Publications by authors named "Laura S Rozek"

94 Publications

Statin use and head and neck squamous cell carcinoma outcomes.

Int J Cancer 2020 Dec 15. Epub 2020 Dec 15.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Head and neck squamous cell carcinoma (HNSCC) is a morbid cancer with poor outcomes. Statins possess anticancer properties such as immunomodulatory and anti-inflammatory effects. The objective of our study is to identify the association between statin use among untreated HNSCC patients and overall death, disease-specific death and recurrence. HNSCC patients were recruited to participate in the University of Michigan Head and Neck Cancer Specialized Program of Research Excellence (SPORE) from 2003 to 2014. Statin use data were collected through medical record review. Participants were considered a statin user if they used a statin at or after diagnosis. Outcome data were collected through medical record review, Social Security Death Index or LexisNexis. Our analytic cohort included 1638 participants. Cox proportional hazard models were used to estimate the association between ever statin use and HNSCC outcomes. Statin use was seen in 36.0% of participants. We observed a statistically significant inverse association between ever using a statin and overall death (HR = 0.75, 95% CI = 0.63-0.88) and HNSCC-specific death (HR = 0.79, 95% CI = 0.63-0.99) and a nonstatistically significant inverse association for recurrence (HR = 0.85, 95% CI = 0.70-1.04). When investigating the association between statin use and HNSCC outcomes utilizing interaction terms between statin use and human papillomavirus (HPV), statistically significant interactions for HNSCC-specific death and recurrence were identified (HNSCC-specific death: HPV-positive HR = 0.41, 95% CI = 0.21-0.84; HPV-negative HR = 1.04, 95% CI = 0.71-1.51; p-int=0.02; recurrence: HPV-positive HR = 0.49, 95% CI = 0.29-0.84; HPV-negative HR = 1.03, 95% CI = 0.74-1.43; p=int-0.02). Statin use may be protective for adverse outcomes in HNSCC patients, particularly those with HPV-positive disease. If true, these findings could have a meaningful impact on tertiary prevention for this cancer.
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http://dx.doi.org/10.1002/ijc.33441DOI Listing
December 2020

Pretreatment Dietary Patterns, Serum Carotenoids and Tocopherols Influence Tumor Immune Response in Head and Neck Squamous Cell Carcinoma.

Nutr Cancer 2020 Dec 11:1-13. Epub 2020 Dec 11.

Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA.

Background: Tumor infiltrating lymphocytes (TILs) aid in informing treatment for head and neck squamous cell carcinoma (HNSCC). Nevertheless, little is known about the role of diet on TILs.

Methods: Immunohistologic expression of CD4, CD8, CD68, CD103, CD104 and FOXP3 were assessed in tissue microarrays from 233 previously untreated HNSCC patients. Associations between these markers and pretreatment dietary patterns were evaluated using linear regression. Associations between baseline serum carotenoids, tocopherols and TILs were assessed using logistic regression. Cox models evaluated the association between diet and TILs on overall and recurrence-free survival.

Results: Consumption of a Western dietary pattern was associated with lower CD8+ and FOXP3+ infiltrates (p-value:0.03 and 0.02, respectively). Multivariable logistic regression models demonstrated significantly higher CD8+ (OR:2.21;p-value:0.001) and FOXP3+ (OR:4.26;p-value:<0.0001) among patients with high gamma tocopherol. Conversely, high levels of xanthophylls (OR:0.12;p-value:<0.0001), lycopene (OR:0.36;p-value:0.0001) and total carotenoids(OR:0.31;p-value: <0.0001) were associated with significantly lower CD68+. Among those with high CD4+ (HR:1.77;p-value:0.03), CD68+ (HR:2.42;p-value:0.004), CD103+ (HR:3.64;p-value:0.03) and FOXP3+ (HR:3.09;p-value:0.05), having a high Western dietary pattern increased the risk of overall mortality when compared to a low Western dietary pattern.

Conclusion: Dietary patterns and serum carotenoids may play an important role in modifying TILs, and ultimately, outcome after diagnosis with HNSCC.
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http://dx.doi.org/10.1080/01635581.2020.1842895DOI Listing
December 2020

Subtype Specific Nasopharyngeal Carcinoma Incidence and Survival Trends: Differences between Endemic and Non-Endemic Populations.

Asian Pac J Cancer Prev 2020 Nov 1;21(11):3291-3299. Epub 2020 Nov 1.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, Thailand.

Background: While nasopharyngeal carcinoma (NPC) is rare in non-endemic regions such as the North America, endemic countries, such as Thailand, continue to struggle with high incidence and mortality rates. NPC has a complex etiology that varies by histological subtype.

Methods: NPC cases (1990-2014) were identified using the International Classification of Diseases for Oncology (ICD-O) code C11 from the Chiang Mai, Khon Kaen, Lampang, and Songkhla cancer registries and compared to Asian/Pacific Islanders (A/PI) from the US SEER program. Age-standardized incidence rates and changes in annual percent change (APC) for overall and subtype specific NPC were assessed using R and Joinpoint. Kaplan Meier curves were generated in SAS to evaluate differences in survival by sex, year of diagnosis and histological subtype. Five-year relative survival estimates were calculated between 2000-2014.

Results: Non-keratinizing NPC predominated across all registries except Songkhla, where the keretinizing subtype made up ~60% of all reported cases. Incidence of keratinizing NPC significantly decreased among Chiang Mai males between 1996 and 2014 (APC:-13.0 [95%CI:-16.2, -9.6]), Songkhla females (APC:-4.0 [95%CI: -7.4, -0.5]) and males between 2006 and 2014 (APC:-15.5 [95%CI:-25.0, -4.7]), as well as A/PI females (APC:-5.1 [95%CI:-6,7, -3.4]) and males (APC: -4.8 [95%CI:-5.9, -3.7]). Non-keratinizing NPC increased among Songkhla males (APC:4.3 [95%CI:1.8, 6.9]). The keratinizing subtype exhibited the worst survival, while the non-keratinizing undifferentiated subtype had the best survival. Although US A/PI had the highest 5-year relative survival estimates, among the Thai registries Chiang Mai had the best and Lampang the worst survival.

Conclusion: Although US A/PIs exhibited similar rates of NPC as seen in the endemic Thai population, improved tobacco control has led to a decrease in keratinizing NPC incidence irrespective of geography. Additionally, while challenges associate with access to care may still exist among rural Thais, chemoradiation was shown to confer a survival benefit in non-keratinizing NPC treatment.
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http://dx.doi.org/10.31557/APJCP.2020.21.11.3291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033109PMC
November 2020

5-Hydroxymethylation highlights the heterogeneity in keratinization and cell junctions in head and neck cancers.

Clin Epigenetics 2020 11 17;12(1):175. Epub 2020 Nov 17.

Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Ave., Ann Arbor, MI, 48109-2218, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide, with human papillomavirus (HPV)-related HNSCC rising to concerning levels. Extensive clinical, genetic and epigenetic differences exist between HPV-associated HNSCC and HPV-negative HNSCC, which is often linked to tobacco use. However, 5-hydroxymethylation (5hmC), an oxidative derivative of DNA methylation and its heterogeneity among HNSCC subtypes, has not been studied.

Results: We characterized genome-wide 5hmC profiles in HNSCC by HPV status and subtype in 18 HPV(+) and 18 HPV(-) well-characterized tumors. Results showed significant genome-wide hyper-5hmC in HPV(-) tumors, with both promoter and enhancer 5hmC able to distinguish meaningful tumor subgroups. We identified specific genes whose differential expression by HPV status is driven by differential hydroxymethylation. CDKN2A (p16), used as a key biomarker for HPV status, exhibited the most extensive hyper-5hmC in HPV(+) tumors, while HPV(-) tumors showed hyper-5hmC in CDH13, TIMP2, MMP2 and other cancer-related genes. Among the previously reported two HPV(+) subtypes, IMU (stronger immune response) and KRT (more keratinization), the IMU subtype revealed hyper-5hmC and up-regulation of genes in cell migration, and hypo-5hmC with down-regulation in keratinization and cell junctions. We experimentally validated our key prediction of higher secreted and intracellular protein levels of the invasion gene MMP2 in HPV(-) oral cavity cell lines.

Conclusion: Our results implicate 5hmC in driving differences in keratinization, cell junctions and other cancer-related processes among tumor subtypes. We conclude that 5hmC levels are critical for defining tumor characteristics and potentially used to define clinically meaningful cancer patient subgroups.
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http://dx.doi.org/10.1186/s13148-020-00965-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672859PMC
November 2020

Increasing prevalence of HPV in oropharyngeal carcinoma suggests adaptation of p16 screening in Southeast Asia.

J Clin Virol 2020 11 9;132:104637. Epub 2020 Sep 9.

Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, United States; Department of Otolaryngology - Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.

Background: Human papillomavirus (HPV) is etiologically linked to increasing oropharyngeal squamous cell carcinoma (OPSCC) rates in the Western world. However, the role of HPV in Southeast Asia, a high incidence region, hasn't been assessed.

Methods: 96 formalin-fixed, paraffin-embedded (FFPE) tissue blocks and corresponding patient data were obtained from Srinagarind Hospital, Thailand from 2012-2017. DNA from areas of 70 %+ cellularity were genotyped using polymerase chain reaction (PCR) and stained for p16, a surrogate marker for HPV. Inverse probability weights based on data from the hospital-based cancer registry were used in statistical analyses. Adjusted linear regression was used to assess changes in OPSCC HPV prevalence and conduct projections. Kaplan-Meier and Cox proportional hazard models were used to determine HPV-specific survival differences.

Results: 14 patients exhibited monoinfection with HPV16, two with HPV18 and one was HPV16/18 coinfected. PCR results were in agreement with p16 staining. On average, HPV + patients were more likely to have tonsil cancer (p-value:0.002). HPV prevalence increased by 2% annually (pvalue: 0.01), from 16 % in 2012 to 26 % in 2017. At the current rate, OPSCC HPV positivity will exceed 50 % by 2030. HPV positivity was shown to be protective in Kaplan-Meier (log-rank p = 0.02) and sex, age and stage adjusted Cox models (HR:0.34 [95 %CI:0.22, 0.52]).

Conclusion: Given the increased prevalence and similarities in presentation of HPV + OPSCC to those observed in Western countries, the data suggest the adaptation of p16 staining and subsequent restaging of OPSCC tumors as suggested by the American Joint Committee on Cancer in Southeast Asia.
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http://dx.doi.org/10.1016/j.jcv.2020.104637DOI Listing
November 2020

Effect of vitamin D receptor polymorphisms on plasma oxidative stress and apoptotic biomarkers among breast cancer survivors supplemented vitamin D3.

Eur J Cancer Prev 2020 09;29(5):433-444

Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA.

We investigated whether plasma oxidative stress and apoptotic biomarkers were associated with the VDR polymorphisms in breast cancer survivors supplemented with vitamin D3. Two hundred fourteen breast cancer survivors received 4000 IU of vitamin D3 daily for 12 weeks. Linear regression was used to analyze whether the effect of vitamin D3 supplementation on response variables was associated with the selected VDR single nucleotide polymorphisms executing by 'association' function in the R package 'SNPassoc'. Linear regression analyses adjusted for age, BMI and on-study plasma 25(OH)D changes indicated that the aa genotype of the ApaI [codominant model (aa vs. AA): -0.21 (-0.39 to -0.03); recessive model (aa vs. AA and Aa): -0.20 (-0.37 to -0.03)] and bb genotypes of the BsmI [recessive model (bb vs. BB and Bb): -0.20 (-0.39 to -0.01)] on VDR were associated with greater decrease in plasma Bcl2. Our findings indicated that, the Ff genotype of FokI was accompanied by higher increase in plasma MDA levels [codominant model (Ff vs. FF): 0.64 (0.18-1.11); dominant model (ff and Ff vs. FF): 0.52 (0.09-0.05)]. This observed association was not remained statistically significant after correction for multiple testing. Haplotype score analyses revealed statistically significant association between the FokI BsmI ApaI haplotype and circulating MDA changes (P-value for global score = 0.001) after false-discovery rate correction. Our study suggests that genetic variations in the VDR do not powerfully modify the effects of vitamin D3 intake on biomarkers associated with antioxidant activity, oxidative stress and apoptosis in breast cancer survivors.
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http://dx.doi.org/10.1097/CEJ.0000000000000576DOI Listing
September 2020

Significant association between host transcriptome-derived HPV oncogene E6* influence score and carcinogenic pathways, tumor size, and survival in head and neck cancer.

Head Neck 2020 09 14;42(9):2375-2389. Epub 2020 May 14.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

Background: Human papillomavirus (HPV) oncogenes E6, E7, and shorter isoforms of E6 (E6*) are known carcinogenic factors in head and neck squamous cell carcinoma (HNSCC). Little is known regarding E6* functions.

Methods: We analyzed RNA-seq data from 68 HNSCC HPV type 16-positive tumors to determine host genes and pathways associated with E6+E7 expression (E6E7) or the percent of full-length E6 (E6%FL). Influence scores of E6E7 and E6%FL were used to test for associations with clinical variables.

Results: For E6E7, we recapitulated all major known affected pathways and revealed additional pathways. E6%FL was found to affect mitochondrial processes, and E6%FL influence score was significantly associated with overall survival and tumor size.

Conclusions: HPV E6E7 and E6* result in extensive, dose-dependent compensatory effects and dysregulation of key cancer pathways. The switch from E6 to E6* promotes oxidative phosphorylation, larger tumor size, and worse prognosis, potentially serving as a prognostic factor for HPV-positive HNSCC.
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http://dx.doi.org/10.1002/hed.26244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052131PMC
September 2020

Descriptive Epidemiology of breast and gynecological cancers among patients attending Saint Paul's Hospital Millennium Medical College, Ethiopia.

PLoS One 2020 20;15(3):e0230625. Epub 2020 Mar 20.

Department of Public Health, Saint Paul's Hospital Millennium Medical College, AA, Ethiopia.

Introduction: Cancer is a leading cause of death in both more and less economically developed countries; the burden is expected to grow in less developed countries, such as Ethiopia. Lack of adequate information is one of the major problems preventing the design of cancer control strategies in Ethiopia.

Objective: To characterize gynecological and breast cancers among clients attending Gynecologic clinic of Saint Paul Hospital Millennium Medical college over 5 year period.

Methods: We retrospectively reviewed characteristics of 2,002 female cancer patients who visited the Oncology unit of Saint Paul's Hospital Millennium Medical College from 2014-2018. We estimated the proportion, pattern and trend of common types of gynecologic cancers as well as breast cancer. The ten years incidence projection was also computed.

Result: From the 2,002 malignancies, cervical (46.7%) was the most frequent cancer followed by breast (29.3%) and ovarian cancers (13%). The majority of breast cancers were observed among younger patients whereas cervical cancer was predominantly observed among older women. An overall increment in number of breast and gynecologic cancer was observed over the five years period.

Conclusion: In this descriptive study, we found that breast and gynecologic cancers are important public health problems among women in Addis Ababa, and that the number of patients seeking care for these cancers is increasing. Additional studies are needed to identify risk factors for these cancers, particularly among younger women, to characterize the trends over time and to project the scope of the cancer problem expected in the future to inform cancer control programs. Increasing public awareness on the possible risk factors and screening is mandatory in addition to resource allocation for further studies and targeted intervention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083302PMC
June 2020

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples.

Oral Oncol 2020 01 10;100:104487. Epub 2019 Dec 10.

Section of Otolaryngology -- Head & Neck Surgery, Cumming School of Medicine, University of Calgary, 3330 Hospital Dr NW, Calgary Alberta, Canada.

Objectives: To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer.

Materials And Methods: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease.

Results: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent.

Conclusions: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386199PMC
January 2020

Dietary Fiber, Whole Grains, and Head and Neck Cancer Prognosis: Findings from a Prospective Cohort Study.

Nutrients 2019 Sep 27;11(10). Epub 2019 Sep 27.

Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

No studies, to date, have examined the relationship between dietary fiber and recurrence or survival after head and neck cancer diagnosis. The aim of this study was to determine whether pretreatment intake of dietary fiber or whole grains predicted recurrence and survival outcomes in newly diagnosed head and neck cancer (HNC) patients. This was a prospective cohort study of 463 participants baring a new head and neck cancer diagnosis who were recruited into the study prior to the initiation of any cancer therapy. Baseline (pre-treatment) dietary and clinical data were measured upon entry into the study cohort. Clinical outcomes were ascertained at annual medical reviews. Cox proportional hazard models were fit to examine the relationships between dietary fiber and whole grain intakes with recurrence and survival. There were 112 recurrence events, 121 deaths, and 77 cancer-related deaths during the study period. Pretreatment dietary fiber intake was inversely associated with risk of all-cause mortality (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.14-0.95, = 0.04). No statistically significant associations between whole grains and prognostic outcomes were found. We conclude that higher dietary fiber intake, prior to the initiation of treatment, may prolong survival time, in those with a new HNC diagnosis.
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http://dx.doi.org/10.3390/nu11102304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835374PMC
September 2019

Increasing incidence of Epstein-Barr virus-related nasopharyngeal carcinoma in the United States.

Cancer 2020 01 16;126(1):121-130. Epub 2019 Sep 16.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.

Background: The incidence of nasopharyngeal carcinoma (NPC) has been historically low in the United States. Although etiological factors differ by histological subtype, Epstein-Barr virus is accepted as the primary risk factor for nonkeratinizing NPC. In light of the changing epidemiology of viral-associated cancers, it is important to evaluate the temporal incidence of NPC in the United States.

Methods: Incidence and survival data from 1973 through 2015 were obtained from the Surveillance, Epidemiology, and End Results program. Stratified analyses were conducted to assess temporal trends in NPC by histological subtype, sex, and race. The data were analyzed using SAS and Joinpoint Regression Software to determine age-adjusted incidence rates, determine trends in the annual percent change, and calculate 5-year relative survival estimates and Kaplan-Meier curves.

Results: Although overall NPC incidence is decreasing in the United States, the nonkeratinizing differentiated subtype is starkly increasing, with an annual percent change of approximately 4% among white males (95% CI, 2.5%-5.2%), white females (95% CI, 1.9%-6.2%), and black males (95% CI, 2.0%, 5.7%); 2.7% among black females (95% CI, 0.8%, 4.6%); and 1.8% among women in the "other" race category (95% CI, 0.4%-3.3%). Racial disparities were noted, with 32% of nonkeratinizing NPC cases among blacks occurring before the age of 40 years. In addition, black males displayed consistently worse survival across all histological subtypes, whereas individuals in the "other" race category, particularly females, experienced the highest 5-year relative survival estimates.

Conclusions: The current results indicate that the Epstein-Barr virus-related, differentiated NPC subtype is increasing across all sexes and races in the United States, with distinct incidence and survival disparities among blacks.
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http://dx.doi.org/10.1002/cncr.32517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906241PMC
January 2020

Pretreatment Dietary Patterns Are Associated with the Presence of Nutrition Impact Symptoms 1 Year after Diagnosis in Patients with Head and Neck Cancer.

Cancer Epidemiol Biomarkers Prev 2019 10 17;28(10):1652-1659. Epub 2019 Jul 17.

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, Illinois.

Background: Dietary inflammatory potential could impact the presence and severity of chronic adverse treatment effects among patients with head and neck cancer. The objective of this study was to determine whether pretreatment dietary patterns are associated with nutrition impact symptoms (NIS) as self-reported 1 year after diagnosis.

Methods: This was a longitudinal study of 336 patients with newly diagnosed head and neck cancer enrolled in the University of Michigan Head and Neck Specialized Program of Research Excellence. Principal component analysis was utilized to derive pretreatment dietary patterns from food frequency questionnaire data. Burden of seven NIS was self-reported 1 year after diagnosis. Associations between pretreatment dietary patterns and individual symptoms and a composite NIS summary score were examined with multivariable logistic regression models.

Results: The two dietary patterns that emerged were prudent and Western. After adjusting for age, smoking status, body mass index, tumor site, cancer stage, calories, and human papillomavirus status, significant inverse associations were observed between the prudent pattern and difficulty chewing [OR 0.44; 95% confidence interval (CI), 0.21-0.93; = 0.03], dysphagia of liquids (OR 0.38; 95% CI, 0.18-0.79; = 0.009), dysphagia of solid foods (OR 0.46; 95% CI, 0.22-0.96; = 0.03), mucositis (OR 0.48; 95% CI, 0.24-0.96; = 0.03), and the NIS summary score (OR 0.45; 95% CI, 0.22-0.94; = 0.03). No significant associations were observed between the Western pattern and NIS.

Conclusions: Consumption of a prudent diet before treatment may help reduce the risk of chronic NIS burden among head and neck cancer survivors.

Impact: Dietary interventions are needed to test whether consumption of a prudent dietary pattern before and during head and neck cancer treatment results in reduced NIS burden.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774815PMC
October 2019

Vitamin D Receptor Genetic Variation and Cancer Biomarkers among Breast Cancer Patients Supplemented with Vitamin D3: A Single-Arm Non-Randomized Before and After Trial.

Nutrients 2019 Jun 4;11(6). Epub 2019 Jun 4.

Department of Environmental Health Sciences, University of Michigan School of Public Health, M6529 SPH II, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA.

We investigated whether vitamin D receptor () polymorphisms were associated with cancer biomarkers, i.e., E-cadherin, matrix metallopeptidase 9 (MMP9), interferon β (IFNβ), soluble intercellular adhesion molecule-1 (s-ICAM-1), soluble vascular cell adhesion molecule-1 (s-VCAM-1), tumor necrosis factorα (TNFα), interleukin 6 (IL6), plasminogen activator inhibitor-1(PAI-1), and human high sensitivity C-reactive protein (hs-CRP), among breast cancer survivors who received vitamin D3 supplementation. In a single-arm non-randomized pre- and post trial, 176 breast cancer survivors who had completed treatment protocol including surgery, radio and chemotherapy were enrolled in the study and received 4000 IU of vitamin D3 daily for 12 weeks. The association between the SNPs (, , , and ) and response variable changes was assessed using linear regression, utilizing the "association" function in the R package "SNPassoc". We observed that women with AA and GA [codominant model (AA compared to GG) and (GA compared to GG); dominant model (AA & GA compared to GG)] genotypes of showed higher increase in plasma MMP9 levels compared to the GG category. In addition, carriers of bb showed greater decrease in circulating TNFα levels after vitamin D3 supplementation [recessive model (bb compared to BB & Bb]. Likewise, significant associations were identified between haplotypes of polymorphisms and on-study plasma MMP9 changes. However, our results indicate that genetic polymorphisms were not associated with longitudinal changes in the remaining cancer biomarkers. Overall, our findings suggest that changes in certain inflammatory biomarkers in breast cancer survivors with low plasma 25(OH)D levels, supplemented with vitamin D3, may depend on SNPs and haplotypes.
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http://dx.doi.org/10.3390/nu11061264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628022PMC
June 2019

Micronutrient status and leukocyte telomere length in school-age Colombian children.

Eur J Nutr 2020 Apr 20;59(3):1055-1065. Epub 2019 Apr 20.

Department of Epidemiology, University of Michigan School of Public Health, Room 5507 SPH II, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.

Purpose: Leukocyte telomere length (LTL) is a biomarker of inflammation and oxidative stress that predicts chronic disease risk. Nutritional factors are related to LTL in adulthood, but these associations are not well characterized in children. We examined whether micronutrient status biomarkers were associated with LTL in school-age children.

Methods: We conducted a cross-sectional study of 330 boys and 393 girls aged 5-12 years from Bogotá, Colombia. We quantified blood concentrations of hemoglobin, ferritin, zinc, vitamin A, folate, and vitamin B-12; and measured LTL using qPCR in DNA extracted from buffy coat. We estimated mean differences in LTL by quartiles of micronutrient status biomarkers and categories of relevant sociodemographic and anthropometric covariates with the use of linear regression.

Results: In girls, plasma vitamin B-12 was positively associated with LTL (adjusted LTL difference between extreme vitamin B-12 quartiles = 0.11; P, trend = 0.02). LTL was also positively associated with birth order in girls (P, trend = 0.02). In boys, LTL was not related to the micronutrient status biomarkers but, unexpectedly, it was positively associated with birth weight (P = 0.02), height-for-age Z score (P, trend = 0.01), and serum C-reactive protein (P, trend = 0.01).

Conclusions: LTL is associated with vitamin B-12 status among girls. LTL is also associated with birth weight, height, and C-reactive protein in boys.
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http://dx.doi.org/10.1007/s00394-019-01966-xDOI Listing
April 2020

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

Nutr Cancer 2019 12;71(5):772-780. Epub 2019 Mar 12.

a University of Michigan , Ann Arbor , Michigan, USA.

Aim: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial.

Methods: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months.

Results: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes.

Conclusion: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.
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http://dx.doi.org/10.1080/01635581.2019.1577981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513708PMC
May 2020

Temporal Changes in Head and Neck Cancer Incidence in Thailand Suggest Changing Oropharyngeal Epidemiology in the Region.

J Glob Oncol 2019 03;5:1-11

University of Michigan School of Public Health, Ann Arbor, MI.

Purpose: Head and neck cancer is the sixth most common cancer in the world, and the largest burden occurs in developing countries. Although the primary risk factors have been well characterized, little is known about temporal trends in head and neck cancer across Thailand.

Methods: Head and neck squamous cell carcinoma (HNSCC) occurrences diagnosed between 1990 and 2014 were selected by International Classification of Diseases (10th revision; ICD10) code from the Songkhla, Lampang, Chiang Mai, and Khon Kaen cancer registries and the US SEER program for oral cavity (ICD10 codes 00, 03-06), tongue (ICD10 codes 01-02), pharynx (ICD10 codes 09-10, 12-14), and larynx (ICD10 code 32). The data were analyzed using R and Joinpoint regression software to determine age-standardized incidence rates and trends of annual percent change (APC). Incidence rates were standardized using the Segi (1960) population. Stratified linear regression models were conducted to assess temporal trends in early-onset HNSCC across 20-year age groups.

Results: Although overall HNSCC rates are decreasing across all registries, subsite analyses demonstrate consistent decreases in both larynx and oral cavity cancers but suggest increases in tongue cancers among both sexes in the United States (APC, 2.36; APC, 0.77) and in pharyngeal cancer in Khon Kaen and US men (APC, 2.1 and 2.23, respectively). Age-stratified APC analyses to assess young-onset (< 60 years old) trends demonstrated increased incidence in tongue cancer in Thailand and the United States as well as in pharyngeal cancers in Khon Kaen men age 40 to 59 years and US men age 50 to 59 years.

Conclusion: Although overall trends in HNSCC are decreasing across both Thailand and the United States, there is reason to believe that the etiologic shift to oropharyngeal cancers in the United States may be occurring in Thailand.
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http://dx.doi.org/10.1200/JGO.18.00219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449079PMC
March 2019

Differences in prostate tumor characteristics and survival among religious groups in Songkhla, Thailand.

BMC Cancer 2018 Nov 27;18(1):1175. Epub 2018 Nov 27.

Department of Epidemiology, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48103, USA.

Background: The incidence and mortality from prostate cancer is expected to increase in the next decade in Thailand. Despite the perceived lower risk in this population vs. developed, western countries, it is becoming an important public health issue. Prostate cancer incidence varies between the most predominant religious groups in Thailand, Buddhists and Muslims. However limited data is available describing the prostate cancer survival in these two populations. Here we examine differences in prostate tumor characteristics and survival between Buddhists and Muslims in the province of Songkhla, Thailand.

Methods: 945 incident prostate cancer cases (1990-2014) from the population-based Songkhla Cancer Registry were used in this analysis. Age, grade, stage, and year at diagnosis were compared across religious groups, using Wilcoxon or Chi-square tests. Kaplan Meier methods were used to estimate the median survival time and 5-year survival probabilities. Cox proportional hazards models were used to estimate hazard ratios (HR) between religious groups and 95% confidence intervals (CI) for mortality in age-adjusted and fully-adjusted models.

Results: Prostate tumor characteristics, age, and year at diagnosis were similar across religious groups. The median survival time after diagnosis of prostate cancer was longer in Buddhists 3.8 years compared with Muslims 3.2 years (p = 0.08). The age-adjusted risk of death after prostate cancer diagnosis was higher in Muslims compared with Buddhists (HR: 1.31; 95%CI: 1.00, 1.72). After adjustment by stage and grade, results were slightly attenuated (HR: 1.27, 95%CI: 0.97, 1.67).

Conclusion: Muslims have shorter survival after prostate cancer diagnosis than do Buddhists in Thailand. The reasons underlying this difference require additional investigation in order to design targeted interventions for both populations.
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http://dx.doi.org/10.1186/s12885-018-5102-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260711PMC
November 2018

Current and Future Burden of Prostate Cancer in Songkhla, Thailand: Analysis of Incidence and Mortality Trends From 1990 to 2030.

J Glob Oncol 2018 09;4:1-11

Christian S. Alvarez, Shama Virani, Rafael Meza, Laura S. Rozek, and Alison M. Mondul, University of Michigan School of Public Health, Ann Arbor, MI; and Shama Virani and Hutcha Sriplung, Prince of Songkla University, Songkhla, Thailand.

Purpose: Prostate cancer is the second most common malignancy among men worldwide, and it poses a significant public health burden that has traditionally been limited mostly to developed countries. However, the burden of the disease is expected to increase, affecting developing countries, including Thailand. We undertook an analysis to investigate current and future trends of prostate cancer in the province of Songkhla, Thailand, using data from the Songkhla Cancer Registry from 1990 to 2013.

Methods: Joinpoint regression analysis was used to examine trends in age-adjusted incidence and mortality rates of prostate cancer and provide estimated annual percent change (EAPC) with 95% CIs. Age-period-cohort (APC) models were used to assess the effect of age, calendar year, and birth cohort on incidence and mortality rates. Three different methods (Joinpoint, Nordpred, and APC) were used to project trends from 2013 to 2030.

Results: Eight hundred fifty-five cases of prostate cancer were diagnosed from 1990 to 2013 in Songkhla, Thailand. The incidence rates of prostate cancer significantly increased since 1990 at an EAPC of 4.8% (95% CI, 3.6% to 5.9%). Similarly, mortality rates increased at an EAPC of 5.3% (95% CI, 3.4% to 7.2%). The APC models suggest that birth cohort is the most important factor driving the increased incidence and mortality rates of prostate cancer. Future incidence and mortality of prostate cancer are projected to continue to increase, doubling the rates observed in 2013 by 2030.

Conclusion: It is critical to allocate resources to provide care for the men who will be affected by this increase in prostate cancer incidence in Songkhla, Thailand, and to design context-appropriate interventions to prevent its increasing burden.
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http://dx.doi.org/10.1200/JGO.17.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223432PMC
September 2018

Childhood cancer incidence and survival in Thailand: A comprehensive population-based registry analysis, 1990-2011.

Pediatr Blood Cancer 2019 01 31;66(1):e27428. Epub 2018 Aug 31.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.

Background: Southeast Asia is undergoing a transition from infectious to chronic diseases, including a dramatic increase in adult cancers. Childhood cancer research in Thailand has focused predominantly on leukemias and lymphomas or only examined children for a short period of time. This comprehensive multisite study examined childhood cancer incidence and survival rates in Thailand across all International Classification of Childhood Cancer (ICCC) groups over a 20-year period.

Methods: Cancer cases diagnosed in children ages 0-19 years (n = 3574) from 1990 to 2011 were extracted from five provincial population-based Thai registries, covering approximately 10% of the population. Descriptive statistics of the quality of the registries were evaluated. Age-standardized incidence rates (ASRs) were calculated using the Segi world standard population, and relative survival was computed using the Kaplan-Meier method. Changes in incidence and survival were analyzed using Joinpoint Regression and reported as annual percent changes (APC).

Results: The ASR of all childhood cancers during the study period was 98.5 per million person-years with 91.0 per million person-years in 1990-2000 and 106.2 per million person-years in 2001-2011. Incidence of all childhood cancers increased significantly (APC = 1.2%, P < 0.01). The top three cancer groups were leukemias, brain tumors, and lymphomas. The 5-year survival for all childhood cancers significantly improved from 39.4% in 1990-2000 to 47.2% in 2001-2011 (P < 0.01).

Conclusions: Both childhood cancer incidence and survival rates have increased, suggesting improvement in the health care system as more cases are identified and treated. Analyzing childhood cancer trends in low- and middle-income countries can improve understanding of cancer etiology and pediatric health care disparities.
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http://dx.doi.org/10.1002/pbc.27428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478028PMC
January 2019

Expressed HNSCC variants by HPV-status in a well-characterized Michigan cohort.

Sci Rep 2018 07 30;8(1):11458. Epub 2018 Jul 30.

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA.

While whole-exome DNA sequencing is the most common technology to study genetic variants in tumors in known exonic regions, RNA-seq is cheaper, covers most of the same exonic regions, and is often more readily available. In this study, we show the utility of mRNA-seq-based variant analysis combined with targeted gene sequencing performed on both tumor and matched blood as an alternative when exome data is unavailable. We use the approach to study expressed variant profiles in the well-characterized University of Michigan (UM) head and neck squamous carcinoma (HNSCC) cohort (n = 36). We found that 441 out of 455 (~97%) identified cancer genes with an expressed variant in the UM cohort also harbor a somatic mutation in TCGA. Fourteen (39%) patients had a germline variant in a cancer-related Fanconi Anemia (FA) pathway gene. HPV-positive patients had more nonsynonymous, rare, and damaging (NRD) variants in those genes than HPV-negative patients. Moreover, the known mutational signatures for DNA mismatch repair and APOBEC activation were attributive to the UM expressed NRD variants, and the APOBEC signature contribution differed by HPV status. Our results provide additional support to certain TCGA findings and suggest an association of expressed variants in FA/DNA repair pathways with HPV-associated HNSCC tumorigenesis. These results will benefit future studies on this and other cohorts by providing the genetic variants of key cancer-related genes.
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http://dx.doi.org/10.1038/s41598-018-29599-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065423PMC
July 2018

Breast Cancer Incidence Trends and Projections in Northeastern Thailand.

J Epidemiol 2018 07 12;28(7):323-330. Epub 2018 May 12.

Department of Pediatrics, Faculty of Medicine, Khon Kaen University.

Background: The northeast has the lowest incidence of breast cancer of all regions in Thailand, although national rates are increasing. The heterogeneity in subnational trends necessitates a comprehensive evaluation of breast cancer incidence trends and projections to provide evidence for future region-specific strategies that may be employed to attenuate this growing burden.

Methods: Joinpoint regression and age-period-cohort modeling were used to describe trends from 1988-2012. Data was projected from three separate models to provide a range of estimates of incidence to the year 2030 by age group.

Results: Age-standardized rates (ASRs) increased significantly for all women from 1995-2012 by 4.5% per year. Rates for women below age 50 increased by 5.1% per year, while women age 50 years and older increased by 6% per year from 1988-2012. Projected rates show that women age 50 years and older have the largest projected increase in ASRs by 2030 compared to younger women and all women combined.

Conclusions: Breast cancer trends in Khon Kaen are presently lower than other regions but are expected to increase and become comparable to other regions by 2030, particularly for women ages 50 years and older.
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http://dx.doi.org/10.2188/jea.JE20170045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004364PMC
July 2018

Vitamin D intake and survival and recurrence in head and neck cancer patients.

Laryngoscope 2018 11 14;128(11):E371-E376. Epub 2018 May 14.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.

Objectives/hypothesis: With an unacceptably low 5-year survival rate and few identified modifiable factors that affect head and neck cancer (HNC) outcomes, HNC survival remains an important public health problem. Vitamin D has been shown to be associated with immune reactivity and improved outcomes for some cancer sites, but findings are mixed, and few studies have examined vitamin D in relation to HNC. This study aimed to assess the association between vitamin D intake and survival outcomes in HNC patients.

Study Design: Prospective cohort study.

Methods: This study utilized data on 434 HNC patients with valid pretreatment food frequency questionnaire data who participated in the University of Michigan Head and Neck Specialized Program of Research Excellence epidemiology project. Cox proportional hazard models were used to estimate the associations between total, dietary, and supplemental vitamin D intake and HNC outcomes, while adjusting for other known prognostic factors.

Results: After multivariable adjustment, we found a statistically significant inverse trend between total vitamin D intake and recurrence (Q4 vs. Q1 hazard ratio: 0.47, 95% confidence interval: 0.20-1.10, P trend = .048). We observed no association with dietary or supplemental intake separately, and no association was observed with all-cause or HNC-specific mortality.

Conclusions: These findings suggest that HNC patients with lower levels of vitamin D intake are at higher risk of recurrence. If borne out in future studies, our results suggest that increased vitamin D intake through dietary intervention or the use of supplements may be a feasible intervention for prevention of recurrence in HNC patients.

Level Of Evidence: 2b. Laryngoscope, E371-E376, 2018.
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http://dx.doi.org/10.1002/lary.27256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235739PMC
November 2018

Cadmium Exposure Inhibits Branching Morphogenesis and Causes Alterations Consistent With HIF-1α Inhibition in Human Primary Breast Organoids.

Toxicol Sci 2018 08;164(2):592-602

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan 48109-2029.

Developmental cadmium exposure in vivo disrupts mammary gland differentiation, while exposure of breast cell lines to cadmium causes invasion consistent with the epithelial-mesenchymal transition (EMT). The effects of cadmium on normal human breast stem cells have not been measured. Here, we quantified the effects of cadmium exposure on reduction mammoplasty patient-derived breast stem cell proliferation and differentiation. Using the mammosphere assay and organoid formation in 3D hydrogels, we tested 2 physiologically relevant doses of cadmium, 0.25 and 2.5 µM, and tested for molecular alterations using RNA-seq. We functionally validated our RNA-seq findings with a hypoxia-inducible factor (HIF)-1α activity reporter line and pharmaceutical inhibition of HIF-1α in organoid formation assays. 2.5 µM cadmium reduced primary mammosphere formation and branching structure organoid formation rates by 33% and 87%, respectively. Despite no changes in mammosphere formation, 0.25 µM cadmium inhibited branching organoid formation in hydrogels by 73%. RNA-seq revealed cadmium downregulated genes associated with extracellular matrix formation and EMT, while upregulating genes associated with metal response including metallothioneins and zinc transporters. In the RNA-seq data, cadmium downregulated HIF-1α target genes including LOXL2, ZEB1, and VIM. Cadmium significantly inhibited HIF-1α activity in a luciferase assay, and the HIF-1α inhibitor acriflavine ablated mammosphere and organoid formation. These findings show that cadmium, at doses relevant to human exposure, inhibited human mammary stem cell proliferation and differentiation, potentially through disruption of HIF-1α activity.
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http://dx.doi.org/10.1093/toxsci/kfy112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061678PMC
August 2018

Ethnic disparity in breast cancer survival in southern Thai women.

Cancer Epidemiol 2018 06 21;54:82-89. Epub 2018 Apr 21.

Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand. Electronic address:

Background: Breast cancer has the highest incidence in women of all cancers and its burden is expected to continue to increase worldwide, especially in middle-income countries such as Thailand. The southern region of Thailand is unique in that it is comprised of 30% Muslims, whereas the rest of Thailand is 95% Buddhist. Breast cancer incidence and survival differ between these religious groups, but the association between clinical subtype of breast cancer and survival has not yet been assessed.

Methods: Here we characterized differences in breast cancer survival with consideration to clinical subtype by religious group (Muslim Thai and Buddhist Thai women). We compared distributions of age, stage and clinical subtype and assessed overall survival by religion.

Results: Our findings show that Muslim Thai women with breast cancer are diagnosed at a younger age, at later stages and have shorter overall survival times compared to Buddhist Thai women with breast cancer. We also observe a higher proportion of triple negative tumors characterized in Muslim Thai women.

Conclusions: Our findings confirm previous studies that have shown lower survival rates in Muslim Thai women compared to Buddhist women with breast cancer and offer novel information on subtype distribution. To date, this is the first study assessing clinical subtypes in southern Thailand by religious status.

Impact: Our findings are critical in providing information on the role of clinical subtype in cancer disparities and provide evidence from the Southeast Asian region for global studies on breast cancer survival.
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http://dx.doi.org/10.1016/j.canep.2018.02.007DOI Listing
June 2018

Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by Transcriptional Profiling.

Stem Cell Reports 2018 05 29;10(5):1596-1609. Epub 2018 Mar 29.

Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

During development, the mammary gland undergoes extensive remodeling driven by stem cells. Breast cancers are also hierarchically organized and driven by cancer stem cells characterized by CD44CD24 or aldehyde dehydrogenase (ALDH) expression. These markers identify mesenchymal and epithelial populations both capable of tumor initiation. Less is known about these populations in non-cancerous mammary glands. From RNA sequencing, ALDH and ALDHCD44CD24 human mammary cells have epithelial-like and mesenchymal-like characteristics, respectively, with some co-expressing ALDH and CD44CD24 by flow cytometry. At the single-cell level, these cells have the greatest mammosphere-forming capacity and express high levels of stemness and epithelial-to-mesenchymal transition-associated genes including ID1, SOX2, TWIST1, and ZEB2. We further identify single ALDH cells with a hybrid epithelial/mesenchymal phenotype that express genes associated with aggressive triple-negative breast cancers. These results highlight single-cell analyses to characterize tissue heterogeneity, even in marker-enriched populations, and identify genes and pathways that define this heterogeneity.
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http://dx.doi.org/10.1016/j.stemcr.2018.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995162PMC
May 2018

Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study.

Int J Cancer 2018 09 17;143(5):1105-1113. Epub 2018 Apr 17.

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.

No studies have evaluated associations between carbohydrate intake and head and neck squamous cell carcinoma (HNSCC) prognosis. We prospectively examined associations between pre- and post-treatment carbohydrate intake and recurrence, all-cause mortality, and HNSCC-specific mortality in a cohort of 414 newly diagnosed HNSCC patients. All participants completed pre- and post-treatment Food Frequency Questionnaires (FFQs) and epidemiologic surveys. Recurrence and mortality events were collected annually. Multivariable Cox Proportional Hazards models tested associations between carbohydrate intake (categorized into low, medium and high intake) and time to recurrence and mortality, adjusting for relevant covariates. During the study period, there were 70 deaths and 72 recurrences. In pretreatment analyses, high intakes of total carbohydrate (HR: 2.29; 95% CI: 1.23-4.25), total sugar (HR: 3.03; 95% CI: 1.12-3.68), glycemic load (HR: 2.10; 95% CI: 1.15-3.83) and simple carbohydrates (HR 2.26; 95% CI 1.19-4.32) were associated with significantly increased risk of all-cause mortality compared to low intake. High intakes of carbohydrate (HR 2.45; 95% CI: 1.23-4.25) and total sugar (HR 3.03; 95% CI 1.12-3.68) were associated with increased risk of HNSCC-specific mortality. In post-treatment analyses, medium fat intake was significantly associated with reduced risk of recurrence (HR 0.08; 95% CI 0.01-0.69) and all-cause mortality (HR 0.27; 95% CI 0.07-0.96). Stratification by tumor site and cancer stage in pretreatment analyses suggested effect modification by these factors. Our data suggest high pretreatment carbohydrate intake may be associated with adverse prognosis in HNSCC patients. Clinical intervention trials to further examine this hypothesis are warranted.
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http://dx.doi.org/10.1002/ijc.31413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103810PMC
September 2018

Cadmium exposure and age-associated DNA methylation changes in non-smoking women from northern Thailand.

Environ Epigenet 2017 May 18;3(2):dvx006. Epub 2017 Jul 18.

Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48104, USA.

DNA methylation changes with age, and may serve as a biomarker of aging. Cadmium (Cd) modifies cellular processes that promote aging and disrupts methylation globally. Whether Cd modifies aging processes by influencing establishment of age-associated methylation marks is currently unknown. In this pilot study, we characterized methylation profiles in > 450 000 CpG sites in 40 non-smoking women (age 40-80) differentially exposed to environmental Cd from Thailand. Based on specific gravity adjusted urinary Cd, we classified them as high (HE) and low (LE) exposed and age-matched within 5 years. Urinary Cd was defined as below 2 µg/l in the LE group. We predicted epigenetic age (DNAm-age) using two published methods by Horvath and Hannum and examined the difference between epigenetic age and chronologic age (Δage). We assessed differences by Cd exposure using linear mixed models adjusted for estimated white blood cell proportions, BMI, and urinary creatinine. We identified 213 age-associated CpG sites in our population ( < 10). Counterintuitively, the mean Δage was smaller in HE vs. LE (Hannum: 3.6 vs. 7.6 years, = 0.0093; Horvath: 2.4 vs. 4.5 years, = 0.1308). The Cd exposed group was associated with changes in methylation ( < 0.05) at 12, 8, and 20 age-associated sites identified in our population, Hannum, and Horvath. From the results of this pilot study, elevated Cd exposure is associated with methylation changes at age-associated sites and smaller differences between DNAm-age and chronologic age, in contrast to expected age-accelerating effects. Cd may modify epigenetic aging, and biomarkers of aging warrant further investigation when examining Cd and its relationship with chronic disease and mortality.
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http://dx.doi.org/10.1093/eep/dvx006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804546PMC
May 2017

Germline Genetic Features of Young Individuals With Colorectal Cancer.

Gastroenterology 2018 03 14;154(4):897-905.e1. Epub 2017 Nov 14.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan.

Background & Aims: The incidence of colorectal cancer (CRC) in individuals younger than 50 years is increasing. We sought to ascertain the proportion of young CRC cases associated with genetic predisposition.

Methods: We performed a retrospective study of individuals diagnosed with CRC at an age younger than 50 years, evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. We collected data on patient histories, tumor phenotypes, and results of germline DNA sequencing. For subjects with uninformative clinical evaluations, germline DNA samples were (re)sequenced using a research-based next-generation sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.

Results: Of 430 young CRC cases, 111 (26%) had a first-degree relative with CRC. Forty-one of the subjects with CRC (10%) had tumors with histologic evidence for mismatch repair deficiency. Of 315 subjects who underwent clinical germline sequencing, 79 had mutations associated with a hereditary cancer syndrome and 21 had variants of uncertain significance. Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis. Thirteen subjects had mutations in other cancer-associated genes (8 in MUTYH, 2 in SMAD4, 1 in BRCA1, 1 in TP53, and 1 in CHEK2), all identified through multigene panel tests. Among 117 patients with uninformative clinical evaluations, next-generation sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%). Only 43 of the 85 subjects with germline mutations associated with a hereditary cancer syndrome (51%) reported a CRC diagnosis in a first-degree relative.

Conclusions: Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.
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http://dx.doi.org/10.1053/j.gastro.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847426PMC
March 2018

Integrating DNA Methylation and Hydroxymethylation Data with the Mint Pipeline.

Cancer Res 2017 11;77(21):e27-e30

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.

DNA methylation (5mC) plays important roles in mammalian development, oncogenesis, treatment response, and responses to the environment. DNA hydroxymethylation (5hmC) is also an informative epigenetic mark with distinct roles in regulation and cancer. Gold-standard, widely used technologies (bisulfite conversion, followed by deep sequencing) cannot distinguish between 5mC and 5hmC. Therefore, additional experiments are required to differentiate the two marks, and methods are needed to analyze, integrate, and interpret these data. We developed the Methylation INTegration (mint) pipeline to support the comprehensive analysis of bisulfite conversion and immunoprecipitation-based methylation and hydroxymethylation assays, with additional steps toward integration, visualization, and interpretation. The pipeline is available as both a command line and a Galaxy graphical user interface tool. Both implementations require minimal configuration while remaining flexible to experiment specific needs. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678940PMC
November 2017

HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers.

Mol Cancer Res 2018 01 19;16(1):90-102. Epub 2017 Sep 19.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.

The incidence of human papillomavirus (HPV)-related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors ( = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4, CD3, regulatory, CD8 T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation. These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752568PMC
January 2018