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ABSTRACT: BACKGROUND & AIMS: Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers. METHODS: We analyzed data from 494,968 participants in the National Institutes of Health (NIH)-AARP Diet and Health study, in which AARP members (51-70 y old) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index. RESULTS: During the follow-up period (1995-2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric non-cardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest: hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.31-0.86; Ptrend=.001) and EAC (HR, 0.75; 95% CI, 0.57-0.98; Ptrend=.01). We observed an inverse association between ESCC, but not EAC, and higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not significantly associated with gastric cardia or noncardia adenocarcinomas. CONCLUSIONS: Using data collected from 1995 through 2006 from the NIH-AARP Diet and Health Study, HEI-2005 and aMED scores were inversely associated with risk for esophageal cancers-particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 04/2013; · 5.64 Impact Factor
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ABSTRACT: Dysplastic nevi are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these 2 entities. Since initially being reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biologic importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still no single, universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi should be considered important because of their association with an increased risk for melanoma. Cancer Epidemiol Biomarkers Prev; 22(4); 528-32. ©2013 AACR.
Cancer Epidemiology Biomarkers & Prevention 04/2013; 22(4):528-32. · 4.12 Impact Factor
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Wen-Qing Li,
Nan Hu,
Paula L Hyland,
Ying Gao,
Zhao-Ming Wang,
Kai Yu,
Hua Su,
Chao-Yu Wang,
Le-Min Wang,
Stephen J Chanock, [......],
Fangyi Gu,
William Wheeler,
Xiao-Qin Xiong,
Carol Giffen,
Margaret A Tucker,
Sanford M Dawsey,
Neal D Freedman,
Christian C Abnet, Alisa M Goldstein,
Philip R Taylor
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ABSTRACT: The DNA repair pathways help maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal and gastric cancers but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases, and 2111 controls, from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P=6.37×10(-4)), but not with GC (P=0.20). The most significant gene in ESCC was CHEK2 (P=2.00×10(-6)), and in GC was CLK2 (P=3.02×10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE, and BRCA1) or GC risk (MRE11A, RAD54L, and POLE) (P<0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
Carcinogenesis 03/2013; · 5.70 Impact Factor
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Mark M Iles,
Matthew H Law,
Simon N Stacey,
Jiali Han,
Shenying Fang,
Ruth Pfeiffer,
Mark Harland,
Stuart Macgregor,
John C Taylor,
Katja K Aben, [......],
Diana Zelenika,
Mingfeng Zhang,
Maria Teresa Landi,
Gudmar Thorleifsson,
D Timothy Bishop,
Christopher I Amos,
Nicholas K Hayward,
Kari Stefansson,
Julia A Newton Bishop,
Jennifer H Barrett
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ABSTRACT: We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10-12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
Nature Genetics 03/2013; · 35.53 Impact Factor
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Hanne Eknes Puntervoll,
Xiaohong R Yang,
Hildegunn Høberg Vetti,
Ingeborg M Bachmann,
Marie Françoise Avril,
Meriem Benfodda,
Caterina Catricalà,
Stéphane Dalle,
Anne B Duval-Modeste,
Paola Ghiorzo, [......],
Alexander J Stratigos,
Luc Thomas,
Julie Tinat,
Hensin Tsao,
Rūta Veinalde,
Margaret A Tucker,
Brigitte Bressac-de Paillerets,
Julia A Newton-Bishop, Alisa M Goldstein,
Lars A Akslen
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ABSTRACT: BACKGROUND:
CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype.
METHODS:
All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced.
RESULTS:
Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010).
CONCLUSION:
Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.
Journal of Medical Genetics 02/2013; 50(4):264-70. · 6.36 Impact Factor
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Hanne Eknes Puntervoll,
Xiaohong R Yang,
Hildegunn Høberg Vetti,
Ingeborg M Bachmann,
Marie Françoise Avril,
Meriem Benfodda,
Caterina Catricalà,
Stéphane Dalle,
Anne B Duval-Modeste,
Paola Ghiorzo, [......],
Luc Thomas,
Julie Tinat,
Hensin Tsao,
Ruta Veinalde,
Margaret A Tucker,
Brigitte Bressac-de Paillerets,
Julia A Newton-Bishop, Alisa M Goldstein,
Lars A Akslen,
Anders Molven
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ABSTRACT: BACKGROUND: CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. METHODS: All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. RESULTS: Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p<0.001). MPM subjects had a higher frequency of MC1R red hair colour variants compared with subjects with one tumour (p=0.010). CONCLUSION: Our study shows that families with CDK4 germline mutations cannot be distinguished phenotypically from CDKN2A melanoma families, which are characterised by early onset of disease, increased occurrence of clinically atypical nevi, and development of MPM. In a clinical setting, the CDK4 gene should therefore always be examined when a melanoma family tests negative for CDKN2A mutation.
Journal of Medical Genetics 02/2013; · 6.36 Impact Factor
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Paula L Hyland,
Neal D Freedman,
Nan Hu,
Ze-Zhong Tang,
Lemin Wang,
Chaoyu Wang,
Ti Ding,
Jin-Hu Fan,
You-Lin Qiao,
Asieh Golozar,
William Wheeler,
Kai Yu,
Jeff Yuenger,
Laurie Burdette,
Stephen J Chanock,
Sanford M Dawsey,
Margaret A Tucker, Alisa M Goldstein,
Christian C Abnet,
Philip R Taylor
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ABSTRACT: In China, esophageal cancer is the fourth leading cause of cancer death, where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently, it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank-truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P=0.14) or subpathways (androgen synthesis: P=0.30; estrogen synthesis: P=0.15; and estrogen removal: P=0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P<0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.
Carcinogenesis 01/2013; · 5.70 Impact Factor
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ABSTRACT: Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. We thus examined whether global methylation was associated with CMM risk in individuals from melanoma-prone families with and without CDKN2A germline mutations. We measured global DNA methylation using bisulfite pyrosequencing at four CpG sites of the long interspersed nucleotide element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from individuals in 64 melanoma-prone families including 114 CMM cases (45 CDKN2A-positive and 69 CDKN2A-negative) and 121 unaffected individuals (31 CDKN2A-positive and 90 CDKN2A-negative). We used unconditional logistic regression to evaluate the association between CMM status and LINE-1 methylation levels, adjusting for age at blood draw and accounting for familial correlation in the variance. We found that male sex was significantly associated with higher overall LINE-1 methylation (P=0.0001). However, the overall and site-specific levels of LINE-1 methylation did not vary significantly by CMM status (overall odds ratio: 1.57, 95% confidence interval: 0.84-2.95, P=0.16; comparing lowest to highest or reference methylation group). Similar results were obtained when CDKN2A-positive and CDKN2A-negative families were analyzed separately. Our findings did not support a significant association between constitutional LINE-1 methylation in PBMCs and risk of CMM in melanoma-prone families with or without CDKN2A mutations.
Melanoma research 12/2012; · 2.06 Impact Factor
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Wusheng Yan,
Joanna Shih,
Jaime Rodriguez-Canales,
Michael A Tangrea,
Audrey Player,
Lixia Diao,
Nan Hu, Alisa M Goldstein,
Jing Wang,
Philip R Taylor,
Scott M Lippman,
Ignacio I Wistuba,
Michael R Emmert-Buck,
Heidi S Erickson
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ABSTRACT: The classic tumor clonal evolution theory postulates that cancers change over time to produce unique molecular subclones within a parent neoplasm, presumably including regional differences in gene expression. More recently, however, this notion has been challenged by studies showing that tumors maintain a relatively stable transcript profile. To examine these competing hypotheses, we microdissected discrete subregions containing approximately 3000 to 8000 cells (500 to 1500 μm in diameter) from ex vivo esophageal squamous cell carcinoma (ESCC) specimens and analyzed transcriptomes throughout three-dimensional tumor space. Overall mRNA profiles were highly similar in all 59 intratumor comparisons, in distinct contrast to the markedly different global expression patterns observed in other dissected cell populations. For example, normal esophageal basal cells contained 1918 and 624 differentially expressed genes at a greater than twofold level (95% confidence level of <5% false positives), compared with normal differentiated esophageal cells and ESCC, respectively. In contrast, intratumor regions had only zero to four gene changes at a greater than twofold level, with most tumor comparisons showing none. The present data indicate that, when analyzed using a standard array-based method at this level of histological resolution, ESCC contains little regional mRNA heterogeneity.
American Journal Of Pathology 12/2012; · 4.89 Impact Factor
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Journal of dermatological science 11/2012; · 3.71 Impact Factor
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09/2012;
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Deborah Tamura,
Sikandar G Khan,
Melissa Merideth,
John J Digiovanna,
Margaret A Tucker, Alisa M Goldstein,
Kyu-Seon Oh,
Takahiro Ueda,
Jennifer Boyle,
Mansi Sarihan,
Kenneth H Kraemer
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ABSTRACT: The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (P<0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development.European Journal of Human Genetics advance online publication, 23 May 2012; doi:10.1038/ejhg.2012.90.
European journal of human genetics: EJHG 05/2012; · 3.56 Impact Factor
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Xiaohong R Yang,
Kevin Brown,
Maria T Landi,
Paola Ghiorzo,
Celia Badenas,
Mai Xu,
Nicholas K Hayward,
Donato Calista,
Giorgio Landi,
William Bruno,
Giovanna Bianchi-Scarrà,
Paula Aguilera,
Susana Puig, Alisa M Goldstein,
Margaret A Tucker
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ABSTRACT: Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma.
Pigment Cell & Melanoma Research 03/2012; 25(2):243-7. · 5.06 Impact Factor
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Wan-Lun Hsu,
Ka-Po Tse,
Sharon Liang,
Yin-Chu Chien,
Wen-Hui Su,
Kelly J Yu,
Yu-Juen Cheng,
Ngan-Ming Tsang,
Mow-Ming Hsu,
Kai-Ping Chang,
I-How Chen,
Tzu-I Chen,
Czau-Siung Yang, Alisa M Goldstein,
Chien-Jen Chen,
Yu-Sun Chang,
Allan Hildesheim
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ABSTRACT: The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region.
To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3).
After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A).
Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.
PLoS ONE 01/2012; 7(8):e42767. · 4.09 Impact Factor
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Wusheng Yan,
Joanna H Shih,
Jaime Rodriguez-Canales,
Michael A Tangrea,
Kris Ylaya,
Jason Hipp,
Audrey Player,
Nan Hu, Alisa M Goldstein,
Philip R Taylor,
Michael R Emmert-Buck,
Heidi S Erickson
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ABSTRACT: Esophageal squamous cell carcinoma (ESCC), the predominant histological subtype of esophageal cancer, is characterized by high mortality. Previous work identified important mRNA expression differences between normal and tumor cells; however, to date there are limited ex vivo studies examining expression changes occurring during normal esophageal squamous cell differentiation versus those associated with tumorigenesis. In this study, we used a unique tissue microdissection strategy and microarrays to measure gene expression profiles associated with cell differentiation versus tumorigenesis in twelve cases of patient-matched normal basal squamous epithelial cells (NB), normal differentiated squamous epithelium (ND), and squamous cell cancer. Class comparison and pathway analysis were used to compare NB versus tumor in a search for unique therapeutic targets.
As a first step towards this goal, gene expression profiles and pathways were evaluated. Overall, ND expression patterns were markedly different from NB and tumor; whereas, tumor and NB were more closely related. Tumor showed a general decrease in differentially expressed genes relative to NB as opposed to ND that exhibited the opposite trend. FSH and IgG networks were most highly dysregulated in normal differentiation and tumorigenesis, respectively. DNA repair pathways were generally elevated in NB and tumor relative to ND indicating involvement in both normal and pathological growth. PDGF signaling pathway and 12 individual genes unique to the tumor/NB comparison were identified as therapeutic targets, and 10 associated ESCC gene-drug pairs were identified. We further examined the protein expression level and the distribution patterns of four genes: ODC1, POSTN, ASPA and IGF2BP3. Ultimately, three genes (ODC1, POSTN, ASPA) were verified to be dysregulated in the same pattern at both the mRNA and protein levels.
These data reveal insight into genes and molecular pathways mediating ESCC development and provide information potentially useful in designing novel therapeutic interventions for this tumor type.
BMC Research Notes 01/2012; 5:73.
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Clara Bodelon,
Ruth M Pfeiffer,
Valentina Bollati,
Julien Debbache,
Donato Calista,
Paola Ghiorzo,
Maria Concetta Fargnoli,
Giovanna Bianchi-Scarra,
Ketty Peris,
Mirjam Hoxha, [......],
Laura Burke,
Shenying Fang,
Margaret A Tucker, Alisa M Goldstein,
Jeffrey E Lee,
Qingyi Wei,
Sharon A Savage,
Xiaohong R Yang,
Christopher Amos,
Maria Teresa Landi
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ABSTRACT: The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
PLoS ONE 01/2012; 7(12):e52466. · 4.09 Impact Factor
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Stuart Macgregor,
Grant W Montgomery,
Jimmy Z Liu,
Zhen Zhen Zhao,
Anjali K Henders,
Mitchell Stark,
Helen Schmid,
Elizabeth A Holland,
David L Duffy,
Mingfeng Zhang, [......],
Graham G Giles,
Bruce K Armstrong,
Joanne F Aitken,
Jiali Han,
John L Hopper,
Jeffrey M Trent,
Kevin M Brown,
Nicholas G Martin,
Graham J Mann,
Nicholas K Hayward
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ABSTRACT: We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.
Nature Genetics 11/2011; 43(11):1114-8. · 35.53 Impact Factor
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Jennifer H Barrett,
Mark M Iles,
Mark Harland,
John C Taylor,
Joanne F Aitken,
Per Arne Andresen,
Lars A Akslen,
Bruce K Armstrong,
Marie-Francoise Avril,
Esther Azizi, [......],
Peter A Kanetsky,
Graham J Mann,
Stuart Macgregor,
David E Elder,
Christopher I Amos,
Nicholas K Hayward,
Nelleke A Gruis,
Florence Demenais,
Julia A Newton Bishop,
D Timothy Bishop
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ABSTRACT: We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
Nature Genetics 11/2011; 43(11):1108-13. · 35.53 Impact Factor
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ABSTRACT: Smoking and alcohol consumption explain little of the risk for upper-gastrointestinal (UGI) cancer in China, where over half of all cases in the world occur.
We evaluated questionnaire-based risk factors for UGI cancers in a case-control study from Shanxi Province, China, including 600 esophageal squamous cell carcinomas (ESCCs), 599 gastric cardia adenocarcinomas (GCAs), 316 gastric noncardia adenocarcinomas (GNCAs), and 1514 age- and gender-matched controls.
Ever smoking and ever use of any alcohol were not associated with risk of UGI cancer; only modest associations were observed between ESCC risk and highest cumulative smoking exposure, as well as GNCA risk and beer drinking. While several associations were noted for socioeconomic and some dietary variables with one or two UGI cancers, the strongest and most consistent relations for all three individual UGI cancers were observed for consumption of scalding hot foods (risk increased 150-219% for daily vs. never users) and fresh vegetables and fruits (risk decreased 48-70% for vegetables and 46-68% for fruits, respectively, for high vs. low quartiles).
This study confirms the minor role of tobacco and alcohol in UGI cancers in this region, and highlights thermal damage as a leading etiologic factor.
Cancer epidemiology. 08/2011; 35(6):e91-9.
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Deborah Tamura,
Melissa Merideth,
John J DiGiovanna,
Xiaolong Zhou,
Margaret A Tucker, Alisa M Goldstein,
Brian P Brooks,
Sikandar G Khan,
Kyu-Seon Oh,
Takahiro Ueda,
Jennifer Boyle,
Roxana Moslehi,
Kenneth H Kraemer
[show abstract]
[hide abstract]
ABSTRACT: To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD).
We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011.
Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and 81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, and 4% had an emergency c-section for fetal distress, while 44% had two or more complications. Only 19% of the pregnancies delivered at term without complications. Eight of the ten pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotrophin. Eighty-five percent of the neonates had complications: 70% were low birth weight (<2500 g), 35% had birth weight < 10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined.
TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities.
Prenatal Diagnosis 07/2011; 31(11):1046-53. · 2.11 Impact Factor
