John D Potter

Publications (264)1552.79 Total impact

• 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
• Source

  Available from: Stephen Fink

  Dataset: 2013 DigDisSci PGDH Stability SUPPfig1

  Stephen P Fink, Dong-Hoon Yang, Jill S Barnholtz-Sloan, Yeon-Mi Ryu, Debra Mikkola, John D Potter, Johanna W Lampe, Sanford D Markowitz, Seung-Jae Myung
• Article: Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing.

  Melissa S Derycke, Shanaka R Gunawardena, Sumit Middha, Yan A Asmann, Dan J Schaid, Shannon K McDonnell, Shaun M Riska, Bruce W Eckloff, Julie M Cunningham, Brooke L Fridley, [......], Robert Haile, Michael O Woods, Steven Gallinger, Graham Casey, John D Potter, Polly A Newcomb, Loic Le Marchand, Noralane M Lindor, Stephen N Thibodeau, Ellen L Goode
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  ABSTRACT: BACKGROUND: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants. METHODS: We completed exome sequencing on 40 affected cases from 16 multi-case pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single nucleotide variants (SNVs) predicted to be benign. RESULTS: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or non-coding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively. CONCLUSIONS: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in colorectal cancer susceptibility. Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.
  Cancer Epidemiology Biomarkers &amp Prevention 05/2013; · 4.12 Impact Factor
• Source

  Available from: Stephen Fink

  Article: Colonic 15-PGDH Levels Are Stable Across Distance and Time and Are Not Perturbed by Aspirin Intervention.

  Stephen P Fink, Dong-Hoon Yang, Jill S Barnholtz-Sloan, Yeon-Mi Ryu, Debra Mikkola, John D Potter, Johanna W Lampe, Sanford D Markowitz, Seung-Jae Myung
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  ABSTRACT: BACKGROUND AND AIMS: 15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin. METHODS: Using real-time PCR, we measured 15-PGDH mRNA to determine the correlation of 15-PGDH level in replicate colon biopsies, in biopsies from throughout the length of the colon, in repeat biopsies taken 4 months apart, and in paired biopsies of individuals taken before and after aspirin treatment, and by Western-blot for 15-PGDH protein in mice. RESULTS: Colonic 15-PGDH levels varied 4.4-fold across the human population. Within individuals, 15-PGDH levels proved highly reproducible (r = 0.81 in duplicate biopsies) and stable along the length of the colon, with average 15-PGDH levels deviating by only 17 % from rectum to cecum. An individual's 15-PGDH levels are also highly stable over time, with a median coefficient of variation over a 4-month interval of only 12 %. Last, colonic 15-PGDH levels proved resistant to alteration by aspirin, with only a 10 % difference in 15-PGDH levels measured before and after aspirin treatment. CONCLUSIONS: 15-PGDH levels vary across the population in a stable and reproducible manner, and are resistant to alteration by aspirin. 15-PGDH represents an independent target for modulation by candidate colon tumor chemopreventive agents.
  Digestive Diseases and Sciences 04/2013; · 2.12 Impact Factor
• Article: Genomic aberrations occuring in subsets of serrated colorectal lesions but not conventional adenomas.

  Andrea N Burnett-Hartman, Polly A Newcomb, John D Potter, Michael N Passarelli, Amanda I Phipps, Michelle A Wurscher, William M Grady, Lee-Ching Zhu, Melissa P Upton, Karen W Makar
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  ABSTRACT: A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 932 polyp cases and 1,027 controls who were ages 24-80, part of a group health program, received a colonoscopy from 1998-2007 and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate odds ratios and 95% confidence intervals for the association between molecularly-defined subsets of polyps and potential risk factors. 580 conventional adenomas and 419 serrated lesions were successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile serrated polyps (SSPs) of ≥10 mm that localized to right-sided/cecal regions of the colon. Risk factors for CIMP-high serrated lesions included Caucasian race, current smoking status and a history of polyps, whereas for serrated lesions with mutant BRAF the significant risk factors were male sex, current smoking status, obesity and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers.
  Cancer Research 03/2013; · 7.86 Impact Factor
• Article: Family History of Colorectal Cancer in BRAF p.V600E mutated Colorectal Cancer Cases.

  Daniel D Buchanan, Aung Ko Win, Michael D Walsh, Rhiannon J Walters, Mark Clendenning, Belinda N Nagler, Sally-Ann Pearson, Finlay Macrae, Susan Parry, Julie Arnold, Ingrid Winship, Graham G Giles, Noralane M Lindor, John D Potter, John L Hopper, Christophe Rosty, Joanne P Young, Mark A Jenkins
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  ABSTRACT: BACKGROUND: Previous reports suggest that relatives of CRC-affected probands carrying the BRAF p.V600E mutation are at an increased risk of colorectal (CRC) and extracolonic cancers (ECCs). In this study, we estimated the association between a family history (FH) of either CRC or ECC and risk of CRC with a BRAF p.V600E mutation. METHODS: Population-based CRC cases (probands; aged 18-59years at diagnosis), recruited irrespective of family cancer history, were characterised for BRAF p.V600E mutation and mismatch repair (MMR) status. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. RESULTS: The 690 eligible probands demonstrated a mean age at CRC diagnosis of 46.9±7.8years, with 313 (47.9%) reporting a FH of CRC and 53 (7.7%) that were BRAF-mutated. Probands with BRAF-mutated, MMR-proficient CRCs were less likely to have a FH of CRC than probands that were BRAF-wildtype (OR=0.46, 95%CI=0.24-0.91; p=0.03). For probands with a BRAF-mutated CRC, the mean age at diagnosis was older for those with a CRC-affected first- or second-degree relative (49.3±6.4 years) compared with those without a FH (43.8±10.2 years; p=0.04). The older the age at diagnosis of CRC with the BRAF p.V600E mutation, the more likely these probands demonstrated a FH of CRC (OR=1.09 per year of age; 95%CI=1.00-1.18; p=0.04). CONCLUSIONS: Probands with early-onset, BRAF-mutated and MMR-proficient CRC were less likely to have a FH of CRC than probands that were BRAF-wildtype. Impact: These findings provide useful insights for cancer risk assessment in families and suggest that familial factors are more important in early-onset, BRAF-wildtype CRC.
  Cancer Epidemiology Biomarkers &amp Prevention 03/2013; · 4.12 Impact Factor
• Article: Differences in Epidemiologic Risk Factors for Colorectal Adenomas and Serrated Polyps by Lesion Severity and Anatomical Site.

  Andrea N Burnett-Hartman, Michael N Passarelli, Scott V Adams, Melissa P Upton, Lee-Ching Zhu, John D Potter, Polly A Newcomb
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  ABSTRACT: Using a case-control design, we evaluated differences in risk factors for colorectal polyps according to histological type, anatomical site, and severity. Participants were enrollees in the Group Health Cooperative aged 20-79 years who underwent colonoscopy in Seattle, Washington, between 1998 and 2007 and comprised 628 adenoma cases, 594 serrated polyp cases, 247 cases with both types of polyps, and 1,037 polyp-free controls. Participants completed a structured interview, and polyps were evaluated via standardized pathology review. We used multivariable polytomous logistic regression to compare case groups with controls and with the other case groups. Factors for which the strength of the association varied significantly between adenomas and serrated polyps were sex (P < 0.001), use of estrogen-only postmenopausal hormone therapy (P = 0.01), and smoking status (P < 0.001). For lesion severity, prior endoscopy (P < 0.001) and age (P = 0.05) had significantly stronger associations with advanced adenomas than with nonadvanced adenomas; and higher education was positively correlated with sessile serrated polyps but not with other serrated polyps (P = 0.02). Statistically significant, site-specific associations were observed for current cigarette smoking (P = 0.05 among adenomas and P < 0.001 among serrated polyps), postmenopausal estrogen-only therapy (P = 0.01 among adenomas), and obesity (P = 0.01 among serrated polyps). These findings further illustrate the epidemiologic heterogeneity of colorectal neoplasia and may help elucidate carcinogenic mechanisms for distinct pathways.
  American journal of epidemiology 03/2013; · 5.59 Impact Factor
• Article: Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels.

  Clare Abbenhardt, Anne McTiernan, Catherine M Alfano, Mark H Wener, Kristin L Campbell, Catherine Duggan, Karen E Foster-Schubert, Angela Kong, Adetunji T Toriola, John D Potter, Caitlin Mason, Liren Xiao, George L Blackburn, Carolyn Bain, Cornelia M Ulrich
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  ABSTRACT: BACKGROUND: Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes, and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. METHODS: Overweight/obese postmenopausal women (n=439) were randomized as follows: 1) a reduced calorie, weight loss diet (diet; N=118); 2) moderate-to-vigorous intensity aerobic exercise (exercise; N=117); 3) a combination of a reduced calorie, weight loss diet and moderate-to-vigorous intensity aerobic exercise (diet+exercise; N=117); or 4) control (N=87). The reduced calorie diet had a 10% weight loss goal. The exercise intervention consisted of 45 minutes of moderate-to-vigorous aerobic activity 5 days/week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. RESULTS: Adiponectin increased by 9.5% in the diet group and 6.6% in the diet+exercise group (both p<0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet+exercise, -40.1%, p<0.0001; diet, -27.1%, p<0.0001; exercise, -12.7%, p=0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, p-trend=0.0002; diet+exercise, p-trend=0.0005) and directly associated with leptin (diet, p-trend<0.0001; diet+exercise, p-trend<0.0001). CONCLUSION: Weight loss through diet or diet+exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet+exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin. © 2013 The Association for the Publication of the Journal of Internal Medicine.
  Journal of Internal Medicine 02/2013; · 5.48 Impact Factor
• Article: Genetic variation in the lipoxygenase pathway and risk of colorectal neoplasia.

  Sarah E Kleinstein, Laura Heath, Karen W Makar, Elizabeth M Poole, Brenna L Seufert, Martha L Slattery, Liren Xiao, David J Duggan, Li Hsu, Karen Curtin, Lisel Koepl, Jill Muehling, Darin Taverna, Bette J Caan, Christopher S Carlson, John D Potter, Cornelia M Ulrich
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  ABSTRACT: Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with nonsteroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20-0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at P ≤ 0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in ALOXs may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia. © 2013 Wiley Periodicals, Inc.
  Genes Chromosomes and Cancer 02/2013; · 3.31 Impact Factor
• Source

  Available from: Julie M Cunningham

  Dataset: cicek et al PLoS one

  Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Daniel J Serie, William R Bamlet, Brenda Diergaarde, Robert W Haile, Loic Le Marchand, Theodore G Krontiris, H Banfield Younghusband, [......], Susan Parry, Graeme P Young, Joanne P Young, Daniel Buchanan, Duncan C Thomas, D Timothy Bishop, Noralane M Lindor, Stephen N Thibodeau, John D Potter, Ellen L Goode
• Source

  Available from: Julie M Cunningham

  Dataset: cicek et al PLoS one

  Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Daniel J Serie, William R Bamlet, Brenda Diergaarde, Robert W Haile, Loic Le Marchand, Theodore G Krontiris, H Banfield Younghusband, [......], Susan Parry, Graeme P Young, Joanne P Young, Daniel Buchanan, Duncan C Thomas, D Timothy Bishop, Noralane M Lindor, Stephen N Thibodeau, John D Potter, Ellen L Goode
• Article: Detection of large scale 3' deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?

  Mark Clendenning, Michael D Walsh, Judith Balmana Gelpi, Stephen N Thibodeau, Noralane Lindor, John D Potter, Polly Newcomb, Loic Lemarchand, Robert Haile, Steve Gallinger, John L Hopper, Mark A Jenkins, Christophe Rosty, Joanne P Young, Daniel D Buchanan
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  ABSTRACT: Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.
  Familial Cancer 01/2013; · 1.30 Impact Factor
• Article: Genetic Variations in SMAD7 Are Associated with Colorectal Cancer Risk in the Colon Cancer Family Registry.

  Xuejuan Jiang, J Esteban Castelao, David Vandenberg, Angel Carracedo, Carmen M Redondo, David V Conti, Jesus P Paredes Cotoré, John D Potter, Polly A Newcomb, Michael N Passarelli, Mark A Jenkins, John L Hopper, Steven Gallinger, Loic Le Marchand, María E Martínez, Dennis J Ahnen, John A Baron, Noralane M Lindor, Robert W Haile, Manuela Gago-Dominguez
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  ABSTRACT: Recent genome-wide studies identified a risk locus for colorectal cancer at 18q21, which maps to the SMAD7 gene. Our objective was to confirm the association between SMAD7 SNPs and colorectal cancer risk in the multi-center Colon Cancer Family Registry. 23 tagging SNPs in the SMAD7 gene were genotyped among 1,592 population-based and 253 clinic-based families. The SNP-colorectal cancer associations were assessed in multivariable conditional logistic regression. Among the population-based families, both SNPs rs12953717 (odds ratio, 1.29; 95% confidence interval, 1.12-1.49), and rs11874392 (odds ratio, 0.80; 95% confidence interval, 0.70-0.92) were associated with risk of colorectal cancer. These associations were similar among the population- and the clinic-based families, though they were significant only among the former. Marginally significant differences in the SNP-colorectal cancer associations were observed by use of nonsteroidal anti-inflammatory drugs, cigarette smoking, body mass index, and history of polyps. SMAD7 SNPs were associated with colorectal cancer risk in the Colon Cancer Family Registry. There was evidence suggesting that the association between rs12953717 and colorectal cancer risk may be modified by factors such as smoking and use of nonsteroidal anti-inflammatory drugs.
  PLoS ONE 01/2013; 8(4):e60464. · 4.09 Impact Factor
• Source

  Available from: Shuo Jiao

  Article: Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-Analysis.

  Ulrike Peters, Shuo Jiao, Fredrick R Schumacher, Carolyn M Hutter, Aaron K Aragaki, John A Baron, Sonja I Berndt, Stéphane Bézieau, Hermann Brenner, Katja Butterbach, [......], Darin Taverna, Stephen N Thibodeau, Cornelia M Ulrich, Emily White, Yongbing Xiang, Brent W Zanke, Yi-Xin Zeng, Ben Zhang, Wei Zheng, Li Hsu
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  ABSTRACT: BACKGROUND & AIMS: Heritable factors contribute to development of colorectal cancer (CRC). Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis we identified a locus that reached the conventional genome-wide significance level at <5.0 x 10-8: an intergenic region on chromosome 2q32.3, close toNABP1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR]=1.15 per risk allele;P =3.7 x 10-8). We also found evidence for 3 additional loci with P values <5.0 x 10-7: a locus within theLAMC1gene on chromosome 1q25.3 (rs10911251; OR=1.10 per risk allele;P =9.5 x 10-8), a locus within theCCND2gene on chromosome 12p13.32 (rs3217810 per risk allele; OR=0.84;P =5.9 x 10-8), and a locus in theTBX3gene on chromosome 12q24.21 (rs59336, OR=0.91 per risk allele;P =3.7 x 10-7). CONCLUSIONS: In a large GWAS, we associated polymorphisms close toNABP (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms inLAMC1 (this is the second gene in the laminin family to be associated with CRCs),CCND2 (which encodes for cyclin D2), andTBX3 (which encodes a T-box transcription factor and is a target of Wnt signaling to -catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
  Gastroenterology 12/2012; · 11.68 Impact Factor
• Article: Common single nucleotide polymorphisms in the estrogen receptor β promoter are associated with colorectal cancer survival in postmenopausal women.

  Michael N Passarelli, Amanda I Phipps, John D Potter, Karen W Makar, Anna E Coghill, Karen J Wernli, Emily White, Andrew T Chan, Carolyn M Hutter, Ulrike Peters, Polly A Newcomb
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  ABSTRACT: Loss of estrogen receptor β (ERβ) expression in the gut is associated with colorectal cancer (CRC) initiation and progression. Germline single nucleotide polymorphisms (SNPs) in genes for the sex-steroid hormone receptors are not strongly associated with CRC risk, however, these SNPs have not previously been evaluated in relation to survival after diagnosis. We enrolled 729 women, ages 50-74, diagnosed with invasive CRC between 1997-2002 in 13 counties covered by the Seattle-Puget Sound SEER cancer registry. Participants provided germline DNA. We selected 99 tag-SNPs for the androgen receptor (AR), ERα (ESR1), ERβ (ESR2), and progesterone receptor (PGR) genes. Mortality outcomes were ascertained from the National Death Index. During a median of 6.6 years of follow-up, 244 deaths occurred (161 from CRC). We identified 20 SNPs (12 of ESR2 and 8 of PGR) for replication in 1,729 women diagnosed with incident invasive CRC (555 deaths; 405 from CRC) from three prospective cohort studies that participate in the Genetics and Epidemiology of Colorectal Cancer Consortium. Three correlated SNPs in the 5' promoter of ESR2 (rs2987983, rs3020443, and rs2978381) were statistically significant predictors of CRC-specific and overall survival. Minor alleles of each were associated with improved survival (for rs2987983, CRC-specific hazard ratio (HR)=0.77; 95% confidence interval (CI)=0.60-0.99 in the initial study, and HR=0.79; CI=0.64-0.98 in replication). No associations were noted for SNPs of AR, ESR1, or PGR. SNPs in the 5' promoter of ESR2 may be important to pathways related to the association between ERβ and tumor progression and metastasis.
  Cancer Research 11/2012; · 7.86 Impact Factor
• Article: Identification of Lynch syndrome among patients with colorectal cancer.

  Leticia Moreira, Francesc Balaguer, Noralane Lindor, Albert de la Chapelle, Heather Hampel, Lauri A Aaltonen, John L Hopper, Loic Le Marchand, Steven Gallinger, Polly A Newcomb, [......], Mark A Jenkins, Daniel D Buchanan, John D Potter, John A Baron, Dennis J Ahnen, Victor Moreno, Montserrat Andreu, Maurizio Ponz de Leon, Anil K Rustgi, Antoni Castells
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  ABSTRACT: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. MAIN OUTCOME :Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.
  JAMA The Journal of the American Medical Association 10/2012; 308(15):1555-65. · 30.03 Impact Factor
• Article: Association of body mass index and risk of death from pancreas cancer in Asians: findings from the Asia Cohort Consortium.

  Yingsong Lin, Rong Fu, Eric Grant, Yu Chen, Jung Eun Lee, Prakash C Gupta, Kunnambath Ramadas, Manami Inoue, Shoichiro Tsugane, Yu-Tang Gao, [......], Faruque Parvez, Betsy Rolland, Dale McLerran, Rashmi Sinha, Paolo Boffetta, Wei Zheng, Mark Thornquist, Ziding Feng, Daehee Kang, John D Potter
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  ABSTRACT: We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium. The data for this pooled analysis included 883 529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios and 95% confidence intervals for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5-19.9, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, ≥30) were used in the analysis, with BMI of 22.5-24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and a history of diabetes. We found no statistically significant overall association between each BMI category and the risk of death from pancreas cancer in all Asians, and obesity was unrelated to the risk of mortality in both East Asians and South Asians. Age, smoking, and a history of diabetes did not modify the association between BMI and the risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI less than 18.5 was observed for individuals with a history of diabetes; hazard ratio=2.01 (95% confidence interval: 1.01-4.00) (P for interaction=0.07). The data do not support an association between BMI and the risk of death from pancreas cancer in these Asian populations.
  European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 10/2012; · 2.21 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: Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk.

  Amy Y Liu, Dominique Scherer, Elizabeth Poole, John D Potter, Karen Curtin, Karen Makar, Martha L Slattery, Bette J Caan, Cornelia M Ulrich
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  ABSTRACT: SCOPE: The importance of folate-mediated one-carbon metabolism (FOCM) in colorectal carcinogenesis is emphasized by observations that high dietary folate intake is associated with decreased risk of colon cancer (CC) and its precursors. Additionally, polymorphisms in FOCM-related genes have been repeatedly associated with risk, supporting a causal relationship between folate and colorectal carcinogenesis. METHODS AND RESULTS: We investigated ten candidate polymorphisms with defined or probable functional impact in eight FOCM-related genes (SHMT1, DHFR, DNMT1, MTHFD1, MTHFR, MTRR, TCN2, and TDG) in 1609 CC cases and 1974 controls for association with CC risk and for interaction with dietary factors. No polymorphism was statistically significantly associated with overall risk of CC. However, statistically significant interactions modifying CC risk were observed for DNMT1 I311V with dietary folate, methionine, vitamin B(2) , and vitamin B(12) intake and for MTRR I22M with dietary folate, a predefined one-carbon dietary pattern, and vitamin B(6) intake. We observed statistically significant gene-diet interactions with five additional polymorphisms. CONCLUSION: Our results provide evidence that FOCM-related dietary intakes modify the association between CC risk and FOCM allelic variants. These findings add to observations showing that folate-related gene-nutrient interactions play an important role in modifying the risk of CC.
  Molecular Nutrition & Food Research 09/2012; · 4.30 Impact Factor
• Article: BRAF Mutation Status and Survival after Colorectal Cancer Diagnosis According to Patient and Tumor Characteristics.

  Amanda I Phipps, Daniel D Buchanan, Karen W Makar, Andrea N Burnett-Hartman, Anna E Coghill, Michael N Passarelli, John A Baron, Dennis J Ahnen, Aung Ko Win, John D Potter, Polly A Newcomb
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  ABSTRACT: BRAF mutations in colorectal cancer (CRC) are disproportionately observed in tumors exhibiting microsatellite instability (MSI) and are associated with other prognostic factors. The independent association between BRAF mutation status and CRC survival, however, remains unclear. We evaluated the association between the BRAF c.1799T>A (p.V600E) mutation and survival in individuals with incident invasive CRC diagnosed between 1997 and 2007 in Western Washington State. Tumor specimens were tested for this BRAF mutation and MSI status. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the association between BRAF mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumor site, stage, and MSI status. Among 1,980 cases tested, 12% were BRAF c.1799T>A (p.V600E) mutation-positive (n = 247). BRAF-mutated CRC was associated with poorer disease-specific survival adjusting for age, sex, time from diagnosis to enrollment, stage, and MSI status (HR, 1.43; 95% CI, 1.05-1.95). This association was limited to cases diagnosed at ages <50 (HR, 3.06; 95% CI, 1.70-5.52) and was not evident in cases with MSI-high tumors (HR, 0.94; 95% CI, 0.44-2.03). Associations with overall survival were similar. Our results show that the prevalence of BRAF mutations in CRC differs by patient and tumor characteristics and suggest that the association between BRAF status and CRC survival may differ by some of these factors. Impact: The presence of a BRAF c.1799T>A (p.V600E) mutation is associated with significantly poorer prognosis after CRC diagnosis among subgroups of patients. Cancer Epidemiol Biomarkers Prev; 21(10); 1792-8. ©2012 AACR.
  Cancer Epidemiology Biomarkers &amp Prevention 08/2012; 21(10):1792-8. · 4.12 Impact Factor