Mingfeng Zhang

• Harvard Medical School

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we perform...

Background: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. Methods: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival...

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in United States with a 5-year survival rate of only 8%. Inherited predisposition plays an important role in PDAC risk. Rare, moderately to highly penetrant mutations in hereditary cancer and pancreatitis genes, identified in families with a high incidence o...

Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a la...

This corrects the article DOI: 10.1038/ncomms15034.

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreat...

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and theUnited States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreati...

Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, includin...

Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs re...

Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues. Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data fr...

Objective To elucidate the genetic architecture of gene expression in pancreatic tissues. Design We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue sa...

Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and t...

Supplementary Figures and Supplementary Tables

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3, and BORA, range in distance from 265-586...

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 co...

Background: Pancreatic tumors cause changes in whole-body metabolism, but whether prediagnostic circulating metabolites predict survival is unknown. Methods: We measured 82 metabolites by liquid chromatography–mass spectrometry in prediagnostic plasma from 484 pancreatic cancer case patients enrolled in four prospective cohort studies. Association...

Background: No GWAS on the risk of cutaneous squamous cell carcinoma (SCC) has been published. We conducted a multistage genome-wide association study (GWAS) to identify novel genetic loci for SCC. Methods: The study included 745 SCC cases and 12,805 controls of European descent in the discovery stage and 531 SCC cases and 551 controls of Europe...

Genome wide association studies (GWAS) have mapped multiple independent cancer risk loci (n = 6) to a small region on chr5p15.33 for at least ten distinct cancers, including bladder, breast, glioma, lung, melanoma, non-melanoma skin, ovarian, pancreas, prostate, and testicular germ cell cancer. This region harbors two plausible target genes, TERT w...

Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk. We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Po...

BACKGROUND Acne reflects hormone imbalance and is a key component of several systemic diseases. We hypothesized that diagnosis of acne as a teenager might predict subsequent risk of hormone-related cancers.METHODS We followed 99,128 female nurses in the Nurses' Health Study II cohort for 20 years (1989-2009) and used Cox proportional hazards models...

STUDY QUESTION: Is there a relationship between severe teenage acne and endometriosis? SUMMARY ANSWER: Endometriosis is positively associated with severe teenage acne. WHAT IS KNOWN ALREADY: No studies have specifically explored a possible association between severe acne in adolescence and risk of endometriosis. STUDY DESIGN, SIZE, DURATION: Thi...

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the ge...

Background: Cutaneous nevi are suggested to be hormone-related. We hypothesized that the number of cutaneous nevi might be a phenotypic marker of plasma hormone levels and predict subsequent breast cancer risk. Methods and findings: We followed 74,523 female nurses for 24 y (1986-2010) in the Nurses' Health Study and estimate the relative risk o...

The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.

Single genetic variants discovered so far have been only weakly associated with melanoma. This study aims to use multiple single nucleotide polymorphisms (SNPs) jointly to obtain a larger genetic effect and to improve the predictive value of a conventional phenotypic model. We analyzed 11 SNPs that were associated with melanoma risk in previous stu...

MicroRNAs (miRNA) are a class of small, noncoding RNA molecules involved in a diversity of cellular functions. Single nucleotide polymorphisms (SNPs) in miRNA biosynthesis genes may affect the biogenesis of miRNAs and consequently affect the miRNAs regulation. In this study, we systematically selected 24 functional SNPs located in 8 key biosynthesi...

Background: Increased risk of skin cancer by indoor tanning has drawn public attention. However, there are arguments that tanning bed use increases vitamin D production, which may therefore prevent internal cancers. Methods: We followed 73,358 female nurses for 20 years (1989–2009) in the Nurses' Health Study II and investigated the frequency of ta...

Despite the family aggregation of severe teenage acne, the genetic basis of this common skin condition remains unclear. We conducted a genome-wide association study (GWAS) on severe teenage acne in 928 European Americans. The SNP rs4133274 on chromosome 8q24 (72 kb upstream of MYC) revealed the most significant association with severe teenage acne...

ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tum...

Aiming to identify novel genetic loci for pigmentation and skin cancer, we conducted a series of genome-wide association studies on hair color, eye color, number of sunburns, tanning ability and number of non-melanoma skin cancers (NMSCs) among 10 183 European Americans in the discovery stage and 4504 European Americans in the replication stage (fo...

Previous biological studies showed evidence of a genetic link between obesity and pigmentation in both animal models and humans. Our study investigated the individual and joint associations between obesity-related single nucleotide polymorphisms (SNPs) and both human pigmentation and risk of melanoma. Eight obesity-related SNPs in the FTO, MAP2K5,...

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...

The production of pigment by melanocytes tans the skin and protects against skin cancers. UV-exposed keratinocytes secrete α-MSH, which then activates melanin formation in melanocytes by inducing the microphthalmia-associated transcription factor (MITF). We show that PPAR-γ coactivator (PGC)-1α and PGC-1β are critical components of this melanogenic...

Genome-wide association studies (GWAS) have become a widely used approach for genetic association studies of various human traits. A few GWAS have been conducted with the goal of identifying novel loci for pigmentation traits, melanoma, and non-melanoma skin cancer. Nevertheless, the phenotype variation explained by the genetic markers identified s...

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Non-melanoma skin cancer (NMSC) is the most common cancer in the world. More than 3.5 million NMSCs were treated in 2006; of those, 700,000 were cutaneous squamous cell carcinomas (cSCC). There are several predisposing factors to cSCC; however, little is known about the...

Background Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.Methods and...

We sought to evaluate the risk effect of tanning bed use on skin cancers among teenage and young adults. We also expected to determine whether a dose-response relationship was evident. We observed 73,494 female nurses for 20 years (from 1989 to 2009) in a large and well-characterized cohort in the United States and investigated whether frequency of...

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 independen...

s: AACR International Conference on Frontiers in Cancer Prevention Research‐‐ Oct 22-25, 2011; Boston, MA Tanning beds are used by 30 million Americans each year. The use of tanning beds has been shown to increase the risk of skin cancers in previous epidemiological studies. A 2007 meta-analysis by the International Agency for Research on Cancer (...

Genome-wide association studies (GWASs) have primarily focused on marginal effects for individual markers and have incorporated external functional information only after identifying robust statistical associations. We applied a new approach combining the genetics of gene expression and functional classification of genes to the GWAS of basal cell c...

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to...

Characteristics of BCC cases and controls in this study. (XLS)

Association results for the 174 KEGG pathways and 205 BioCarta pathways. (a) Association results for the 174 KEGG pathways; (b) Association results for the 205 BioCarta pathways. (XLS)

Description of the GWAS on BCC. (DOC)

The representative SNP information for the two positive control pathways. (XLS)

The representative SNP information for the four pathways with significant enrichment in the BCC GWAS. (XLS)

Recently, a pathway-based approach has been developed to evaluate the cumulative contribution of the functionally related genes for genome-wide association studies (GWASs), which may help utilize GWAS data to a greater extent. In this study, we applied this approach for the GWAS of basal cell carcinoma (BCC) of the skin. We first conducted the BCC...

We conducted a genome-wide association study on the number of melanocytic nevi reported by 9136 individuals of European ancestry, with follow-up replication in 3581 individuals. We identified the nidogen 1 (NID1) gene on 1q42 associated with nevus count (two linked single nucleotide polymorphisms with r(2) > 0.9: rs3768080 A allele associated with...

Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) are 3 types of skin cancer that have distinct biologic characteristics and prognoses. We evaluated phenotypic differences in the risk of these cancers in US women. We conducted a prospective study of 113 139 female nurses from 1984 to 2002. Over the 18 years of follow-up, there...

Reduced DNA repair capacity has been proposed as a predisposing factor for melanoma. We comprehensively evaluated 1463 genetic variants across 60 DNA repair-related pathway genes in relation to melanoma risk in a nested case-control study of 218 melanoma cases (20% on head and neck) and 218 matched controls within the Nurses' Health Study (NHS). We...

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian melanoma cases and 4,387 controls, confirming several previously characterised melanoma-associated loci and identifying two novel susceptibility loci on chromosome 1. The most significant genotyped SNPs in the novel loci were at 1q21.3 nearby several...

SNP graph of rs2736100 from (A) Illumina 610K (B) Illumina 370K based on Beadstudio Genotyping Module v3. (1.47 MB TIF)

Lung cancer risk associated with rs2736100 among never-smoking females from East Asia, by histology, including two previously published studies. (0.03 MB XLS)

Chromosome 5, 6, and 15 SNPs genotyped. (0.04 MB XLS)

Risk of lung cancer associated with rs2736100 for never-smoking female adenocarcinoma cases and never-smoking female controls from East Asia. (0.66 MB TIF)

Lung cancer risk associated with rs2736100 among never-smoking females from East Asia, by study center, including two previously published studies. (0.04 MB XLS)

Lung cancer risk associated with chromosome 5 SNPs, among never-smoking females from East Asia. (0.05 MB XLS)

Lung cancer risk associated with chromosome 6 SNPs, among never-smoking females from East Asia. (0.07 MB XLS)

Lung cancer risk associated with chromosome 15 SNPs, among never-smoking females from East Asia. (0.07 MB XLS)

Supplementary information. (0.09 MB DOC)

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observ...

Over the last decades, combined chemotherapies that inhibit different signalling pathways together have been demonstrated to be more effective to treat the non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) and the vascular endothelium growth factor (VEGF) are two key targets. Polymorphisms in EGFR and VEGF genes have b...

Three potentially functional polymorphisms: -765G>C, -1195G>A, and 8473T>C in the cyclooxygenase-2 (COX-2) gene were identified and proposed to be associated with cancer susceptibility. The aim of this meta-analysis was to evaluate the association between these three polymorphisms and the risk of cancer in diverse populations. All case-control stud...

Disruption of the balance of insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP3) has been implicated in the etiology and progression of lung and other cancers. Single nucleotide polymorphisms (SNP) in IGF1 and IGFBP3 have been reported to be associated with the expression of the IGF-I/IGFBP3 axis. Therefore, we hypothesized that...

Chromosome 6p21.33, containing BAT3 and MSH5 genes, together with chromosome 6p22.1 were recently identified as susceptible regions for lung cancer in Caucasian populations. These findings interest us in assessing whether genetic variants in these regions also contribute to lung cancer risk in Chinese populations. We genotyped the most significant...

Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lu...

Accumulative evidence suggests that interleukin-12 (IL-12) plays a central role in the Th1 responses and thus participates in the carcinogenesis of human papillomavirus-related cervical cancer. We hypothesized that potentially functional polymorphisms in IL12A and IL12B may individually and jointly contribute to cervical cancer risk. We genotyped I...

Background Oral contraceptives were introduced almost 50 years ago, and over 100 million women currently use them. Oral contraceptives can reduce the risk of ovarian cancer, but the eventual public-health effects of this reduction will depend on how long the protection lasts after use ceases. We aimed to assess these effects. Methods Individual dat...