Goode, Ellen L.

Abstract Background: Variation in mitochondrial genes in cancer cells alters the mitochondrial bioenergetic and biosynthetic state, which mediates cross-talk between mitochondria and the nucleus to modulate many cellular processes. The objective of this study was to comprehensively evaluate mitochondria-nuclear cross-talk in terms of SNP-SNP interactions associated with invasive epithelial ovarian cancer (EOC) risk, which may play an important role in unveiling the underlying mechanism of this complex lethal disease. Methods: Our analyses were based on 1,938 invasive EOC cases and 2,009 controls with greater than 80% European ancestry from five case-control studies genotyped using the Illumina 610quad chip. We evaluated 2,488 SNPs in over 1,500 genes in eight mitochondria-related pathways (apoptosis, oxidation-reduction, epithelial-mesenchymal transition, immunomoduation, transmembrane transport, small GTPases, BRCA1-interactors and circadian rhythm). SNPs with strong linkage disequilibrium of r2 > 0.8 were excluded. We examined 2-way SNP-SNP interactions associated with invasive EOC risk using the two-stage Random Forests plus Multivariate Adaptive Regression Splines (TRM) approach. Bootstrapping was further performed to select important variables and reduce false positive findings. Based on the scree plot using 1,000 bootstrap samples, the factors with more than 4% of bootstrap frequency were defined as significant factors. We then included each identified factors separately in model adjusting for study site and first principal component representing European ancestry. Results: Five significant SNP-SNP interactions were observed: (rs2270799 in IQSEC3 (12p13.33) + rs933305 in CUX2 (12q24.3), (p= 6.3x10−5); rs6063251 in PREX1 (20q13.3) + rs9705 in SLC39A8 (4q22-q24), (p= 3.5x10−5); rs933305 in CUX2 (12q24.3) + rs1712957 in ARHGAP15 (2q22.2-q22.3), (p=4.2x10−7), rs2861828 in SLIT1 (10q23.3-q24) + rs6063251 in PREX1 (20q13.3), (p=2.5x10−7); rs10954593 in SEMA3C (7q21-q31) + rs933305 in CUX2 (12q24.3), (p=2.8x10−3). Four of the five interactions involved SNPs from genes in the small GTPases pathway (IQSEC3; PREX1 (twice) and ARHGAP15). In addition, three of the five interaction pairs involved the CUX2 gene. This gene encodes a protein which contains three CUT domains and a homeodomain, which are DNA-binding motifs. The main mitochondrial SNP-SNP interaction involved the nuclear mitochondria gene SLC39A8. Conclusions: Our results suggest that genetic variation in mitochondrial-related pathways may be associated with invasive EOC risk. These findings highlight important genes/pathways that may interact as a network to influence invasive EOC risk and may generate novel therapeutic targets. External validation will be done using other independent studies for future analyses. Citation Format: Hui-Yi Lin, Ya-Yu Tsai, Y. Ann Chen, Zhihua Chen, Xiaotao Qu, Ellen L. Goode, Joellen Schildkraut, Edwin Iversen, Steven A. Narod, Thomas A. Sellers, Catherine M. Phelan. SNP-SNP interactions in mitochondria-related pathways are associated with invasive Epithelial Ovarian Cancer (EOC) risk . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4839. doi:10.1158/1538-7445.AM2013-4839

Abstract Since most GWAS hits fall in non-coding regions of the genome and long non-coding RNAs (lncRNAs) are emerging as drivers of carcinogenesis, we hypothesized that SNPs in lncRNAs influence epithelial ovarian cancer (EOC) risk. A comprehensive lncRNA database (lncRNA db) that contained 104 human lncRNAs when downloaded in November 2011 was used to identify 1,737 variants in 63 unique lncRNAs that were represented in three genome-wide association studies from North America, the United Kingdom, and Poland (3,995 EOC cases and 3,277 controls of European background). SNPs with MAF <5% were excluded, and missing genotypes were inferred with Mach using the HapMap CEU population. Unconditional logistic regression treating alternate alleles as an ordinal variable was used to evaluate individual SNP-EOC risk associations. Subgroup analysis was conducted for serous adenocarcinomas (N= 2,066), the main histologic subtype of EOC. Models were adjusted for study and European ancestry using the first two principal components (PCs). We reduced correlated signals (r2 ≥ 0.8) within each lncRNA and kept the most statistically significant variants based on Wald tests, resulting in 651 SNPs for further analyses. Fisher's product method was used to aggregate evidence of multiple variants within each lncRNA using 10,000 permutations. To adjust for multiple comparisons, a false discovery rate (FDR) of 10% was used. A replication phase was carried out for top-ranked SNPs from an additional 9,854 EOC cases (5,802 serous) and 17,633 controls genotyped through an international effort known as the Collaborative Oncological Gene-Environment study (COGS). Four lncRNAs, WT1-AS (p = 0.005, n = 2 SNPs), Hoxa11as (p = 0.013, n = 2), AK082072 (p = 0.016, n = 4) and H19 (p = 0.020, n = 2), were significantly associated with EOC risk among all histologies (FDR ≤ 10%). The SNP in WT1-AS most significantly associated with EOC risk was rs3809061 (T>C) (minor allele frequency= 36%, odds ratio (OR) = 0.91, CI: 0.84-0.97, p = 0.008). Among serous cases, rs3809061 was also protective (OR = 0.92, p = 0.04). These findings were replicated by a correlated SNP rs2301250 (r2 = 0.84) evaluated in COGS among serous cases (OR = 0.94, CI: 0.90-0.99, p = 0.009) and less significant among all histologies (OR = 0.96, CI: 0.93-1.00, p = 0.054). We further interrogated its functional role by performing an expression quantitative trait locus analysis on WTI-AS mRNA expression using the Cancer Genome Atlas (TCGA) data (N = 462 serous cases). WT1-AS expression was significantly higher among carriers of the variant allele (compared to TT homozygotes) using the Mann-Whitney U test (p = 0.001). WT1-AS is the antisense and possible regulator of WT1, a tumor suppressor gene reported to be prognostic in advanced EOC. These findings implicate germline lncRNA variants associated with EOC risk that merit further investigation. Citation Format: Yian Ann Chen, Zhihua Chen, Jennifer Permuth-Wey, Ya-Yu Tsai, Hui-Yi Lin, Xiaotao Qu, Kate Lawrenson, David Fenstermacher, Catherine M. Phelan, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Rebecca Sutphen, Michael J. Birrer, Nicolas Wentzensen, Joellen M. Schildkraut, Ellen L. Goode, Paul Pharoah, Thomas Sellers. Variants in long non-coding RNAs are associated with epithelial ovarian cancer risk in a pooled analysis of three genome-wide association studies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4579. doi:10.1158/1538-7445.AM2013-4579

Abstract Background. Transmembrane transport (GO:0055085) is the process whereby a solute/hormone/ion/iron is transported from one side of a membrane to the other. Disruption of these processes leads to defects in homeostasis which contributes to cancer risk. We hypothesized that germline single nucleotide polymorphisms (SNPs) in the cellular transport genes are associated with EOC risk and histopathology subtype. Methods. We genotyped 305 SNPs from 120 cellular transport related genes in 14,525 cases and 23,448 controls of European ancestry, 387 African, and 2,388 Asian ancestries from 43 studies in the Ovarian Cancer Association Consortium (OCAC). A custom Illumina iSelect designed for the Collaborative Oncological Gene-environment Study (COGS) was used. For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous (n=8,369), mucinous (n=943), endometroid (n=2,067) and clear cell (n=1,024) carcinoma) were analyzed, while for women of African and Asian ancestry only the serous subtype was analyzed adjusting for study site and first 5 principal components. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. We fitted a log-additive genetic model. Results. In women of European ancestry, the strongest evidence of an association for all invasive EOCs was the iron transport gene, HEPH rs17216603 (OR=0.85, 95%CI=0.78-0.93, P=2.8x10−4), which was also the most significant association for serous histological subtype (OR=0.81, 95%CI=0.73-0.91, P=2.0x10−4). For endometrioid EOC, the strongest association was observed in the glucuronidation gene, UGT1A5 rs11563251 (OR=0.82, 95%CI=0.73-0.92, P=6.6x10−4). For clear cell and mucinous EOC, the thyroid hormone transport protein, SERPINA7 rs1804495 showed the strongest associations (OR=1.06, 95%CI=1.06-1.38, P=0.0041) and (OR=0.85, 95%CI=0.73-0.98, P=0.0407), respectively. For women of African ancestry, the strongest association for serous EOC was the glutathione conjugation gene, MGST rs6488840 (OR=0.55, 95%CI=0.37-0.82, P=0.0035). This SNP was not significant in women of European or Asian ancestry. In women of Asian ancestry, the HEPH rs17216603 (OR=1.45, 95%CI=1.15-1.83, P=0.0019) demonstrated the strongest association, although the directionality of risk was reversed compared to European women. Conclusions. Our results suggest that variation in transmembrane transport genes may influence EOC risk and histopathologic subtype in women of European, African and Asian ancestries, highlighting the differences in the disease etiology across populations. Additional epidemiological and functional studies are warranted to elucidate translational and clinical utility of these associations. Citation Format: Ganna Chornokur, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Chen Zhihua, Ya-Yu Tsai, Ellen L. Goode, Julie M. Cunningham, Edwin Iversen, Susan J. Ramus, Andrew Berchuk, Joellen M. Schildkraut, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Paul Pharoah, Thomas A. Sellers, Catherine M. Phelan. Variation in transmembrane transport genes influence epithelial ovarian cancer risk and histopathologic subtype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2013-3644

Abstract Introduction The epithelial-mesenchymal transition (EMT) pathway contributes to epithelial ovarian cancer (EOC) progression. Previously we identified associations of single nucleotide polymorphisms (SNPs) in EMT-related genes and EOC risk (data not shown). To further investigate the role of EMT-related gene variants in EOC and to derive more reliable risk estimates, we evaluated associations for 795 SNPs from 278 EMT-related genes in a replication study of 43 studies within the Ovarian Cancer Association Consortium (OCAC). Methods The study population included 14,736 cases and 23,448 controls of European ancestry, 89 cases and 200 controls of African ancestry, and 249 cases and 1574 controls of Asian ancestry. The 795 SNPs were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, while for women of African and Asian ancestries only the serous subtype was analyzed. SNP analyses were conducted using unconditional logistic regression under a log-additive model separately for women of each ancestry. All analyses were adjusted for study site and population substructure within each ancestry. Results For women of European ancestry, the strongest evidence of an association for invasive cancers combined was observed for IGF1R rs10794486 (OR=1.05, 95%CI=1.02-1.09, P=0.002), which was also associated with serous (P=0.019), but not the other histological subtypes. In the histological subtype-specific analysis, the most significant association for serous was observed at NRP2 rs3771044 (OR=1.09, 95%CI=1.03-1.15, P=0.00014), for endometroid at rs1770247 (13q31.3, OR=1.16, 95%CI=1.07-1.25, P=0.00028), for clear cell at rs4848300 (2q13, OR=0.84, 95%CI=0.76-0.93, P=0.00099) and for mucinous at SEMA4B rs8030039 (OR=1.09, 95%CI=1.01-1.17, P=0.00019). For women of African ancestry, the strongest association for serous histological subtype was observed at F9 rs6048 (OR=1.71, 95%CI=1.17-2.50, P=0.006). This SNP was not significant in women of European or Asian ancestry. The strongest association for women of Asian ancestry was IGF1R rs10794486 (OR=1.68, 95%CI=1.16-2.45, P=0.007), which was also significant in women of European, but not African, ancestry. Conclusion Findings from this large study provide additional evidence that variants in EMT-related genes may be associated with ovarian cancer risk and that EMT susceptibility loci may differ by ovarian cancer histological subtypes. Furthermore, the findings suggest that susceptibility locus for the serous subtype may be different for women of African ancestry. Future studies are warranted to confirm these findings. Citation Format: Ernest K. Amankwah, Jonathan Tyrer, Hui-Yi Lin, Ya-Yu Tsai, Zhihua Chen, Gang Han, Xiaotao Qu, Ellen Goode, Julie Cunninghan, Edward Iverson, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven Narod, Paul Pharoah, Thomas A. Sellers, Catherine Phelan. Epithelial-mesenchymal transition (EMT) gene variants influence epithelial ovarian cancer risk in women of European, African and Asian ancestry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1352. doi:10.1158/1538-7445.AM2013-1352

Abstract Background: Circadian rhythms of biological processes are regulated by endogenous clock genes and clock-controlled genes. Aberrant expression of circadian clock genes may have important consequences on the transactivation of downstream targets that control the cell cycle and cellular proliferation potentially promoting carcinogenesis. Animal models indicate that several circadian rhythm genes are expressed in the ovaries, where they influence and are influenced by estrous cycles. The goal of the current study was to examine the association of circadian gene variants and epithelial ovarian cancer (EOC) risk. Methods: Thirty-one SNPs from five circadian genes (i.e., ARNTL, CRY2, KLF10, NPAS2, PER3, TIMELESS) were genotyped in 14,736 cases and 23,448 control women of European ancestry from 43 studies in the Ovarian Cancer Association Consortium (OCAC), on a custom Illumina iSelect designed for the Collaborative Oncological Gene-Environment Study (COGS). Both invasive cancers combined and the four main histological subtypes (serous [n=8,372], endometroid [n=2,068], clear cell [n=1,025] and mucinous [n=943] were analyzed, SNP analyses were conducted using unconditional logistic regression under a log-additive model. All analyses were adjusted for study site and population substructure. Results: Eleven SNPs were found to be associated with ovarian cancer risk. The SNPs most associated with serous cancer risk were KLF10 rs2513928 (OR=.95 p=6.1x10−3), rs2513927 (OR=1.05 p=6.1x10−3), rs2511703 (OR=1.05 p=9.8x10−3), rs3191333 (OR=1.05, p=1.5x10−2) and NPAS2 rs13012930 (OR=.95, p=3.5x10−2). Endometroid cancer risk was significantly associated with ARNTL SNPs rs10732458 (OR=1.3, p=1.0x10−2) and rs7117836 (OR=1.2, p=4.6x10−2), while clear cell cancer risk was associated with ARNTL rs1562438 (OR=.88, p=1.5x10−2), rs1026071 (OR=.89, p=1.8x10−2), and rs3816360 (OR=.91, p=4.8x10−2) and KLF10 rs2388232 (OR=1.1, p=3.3x10−2). No variants were significantly associated with mucinous cancer risk. Four SNPs in KLF10 were associated with cancer invasiveness; they were rs2513928 (OR=.95, p=1.8x10−3), rs3191333 (OR=1.04, p=1.4x10−2), rs2513927 (OR=1.04, p=1.9x10−2), and rs2511703 (OR=1.03, p=2.8x10−2). Conclusions: Data from the current study suggest that polymorphisms in circadian genes ARNTL, KLF10, and NPAS2 are significantly associated with ovarian cancer histopathologic subtypes and invasiveness. These findings merit further investigation and replication. Funding: R01 CA149429 Citation Format: Heather Jim, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Ellen L. Goode, Zhihua Chen, Ya-Yu Tsai, Julie M. Cunningham, Edward Iversen, Susan Ramus, Andrew Berchuck, Joellen Schildkraut, Alvaro Monteiro, Simon Gayther, Steven A. Narod, Thomas A. Sellers, Paul Pharoah, Catherine M. Phelan. Variation in circadian rhythm genes influence epithelial ovarian cancer risk and invasiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4850. doi:10.1158/1538-7445.AM2013-4850 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract Colorectal cancer (CRC) is estimated to be the third most common cancer in both men and women in the US in 2012, accounting for over 50,000 deaths. Familial CRC accounts for approximately 30% of all CRC, yet only 5% of familial CRCs can be attributed to mutations in known hereditary colon cancer (HCC) genes. Many families with a strong family history of CRC do not have mutations in known CRC genes. Finding the genes underpinning CRC in these families may improve screening for disease and allow the development of more targeted therapeutics. We completed targeted sequencing of over 2,000 genes and miRNAs in 1,500 cases of CRC from the Colon Cancer Family Registry (CCFR) in an effort to identify rare variants associated with CRC risk and to identify mutations in known CRC genes missed by conventional sequencing. Several categories of genes were included: 18 known HCC genes; 18 candidate HCC genes; 185 genes in previously reported CRC linkage peaks; 1,423 miRNAs; and 363 genes identified through whole exome sequencing of 40 affected cases in 16 families with hereditary CRC (n=2,007 total genes sequenced). Genomic DNA samples were indexed, then libraries were made using Agilent's SureSelect Targeted Enrichment kit. Samples were pooled (96 samples/pool), then each pool of samples was run on five lanes on an Illumina HiSeq2000 (average of 19.2 samples/lane). GenomeGPS, an in-house developed workflow, was used for read alignment, variant calling, and annotation. In early analyses of the first 161 cases, the mean number of mapped reads exceeded 20 million per sample and over 90% of the target region exceeded 40x coverage. A total of 26,484 SNPs were identified and passed quality filtering. Sequencing identified known mutations in MMR genes in positive control cases as well as mutations in HCC genes in previously untested cases. Analysis is currently on-going on the remaining samples and we will report results on the full set of 1500 cases at the meeting. Citation Format: Melissa S. DeRycke, Shanaka R. Gunawardena, Sumit Middha, Shannon K. McDonnell, Shaun M. Riska, Zachary C. Fogarty, Bruce W. Eckloff, Daniel J. Schaid, Ellen L. Goode, Stephen N. Thibodeau. Targeted sequencing to identify rare variants in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2548. doi:10.1158/1538-7445.AM2013-2548

Abstract Our understanding of ovarian cancer is complicated by disease heterogeneity. There are five major histological types, each with alterations in different pathways and distinct clinical outcomes. Even within these histological types there is clinical and molecular heterogeneity. The Ovarian Tumor Tissue Analysis (OTTA) consortium was established to validate prognostic markers for ovarian cancer in a large population of patients to allow stratification by histological type and molecular subtype. OTTA is currently a collaboration among 38 studies and has tissue microarrays (TMAs) from over 8,000 tumors available for immunohistochemical (IHC) analysis. In addition formalin fixed paraffin embedded (FFPE) tissue on slides or cores are available from the majority of OTTA studies for DNA and RNA analysis. Approximatley 60% of the cases are part of the Ovarian Cancer Association Consortium (OCAC) and have genotype data on over 200,000 single nucleotide polymorphisms and extensive epidemiological data. We recently performed IHC analysis of 12 markers using centralised staining and scoring to reduce heterogeneity and improve power to validate biomarkers. We showed that estrogen receptor and progesterone receptor were prognostic markers for endometrioid and high-grade serous carcinomas by performing the first robust subtype-specific analyses of these biomarkers in nearly 3000 patients. In contrast, FOLR1 expression was not associated with survival in 1507 high-grade serous carcinomas. We have shown that FFPE material from OTTA is suitable for RNA expression analysis on high through-put platforms such as the NanoString GX system. Expression analysis of 50 candidate genes in 244 high grade serous ovarian cancer cases has validated prognostic markers identified by The Cancer Genome Atlas (TCGA) project and investigated a series of novel candidate genes. IHC and RNA expression profiling from formalin fixed paraffin embedded (FFPE) tumor tissue is being used to better subclassify the ovarian tumors for further analysis. We would welcome groups with collections of ovarian tumor samples and corrsponding clinical data to join OTTA and participate in ongoing collaborative projects. Citation Format: Susan J. Ramus, Martin Köbel, Weiva Sieh, Michael S. Anglesio, Joshua Millstein, David D. Bowtell, James D. Brenton, Estrid Høgdall, Paul DP Pharoah, Ellen L. Goode, David G. Huntsman. The ovarian tumor tissue analysis (OTTA) consortium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A27.

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Abstract Inflammation is a facilitating process for multiple cancer types. It is believed to affect cancer development and progression through several etiologic pathways, including increased levels of DNA adduct formation, increased angiogenesis, and altered antiapoptotic signaling. This review highlights the application of inflammatory biomarkers in epidemiologic studies and discusses the various cellular mediators of inflammation characterizing the innate immune system response to infection and chronic insult from environmental factors. Included is a review of six classes of inflammation-related biomarkers: cytokines/chemokines, immune-related effectors, acute-phase proteins, reactive oxygen and nitrogen species, prostaglandins and cyclooxygenase-related factors, and mediators such as transcription factors and growth factors. For each of these biomarkers, we provide a brief overview of the etiologic role in the inflammation response and how they have been related to cancer etiology and progression within the literature. We provide a discussion of the common techniques available for quantification of each marker, including strengths, weaknesses, and potential pitfalls. Subsequently, we highlight a few under-studied measures to characterize the inflammatory response and their potential utility in epidemiologic studies of cancer. Finally, we suggest integrative methods for future studies to apply multifaceted approaches to examine the relationship between inflammatory markers and their roles in cancer development. Cancer Epidemiol Biomarkers Prev; 23(9); 1729–51. ©2014 AACR.