Faculty Bibliography

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (Ppathway <0.00625). The two most significant genes were NPAS2 (Pgene =0.0062) and AANAT (Pgene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (Ppathway =0.021); this association was not confirmed in GECCO (Ppathway =0.76) or the combined data (Ppathway =0.17). No association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms

PURPOSE: Results from previous sero-epidemiologic studies of Trichomonas vaginalis infection and prostate cancer (PCa) support a positive association between this sexually transmitted infection and aggressive PCa. However, findings from previous studies are not entirely consistent, and only one has investigated the possible relation between T. vaginalis seropositivity and PCa in African-American men who are at highest risk of both infection and PCa. Therefore, we examined this possible relation in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, including separate analyses for aggressive PCa and African-American men. METHODS: We included a sample of participants from a previous nested case-control study of PCa, as well as all additional Caucasian, aggressive, and African-American cases diagnosed since the previous study (total n = 438 Gleason 7 Caucasian cases, 487 more advanced Caucasian cases (>/=Gleason 8 or stage III/IV), 201 African-American cases, and 1216 controls). We tested baseline sera for T. vaginalis antibodies. RESULTS: No associations were observed for risk of Gleason 7 (odds ratio (OR) = 0.87, 95% confidence interval (CI) 0.55-1.37) or more advanced (OR = 0.90, 95% CI 0.58-1.38) PCa in Caucasian men, or for risk of any PCa (OR = 1.06, 95% CI 0.67-1.68) in African-American men. CONCLUSIONS: Our findings do not support an association between T. vaginalis infection and PCa.

BACKGROUND: The oral fungal microbiome (mycobiome) is not well characterized, particularly in relation to oral diseases such as periodontal disease. We aimed to describe and compare the oral mycobiome of subjects with and without periodontal disease. RESULTS: We characterized the oral mycobiome in 30 adult subjects (15 with periodontal disease, 15 with good oral health) by sequencing the taxonomically informative pan-fungal internal transcribed spacer (ITS) gene in DNA extracted from oral wash samples. We observed at least 81 genera and 154 fungal species across all samples. Candida and Aspergillus were the most frequently observed genera (isolated from 100% of participants), followed by Penicillium (97%), Schizophyllum (93%), Rhodotorula (90%), and Gibberella (83%). Candida and Aspergillus were also the most highly abundant genera in the samples (median relative abundance = 21% and 44%, respectively). Aspergillus niger was the most highly abundant species in the samples (median relative abundance = 44%). We did not observe significant differences in overall oral mycobiome diversity or composition between participants with periodontal disease and participants with good oral health, nor did we observe significant differences in phylum through species level taxon relative abundance or carriage between the two groups. Genus Candida, previously associated with periodontal disease in culture-based studies, had higher median relative abundance in participants with periodontal disease (33.2%) compared to participants with oral health (2.2%), though the difference was not significant (p = 0.52). Additionally, within the periodontal disease group, median relative abundance of Candida increased with increasing number of permanent teeth lost (1-2 teeth lost: 3.2%; 3-4 teeth lost: 16.6%; >/=5 teeth lost: 73.9%; p = 0.11), though sample size was small for this analysis. CONCLUSIONS: In this first study comprehensively characterizing the oral mycobiome of adults with periodontal disease or good oral health, we observed trends of higher Candida abundance in participants with periodontal disease, and participants with greater tooth loss. Small sample size may have limited the power to detect significant associations. Larger studies including subgingival samples may further establish the core oral mycobiome in health, and relate it to periodontal disease.

Background: The two most common types of esophageal cancer, esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC), are highly fatal. The human microbiota have been suggested to play a role in esophageal cancer etiology, although the evidence is limited to small, cross-sectional studies. We hypothesized that the oral microbiota, which shape the esophageal microbiota, may be causative agents in esophageal carcinogenesis. Methods: We conducted a prospective study nested in two large U.S. cohorts: ACS CPS-II and NCI-PLCO. Oral bacteria were assessed in pre-diagnostic mouth-wash samples collected from cases and controls (n=81/160 EAC and n=25/50 ESCC cases/matched controls), using 16S rRNA gene sequencing. We compared overall microbial composition between cases and controls using permutational multivariate analysis of variance (PERMANOVA) of UniFrac distances, and we examined associations between centered log-ratio transformed taxon abundances and cancer risk using conditional logistic regression. Metagenome functional content was predicted from taxonomic composition using PiCRUST. Results: Overall microbial composition did not differ between EAC cases and matched controls or ESCC cases and matched controls, adjusting for matching factors (age, sex, race, cohort, time to diagnosis/selection), BMI, smoking, and alcohol intake (all p>0.40). The periodontal pathogens Tannerella forsythia and Porphyromonas gingivalis were nominally associated with increased risk for EAC (OR [95% CI] = 1.21 [1.01, 1.46], p=0.04) and ESCC (OR [95% CI] = 1.3 [0.96, 1.77], p=0.09), respectively. Conversely, genus Neisseria, previously shown to be depleted by cigarette smoking, was associated with protection against EAC (OR [95% CI] = 0.88 [0.8, 0.97], p=0.01). Other species associated with EAC risk (p<0.05) included Corynebacterium durum, Prevotella nanceiensis, and Streptococcus pneumoniae (inversely associated with EAC), and Actinomyces cardiffensis, Selenomonas oral taxon 134, and Veillonella oral taxon 917 (positively associated with EAC). Other species associated with ESCC risk (p<0.05) included Aggregatibacter paraphrophilus (inversely associated with ESCC) and Prevotella nanceiensis, Bergeyella oral taxon 322, and Neisseria weaveri (positively associated with ESCC). Analysis of inferred metagenomes revealed that bacterial carotenoid biosynthesis was associated with protection against EAC (OR [95% CI] = 0.84 [0.7, 1.0], p=0.05). Conclusions: Our findings from this prospective study suggest that specific bacterial pathogens may play a causal role in esophageal cancer, while members of the healthy oral microbiota may protect against carcinogenesis. Unique microbial profiles may contribute to each of the distinct esophageal cancer types, EAC and ESCC. Oral microbiota manipulation may be a future strategy for preventing this highly fatal disease

Higher carbohydrate intake, glycaemic index (GI), and glycaemic load (GL) are hypothesised to increase cancer risk through metabolic dysregulation of the glucose-insulin axis and adiposity-related mechanisms, but epidemiological evidence is inconsistent. This prospective cohort study investigates carbohydrate quantity and quality in relation to risk of adiposity-related cancers, which represent the most commonly diagnosed preventable cancers in the USA. In exploratory analyses, associations with three site-specific cancers: breast, prostate and colorectal cancers were also examined. The study sample consisted of 3184 adults from the Framingham Offspring cohort. Dietary data were collected in 1991-1995 using a FFQ along with lifestyle and medical information. From 1991 to 2013, 565 incident adiposity-related cancers, including 124 breast, 157 prostate and sixty-eight colorectal cancers, were identified. Cox proportional hazards models were used to evaluate the role of carbohydrate nutrition in cancer risk. GI and GL were not associated with risk of adiposity-related cancers or any of the site-specific cancers. Total carbohydrate intake was not associated with risk of adiposity-related cancers combined or prostate and colorectal cancers. However, carbohydrate consumption in the highest v. lowest quintile was associated with 41 % lower breast cancer risk (hazard ratio (HR) 0.59; 95 % CI 0.36, 0.97). High-, medium- and low-GI foods were not associated with risk of adiposity-related cancers or prostate and colorectal cancers. In exploratory analyses, low-GI foods, were associated with 49 % lower breast cancer risk (HR 0.51; 95 % CI 0.32, 0.83). In this cohort of Caucasian American adults, associations between carbohydrate nutrition and cancer varied by cancer site. Healthier low-GI carbohydrate foods may prevent adiposity-related cancers among women, but these findings require confirmation in a larger sample.

BACKGROUND: Prior studies of the mortality risk associated with glycosylated hemoglobin (A1c) have systematically excluded patients with key comorbidities, and thus may not reflect the true association of A1C with mortality. The objective of the study is to determine mortality risk after accounting for all comorbidities. Design: Retrospective, secondary data analysis from all 168 VA Medical Centers and 1,053 VA Community Based Outpatient Clinics; All patients who from 1/2008 to 12/2015 had >2 primary care visits, not more than 2 years apart, to a VA facility, who had no prevalent diabetes diagnosis before 1/2008, and who had at least 2 A1c measurements METHODS: The A1c level for each patient was defined as the max of the average of two consecutive A1c test results during the study period. The primary outcome was mortality within 6 months of the date of the latter of two consecutive A1c tests. Stratified covariate balancing was used to measure unconfounded impact of A1c on mortality rate, adjusting for the impact of comorbidities. RESULTS: 2,672,558 patients met the entry criteria. Average age was 62 (standard deviation = 14.6), 93% were male, and 71% White. 48% had 1 comorbidity; 19% had 2; 11% had 3; 7% had 4; and 15% had 5 or more. 0.7% had low A1c (<5.0%), 69.7% had normal A1c (5.0 to 5.7%); 26.7% had prediabetic A1C (5.7 to 6.4%), and 2.9% had A1c levels in diabetic range (A1c > 6.5%). The solid line in the Figure shows the 6-month mortality risk associated with unadjusted A1c levels; note that the Figure has deleted A1c levels with less than 1,000 unique patients. All diseases (e.g. cancer) affected both A1c levels and mortality rates. After stratification removed the impact of comorbidities (dashed line), risk of mortality associated with A1c levels dropped. The comorbidity-adjusted risk (e.g. risk at A1c of 4.6%) was lower than unadjusted normal levels (e.g. risk at A1c levels of 5.4%). Prior to adjustment, a change from normal (A1c = 5.4%) to diabetic (A1c = 7%) was associated with 8% higher mortality, while afterwards the same A1C was associated with only 3% higher mortality. CONCLUSIONS: A1c level is associated with mortality across the full range, with risk greatest for those with A1c >6.5% but most of the increase is accounted for by patients' comorbidities, so clinicians should focus on the progression of the underlying diseases and not simply on A1c test results among their patients at risk for diabetes. (Table Presented)

BACKGROUND: United States Veterans are at excess risk for Type 2 diabetes and early mortality. Our objective is to determine the impact of prediabetes and related risk factors on the occurrence of diabetes and mortality in this at-risk population. METHODS: At the primary care practices of the VA New York Harbor (VA NYHHS) during 2004-2014, we identified 15,173 diabetes-free Veterans, among those who received 2 or more hemoglobin A1c tests (HbA1c). Among these participants, we identified 14,361 veterans with HbA1c values below the diabetic range (i.e., <6.5% HbA1c) and characterized these individuals with respect to selected risk factors. We followed these individuals through 2014 for incident diabetes and all-cause mortality. Cox proportional hazard regression was used to relate HbA1c levels, age, sex, race/ethnicity, anthropometric measures, and comorbid cardiovascular conditions (ischemic heart disease, cerebral vascular accident, congestive heart failure and peripheral vascular disease) to incident diabetes and all-cause mortality (Hazard Ratio [HR] and 95% confidence intervals). RESULTS: Among 8,145 Veterans with prediabetes (HbA1c 5.7-6.4%), 1,170 (14.4%) developed diabetes and 1,139 (14%) died during the course of follow-up. Compared to 5,292 normoglycemic Veterans (HbA1c: 5.0-5.6%), 4,207 prediabetics in the moderate risk group (HbA1c 5.7-5.9%) had a greater than 2-fold increased risk of incident diabetes (HR 2.46 [2.08-2.92]), and those 3,938 in the prediabetic high risk group (HbA1c 6.0-6.4%) had a greater than 5-fold risk (HR 5.70 [4.88-6.65]). Furthermore, all-cause mortality was increased in 924 participants with low glycemia (HbA1c <5.0%: HR 1.40 [1.17- 1.68]) and among those 812 in the diabetes risk range (HbA1c >6.5%:HR 1.44 [1.22-1.71]) compared with the normoglycemic group. Excess all-cause mortality was not observed among the prediabetic group, compared to the normoglycemic group. CONCLUSIONS: Among Veterans, prospective risk of transition to Type 2 diabetes ranged from 2.5-fold to 5.7-fold among prediabetics, depending on HbA1c level. Patients with HbA1c < 5.0 and those in the diabetic range had increased risks of all-cause mortality, while prediabetics showed no excess mortality. The higher risk population (HbA1c 6.0-6.4%) is an important group to target with diabetes prevention efforts

BACKGROUND: Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma (CA) and the serrated polyp. We and others have previously shown a relationship between the human gut microbiota and colorectal cancer; however, its relationship to the different early precursors of colorectal cancer is understudied. We tested, for the first time, the relationship of the gut microbiota to specific colorectal polyp types. RESULTS: Gut microbiota were assessed in 540 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples. Participants were categorized as CA cases (n = 144), serrated polyp cases (n = 73), or polyp-free controls (n = 323). CA cases were further classified as proximal (n = 87) or distal (n = 55) and as non-advanced (n = 121) or advanced (n = 22). Serrated polyp cases were further classified as hyperplastic polyp (HP; n = 40) or sessile serrated adenoma (SSA; n = 33). We compared gut microbiota diversity, overall composition, and normalized taxon abundance among these groups. CA cases had lower species richness in stool than controls (p = 0.03); in particular, this association was strongest for advanced CA cases (p = 0.004). In relation to overall microbiota composition, only distal or advanced CA cases differed significantly from controls (p = 0.02 and p = 0.002). In taxon-based analysis, stool of CA cases was depleted in a network of Clostridia operational taxonomic units from families Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and enriched in the classes Bacilli and Gammaproteobacteria, order Enterobacteriales, and genera Actinomyces and Streptococcus (all q < 0.10). SSA and HP cases did not differ in diversity or composition from controls, though sample size for these groups was small. Few taxa were differentially abundant between HP cases or SSA cases and controls; among them, class Erysipelotrichi was depleted in SSA cases. CONCLUSIONS: Our results indicate that gut microbes may play a role in the early stages of colorectal carcinogenesis through the development of CAs. Findings may have implications for developing colorectal cancer prevention therapies targeting early microbial drivers of colorectal carcinogenesis.

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.