
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  ABSTRACT: Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation.
  Cell 03/2013; 153(1):38-55. · 32.40 Impact Factor
• Article: Low-level processing of Illumina Infinium DNA Methylation BeadArrays.

  Timothy J Triche, Daniel J Weisenberger, David Van Den Berg, Peter W Laird, Kimberly D Siegmund
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  ABSTRACT: We propose a novel approach to background correction for Infinium HumanMethylation data to account for technical variation in background fluorescence signal. Our approach capitalizes on a new use for the Infinium I design bead types to measure non-specific fluorescence in the colour channel opposite of their design (Cy3/Cy5). This provides tens of thousands of features for measuring background instead of the much smaller number of negative control probes on the platforms (n = 32 for HumanMethylation27 and n = 614 for HumanMethylation450, respectively). We compare the performance of our methods with existing approaches, using technical replicates of both mixture samples and biological samples, and demonstrate that within- and between-platform artefacts can be substantially reduced, with concomitant improvement in sensitivity, by the proposed methods.
  Nucleic Acids Research 03/2013; · 8.03 Impact Factor
• Article: Associations Between Intake of Folate and Related Micronutrients with Molecularly Defined Colorectal Cancer Risks in the Iowa Women's Health Study.

  Anthony A Razzak, Amy S Oxentenko, Robert A Vierkant, Lori S Tillmans, Alice H Wang, Daniel J Weisenberger, Peter W Laird, Charles F Lynch, Kristin E Anderson, Amy J French, Robert W Haile, Lisa J Harnack, John D Potter, Susan L Slager, Thomas C Smyrk, Stephen N Thibodeau, James R Cerhan, Paul J Limburg
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  ABSTRACT: Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.
  Nutrition and Cancer 10/2012; 64(7):899-910. · 2.78 Impact Factor
• Article: Discovery of multi-dimensional modules by integrative analysis of cancer genomic data.

  Shihua Zhang, Chun-Chi Liu, Wenyuan Li, Hui Shen, Peter W Laird, Xianghong Jasmine Zhou
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  ABSTRACT: Recent technology has made it possible to simultaneously perform multi-platform genomic profiling (e.g. DNA methylation (DM) and gene expression (GE)) of biological samples, resulting in so-called 'multi-dimensional genomic data'. Such data provide unique opportunities to study the coordination between regulatory mechanisms on multiple levels. However, integrative analysis of multi-dimensional genomics data for the discovery of combinatorial patterns is currently lacking. Here, we adopt a joint matrix factorization technique to address this challenge. This method projects multiple types of genomic data onto a common coordinate system, in which heterogeneous variables weighted highly in the same projected direction form a multi-dimensional module (md-module). Genomic variables in such modules are characterized by significant correlations and likely functional associations. We applied this method to the DM, GE, and microRNA expression data of 385 ovarian cancer samples from the The Cancer Genome Atlas project. These md-modules revealed perturbed pathways that would have been overlooked with only a single type of data, uncovered associations between different layers of cellular activities and allowed the identification of clinically distinct patient subgroups. Our study provides an useful protocol for uncovering hidden patterns and their biological implications in multi-dimensional 'omic' data.
  Nucleic Acids Research 08/2012; 40(19):9379-91. · 8.03 Impact Factor