bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer
Authors: Ichimura Norihisa , Shinjo Keiko , An Byonggu , Shimizu Yasuhiro , Yamao Kenji , Ohka Fumiharu , Katsushima Keisuke , Hatanaka Akira , Tojo Masayuki , Yamamoto Eiichiro , Suzuki Hiromu , Ueda Minoru , Kondo Yutaka
Published: March 2024

Abstract
Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP-positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP-N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. Cancer Prev Res; 8(8); 702–11. ©2015 AACR.
Data from Development and Validation of a Noninvasive Risk Score Model for Liver Cirrhosis in At-Risk Alcohol Drinkers Without HBV/HCV Infection
Authors: Liu Yin , Guo Lan-Wei , Xu Hui-Fang , Kang Rui-Hua , Zheng Li-Yang , Zhang Lu-Yao , Chen Qiong , Sun Xi-Bin , Qiao You-Lin , Zhang Shao-Kai
Published: March 2024

Abstract
At-risk alcohol consumption is the established most important risk factor for cirrhosis in people without HBV/HCV infection. We aimed to develop and validate a simple and non-invasive tool for triaging cirrhosis risk in at-risk alcohol drinkers without HBV/HCV infection. A large-sample size, cross-sectional study within the framework of a population-based Cancer Screening Program in Urban China (CanSPUC) was conducted. Data on the liver cancer screening in Henan province, China were used. At-risk alcohol drinkers were those who currently drink one or more alcohol units per week for at least six months. A total of 6,581 eligible participants enrolled from October 1, 2013 to December 31, 2016 were included into the derivation dataset, and 2,096 eligible participants enrolled from January 1, 2017 to October 31, 2018 were included into the external validation dataset, respectively. Using the derivation dataset, a 20-point scale risk score model was developed, based on sex, education background, dietary intake of vegetables, dietary intake of roughage, smoking index, length of secondhand smoke exposure, history of fatty liver, history of diabetes, and first-degree family history of liver cancer. The model showed excellent discrimination (AUC  =  0.787; 95% CI, 0.7603–0.812) and calibration (Hosmer–Lemeshow test: P = 0.123) in the derivation dataset and an optimal cut-off value of 12 yield sensitivity of 61.3%, specificity of 82.7%. The model also had achieved similar performance in the external validation dataset. In conclusion, this model can be a practical tool to identify and triage population at high risk of cirrhosis in at-risk alcohol drinkers without HBV/HCV infection.
Prevention Relevance:
The risk model we developed will not only be used as a practical tool to triage high risk groups for liver cirrhosis, but also have implications for public health measures, such as guidelines for the prevention of liver cancer, in at-risk alcohol drinkers without HBV/HCV infection.
Data from Association of Plasma Iron Status with Subsequent Risk of Total and Site-Specific Cancer: A Large Case–Cohort Study within JPHC Study
Authors: Miyamoto Yoshihisa , Nakano Shiori , Ihira Hikaru , Yamaji Taiki , Katagiri Ryoko , Sawada Norie , Inoue Manami , Tsugane Shoichiro , Iwasaki Motoki
Published: March 2024

Abstract
It is unclear whether prediagnostic iron-related biomarkers in circulation are associated with cancer risk. We constructed a case-cohort of participants who had plasma samples available from the Japan Public Health Center—based Prospective Study and determined the incidence of cancer in these participants. We measured plasma concentrations of iron, ferritin, and hepcidin, and assessed the association between each biomarker and cancer incidence using a weighted Cox regression model. There were 4,253 participants in the sub-cohort (the randomly selected participants from an eligible, at-risk population) and 3,596 incident cancer cases (499 cases occurred in the sub-cohort). Median follow-up was for 16.5 years. In the multivariable adjusted analysis, iron deficiency (plasma ferritin <30 ng/mL) was associated with a higher risk of total cancer [adjusted HR, 1.23; 95% confidence interval (CI), 1.07–1.42] and the association was weaker after excluding those followed-up for <3 years. Iron overload was not significantly associated with total cancer (HR, 1.04; 95% CI, 0.82–1.33), but was associated with liver cancer (HR, 4.49; 95% CI, 2.71–7.43). Lower plasma levels of hepcidin and ferritin are associated with an increased gastrointestinal cancer risk. Meanwhile, lower plasma hepcidin and higher plasma ferritin levels were associated with an increased liver cancer risk. In conclusion, there was no association between iron overload and cancer risk, besides liver cancer.
Prevention relevance:
High ferritin and low hepcidin levels in the plasma were associated with increased liver cancer risk. Evaluating iron metabolism including hepcidin levels may help identify people with high liver cancer risk.
Data from Risk Prediction Models for Colorectal Cancer: A Systematic Review
Authors: Usher-Smith Juliet A. , Walter Fiona M. , Emery Jon D. , Win Aung K. , Griffin Simon J.
Published: March 2024

Abstract
Colorectal cancer is the second leading cause of cancer-related death in Europe and the United States. Survival is strongly related to stage at diagnosis and population-based screening reduces colorectal cancer incidence and mortality. Stratifying the population by risk offers the potential to improve the efficiency of screening. In this systematic review we searched Medline, EMBASE, and the Cochrane Library for primary research studies reporting or validating models to predict future risk of primary colorectal cancer for asymptomatic individuals. A total of 12,808 papers were identified from the literature search and nine through citation searching. Fifty-two risk models were included. Where reported (n = 37), half the models had acceptable-to-good discrimination (the area under the receiver operating characteristic curve, AUROC >0.7) in the derivation sample. Calibration was less commonly assessed (n = 21), but overall acceptable. In external validation studies, 10 models showed acceptable discrimination (AUROC 0.71–0.78). These include two with only three variables (age, gender, and BMI; age, gender, and family history of colorectal cancer). A small number of prediction models developed from case–control studies of genetic biomarkers also show some promise but require further external validation using population-based samples. Further research should focus on the feasibility and impact of incorporating such models into stratified screening programmes. Cancer Prev Res; 9(1); 13–26. ©2015 AACR.

See related article by Frank L. Meyskens, Jr., p. 11
Data from Randomized Double-Blind Placebo-Controlled Biomarker Modulation Study of Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer (SWOG S0812)
Authors: Crew Katherine D. , Anderson Garnet L. , Hershman Dawn L. , Terry Mary Beth , Tehranifar Parisa , Lew Danika L. , Yee Monica , Brown Eric A. , Kairouz Sebastien S. , Kuwajerwala Nafisa , Bevers Therese , Doster John E. , Zarwan Corrine , Kruper Laura , Minasian Lori M. , Ford Leslie , Arun Banu , Neuhouser Marian , Goodman Gary E. , Brown Powel H.
Published: March 2024

Abstract
Observational studies have reported an inverse association between vitamin D intake and breast cancer risk. We examined whether vitamin D supplementation in high-risk premenopausal women reduces mammographic density (MD), an established breast cancer risk factor. We conducted a multicenter randomized double-blind placebo-controlled trial in premenopausal women at high risk for breast cancer [5-year risk ≥ 1.67%, lifetime risk ≥ 20%, lobular carcinoma in situ, prior stage 0–II breast cancer, hereditary breast cancer syndrome, or high MD (heterogeneously/extremely dense)], with a baseline serum 25-hydroxyvitamin D [25(OH)D] ≤ 32 ng/mL. Participants were randomized to 12 months of vitamin D3 20,000 IU/week or matching placebo. The primary endpoint was change in MD from baseline to 12 months using the Cumulus technique. Secondary endpoints included serial blood biomarkers [25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)D), insulin-like growth factor (IGF)-1, IGF-binding protein-3] and MD change at 24 months. Among 208 women randomized, median age was 44.6 years, 84% were white, 33% had baseline 25(OH)D < 20 ng/mL, and 78% had high baseline MD. Comparing the active and placebo groups at 12 months, MD changes were small and did not significantly differ. Mean MD changes at 12 and 24 months were −0.3% and −1.2%, respectively, in the active arm and +1.5% and +1.6% with placebo (P > 0.05). We observed a mean change in serum 25(OH)D of +18.9 versus +2.8 ng/mL (P < 0.01) and IGF-1 of −9.8 versus −1.8 ng/mL (P = 0.28), respectively. At 12 months, MD was positively correlated with serum IGF-1 and IGF-1/IGFBP-3 (P < 0.01). This trial does not support the use of vitamin D supplementation for breast cancer risk reduction.
Data from Mitotic Spindle Apparatus Abnormalities in Chronic Obstructive Pulmonary Disease Cells: A Potential Pathway to Lung Cancer
Authors: Thaiparambil Jose , Dong Lingyun , Jasso Diana , Huang Jian-An , El-Zein Randa A.
Published: March 2024

Abstract
Chronic obstructive pulmonary disease (COPD) is a long-term lung disease characterized by irreversible lung damage resulting in airflow limitation, abnormal permanent air-space enlargement, and emphysema. Cigarette smoking is the major cause of COPD with 15% to 30% of smokers developing either disease. About 50% to 80% of patients with lung cancer have preexisting COPD and smokers who have COPD are at an increased risk for developing lung cancer. Therefore, COPD is considered an independent risk for lung cancer, even after adjusting for smoking. A crucial early event in carcinogenesis is the induction of the genomic instability through alterations in the mitotic spindle apparatus. To date, the underlying mechanism by which COPD contributes to lung cancer risk is unclear. We hypothesized that tobacco smoke carcinogens induce mitotic spindle apparatus abnormalities and alter expression of crucial genes leading to increased genomic instability and ultimately tumorigenesis. To test our hypothesis, we assessed the genotoxic effects of a potent tobacco-smoke carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)] on bronchial epithelial cells from patients with COPD and normal bronchial epithelial cells and identified genes associated with mitotic spindle defects and chromosome missegregation that also overlap with lung cancer. Our results indicate that exposure to NNK leads to a significantly altered spindle orientation, centrosome amplification, and chromosome misalignment in COPD cells as compared with normal epithelial cells. In addition, we identified several genes (such as AURKA, AURKB, and MAD2L2) that were upregulated and overlap with lung cancer suggesting a potential common pathway in the transition from COPD to lung cancer.
Data from Genome-Wide Meta-analysis of Gene–Environmental Interaction for Insulin Resistance Phenotypes and Breast Cancer Risk in Postmenopausal Women
Authors: Jung Su Yon , Mancuso Nick , Yu Herbert , Papp Jeanette , Sobel Eric , Zhang Zuo-Feng
Published: March 2024

Abstract
Insulin resistance (IR)–related genetic variants are possibly associated with breast cancer, and the gene–phenotype–cancer association could be modified by lifestyle factors including obesity, physical inactivity, and high-fat diet. Using data from postmenopausal women, a population highly susceptible to obesity, IR, and increased risk of breast cancer, we implemented a genome-wide association study (GWAS) in two steps: (1) GWAS meta-analysis of gene–environmental (i.e., behavioral) interaction (G*E) for IR phenotypes (hyperglycemia, hyperinsulinemia, and homeostatic model assessment–insulin resistance) and (2) after the G*E GWAS meta-analysis, the identified SNPs were tested for their associations with breast cancer risk in overall or subgroup population, where the SNPs were identified at genome-wide significance. We found 58 loci (55 novel SNPs; 5 index SNPs and 6 SNPs, independent of each other) that are associated with IR phenotypes in women overall or women stratified by obesity, physical activity, and high-fat diet; among those 58 loci, 29 (26 new loci; 2 index SNPs and 2 SNPs, independently) were associated with postmenopausal breast cancer. Our study suggests that a number of newly identified SNPs may have their effects on glucose intolerance by interplaying with obesity and other lifestyle factors, and a substantial proportion of these SNPs’ susceptibility can also interact with the lifestyle factors to ultimately influence breast cancer risk. These findings may contribute to improved prediction accuracy for cancer and suggest potential intervention strategies for those women carrying genetic risk that will reduce their breast cancer risk.
Data from In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation
Authors: Borras Ester , Chang Kyle , Pande Mala , Cuddy Amanda , Bosch Jennifer L. , Bannon Sarah A. , Mork Maureen E. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , Lynch Patrick M. , You Y. Nancy , Vilar Eduardo
Published: March 2024

Abstract
Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580–7. ©2017 AACR.
Data from A Systematic Review on Cost-effectiveness Studies Evaluating Ovarian Cancer Early Detection and Prevention Strategies
Authors: Sroczynski Gaby , Gogollari Artemisa , Kuehne Felicitas , Hallsson Lára R. , Widschwendter Martin , Pashayan Nora , Siebert Uwe
Published: March 2024

Abstract
Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.
Data from Effect of Green Tea Supplements on Liver Enzyme Elevation: Results from a Randomized Intervention Study in the United States
Authors: Yu Zheming , Samavat Hamed , Dostal Allison M. , Wang Renwei , Torkelson Carolyn J. , Yang Chung S. , Butler Lesley M. , Kensler Thomas W. , Wu Anna H. , Kurzer Mindy S. , Yuan Jian-Min
Published: March 2024

Abstract
Liver injury effects of green tea–based products have been reported in sporadic case reports. However, no study has examined systematically such adverse effects in an unbiased manner. We examined the potential effects of a high, sustained oral dose of green tea extract (GTE) on liver injury measures in a randomized, placebo-controlled, double-blinded phase II clinical trial, which enrolled 1,075 women with the original aim to assess the effect of daily GTE consumption for 12 months on biomarkers of breast cancer risk. The current analysis examined the effect of GTE consumption on liver injury in 1,021 participants (513 in GTE and 508 in placebo arm) with normal baseline levels of liver enzymes. Among women in the GTE arm, alanine aminotransferase (ALT) increased by 5.4 U/L [95% confidence interval (CI), 3.6–7.1] and aspartate aminotransferase increased by 3.8 U/L (95% CI, 2.5–5.1), which were significantly higher than those among women in the placebo arm (both P < 0.001). Overall, 26 (5.1%) women in GTE developed moderate or more severe abnormalities in any liver function measure during the intervention period, yielding an OR of 7.0 (95% CI, 2.4–20.3) for developing liver function abnormalities as compared with those in the placebo arm. ALT returned to normal after dechallenge and increased again after one or more rechallenges with GTE. The rise–fall pattern of liver enzyme values following the challenge–dechallenge cycles of GTE consumption strongly implicates the effect of high-dose GTE on liver enzyme elevations. Cancer Prev Res; 10(10); 571–9. ©2017 AACR.
Data from Epigenome-Wide Study Identifies Epigenetic Outliers in Normal Mucosa of Patients with Colorectal Cancer
Authors: Ghosh Jayashri , Schultz Bryant M. , Chan Joe , Wultsch Claudia , Singh Rajveer , Shureiqi Imad , Chow Stephanie , Doymaz Ahmet , Varriano Sophia , Driscoll Melissa , Muse Jennifer , Kleiman Frida E. , Krampis Konstantinos , Issa Jean-Pierre J. , Sapienza Carmen
Published: March 2024

Abstract
Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (P < 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.
Prevention Relevance:
Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.
Data from ERα-Dependent E2F Transcription Can Mediate Resistance to Estrogen Deprivation in Human Breast Cancer
Authors: Miller Todd W. , Balko Justin M. , Fox Emily M. , Ghazoui Zara , Dunbier Anita , Anderson Helen , Dowsett Mitch , Jiang Aixiang , Smith R. Adam , Maira Sauveur-Michel , Manning H. Charles , González-Angulo Ana M. , Mills Gordon B. , Higham Catherine , Chanthaphaychith Siprachanh , Kuba Maria G. , Miller William R. , Shyr Yu , Arteaga Carlos L.
Published: March 2024

Abstract
Most estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens, but many eventually become estrogen-independent and recur. We identified an estrogen-independent role for ER and the CDK4/Rb/E2F transcriptional axis in the hormone-independent growth of breast cancer cells. ER downregulation with fulvestrant or small interfering RNA (siRNA) inhibited estrogen-independent growth. Chromatin immunoprecipitation identified ER genomic binding activity in estrogen-deprived cells and primary breast tumors treated with aromatase inhibitors. Gene expression profiling revealed an estrogen-independent, ER/E2F-directed transcriptional program. An E2F activation gene signature correlated with a lesser response to aromatase inhibitors in patients' tumors. siRNA screening showed that CDK4, an activator of E2F, is required for estrogen-independent cell growth. Long-term estrogen-deprived cells hyperactivate phosphatidylinositol 3-kinase (PI3K) independently of ER/E2F. Fulvestrant combined with the pan-PI3K inhibitor BKM120 induced regression of ER+ xenografts. These data support further development of ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for treatment of antiestrogen-resistant breast cancers.

Significance: ERα retains genomic activity and drives a CDK4/E2F-dependent transcriptional program despite estrogen deprivation therapy. Combined inhibition of ER and PI3K induced regression of ER+ xenografts, supporting further development of strong ER downregulators and CDK4 inhibitors, and their combination with PI3K inhibitors for the treatment of antiestrogen-resistant breast cancers. Cancer Discovery; 1(4); 338–51. ©2011 AACR.

Read the Commentary on this article by Van Tine et al., p. 287

This article is highlighted in the In This Issue feature, p. 275
Data from The Outgrowth of Micrometastases Is Enabled by the Formation of Filopodium-like Protrusions
Authors: Shibue Tsukasa , Brooks Mary W. , Inan M. Fatih , Reinhardt Ferenc , Weinberg Robert A.
Published: March 2024

Abstract
Disseminated cancer cells that have extravasated into the tissue parenchyma must interact productively with its extracellular matrix components to survive, proliferate, and form macroscopic metastases. The biochemical and cell biologic mechanisms enabling this interaction remain poorly understood. We find that the formation of elongated integrin β1–containing adhesion plaques by cancer cells that have extravasated into the lung parenchyma enables the proliferation of these cells via activation of focal adhesion kinase. These plaques originate in and appear only after the formation of filopodium-like protrusions (FLP) that harbor integrin β1 along their shafts. The cytoskeleton-regulating proteins Rif and mDia2 contribute critically to the formation of these protrusions and thereby enable the proliferation of extravasated cancer cells. Hence, the formation of FLPs represents a critical rate-limiting step for the subsequent development of macroscopic metastases.

Significance: Although the mechanisms of metastatic dissemination have begun to be uncovered, those involved in the establishment of extravasated cancer cells in foreign tissue microenvironments remained largely obscure. We have studied the behavior of recently extravasated cancer cells in the lungs and identified a series of cell biologic processes involving the formation of filopodium-like protrusions and the subsequent development of elongated, mature adhesion plaques, which contribute critically to the rapid proliferation of the micrometastatic cells and thus are prerequisites to the eventual lung colonization by these cells. Cancer Discov; 2(8); 706–21. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 653.
Data from Prevention of Persistent Human Papillomavirus Infection by an HPV16/18 Vaccine: A Community-Based Randomized Clinical Trial in Guanacaste, Costa Rica
Authors: Herrero Rolando , Wacholder Sholom , Rodríguez Ana C. , Solomon Diane , González Paula , Kreimer Aimee R. , Porras Carolina , Schussler John , Jiménez Silvia , Sherman Mark E. , Quint Wim , Schiller John T. , Lowy Douglas R. , Schiffman Mark , Hildesheim Allan
Published: March 2024

Abstract
Target groups for human papillomavirus (HPV) vaccination are controversial. We evaluated vaccine efficacy (VE) against 1-year persistent infection, stratified by age and sexual behavior, among young women in Costa Rica. We randomized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine (follow-up, 50.4 months). According-to-protocol (ATP) cohorts included compliant HPV-negative women; intention-to-treat (ITT) included all randomized women. ATP VE was 90.9% (95% CI, 82.0–95.9) against HPV16/18 infections, 44.5% against HPV31/33/45 (95% CI, 17.5–63.1), and 12.4% (95% CI, −3.2 to 25.6) against any oncogenic infection. Overall ITT VE against HPV16/18 infections was 49.0%, but ATP and ITT VE almost reached 100% in year 4 of follow-up. ATP efficacy against HPV16/18 was similar by age, but ITT VE was greatest among youngest women (68.9% among those 18–19 years of age; 21.8% among those 24–25 years of age) and 79.8% among virgins. Among previously unexposed women, vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45. Vaccination is most effective in women and girls before they initiate sexual activity, with programmatic and individual decision implications.

Significance: In an independent trial of the bivalent ASO4-adjuvanted HPV16/18 vaccine (Cervarix) conducted among young women in Costa Rica, we confirmed the high efficacy against HPV16/18 persistent infection and partial cross-protection against HPV31/33/45. Furthermore, efficacy data suggest that the benefit of HPV vaccination is maximal when the vaccine is given to young women before they initiate sexual activity. Cancer Discovery; 1(5): 408–19. ©2011 AACR.

Read the Commentary on this article by Bosch et al., p. 377

This article is highlighted in the In This Issue feature, p. 367
Data from Molecular Ontogeny of Donor-Derived Follicular Lymphomas Occurring after Hematopoietic Cell Transplantation
Authors: Weigert Oliver , Kopp Nadja , Lane Andrew A. , Yoda Akinori , Dahlberg Suzanne E. , Neuberg Donna , Bahar Anita Y. , Chapuy Bjoern , Kutok Jeffery L. , Longtine Janina A. , Kuo Frank C. , Haley Terry , Salois Maura , Sullivan Timothy J. , Fisher David C. , Fox Edward A. , Rodig Scott J. , Antin Joseph H. , Weinstock David M.
Published: March 2024

Abstract
The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor–recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo.

Significance: For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation. Cancer Discovery; 2(1); 47–55. ©2011 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression
Authors: Ling Chen , Su Vi-Minh-Tri , Zuo Dongmei , Muller William J.
Published: March 2024

Abstract
14-3-3σ is a putative tumor suppressor involved in cell-cycle progression and epithelial polarity. We demonstrate that loss of one or both copies of the conditional 14-3-3σ allele results in accelerated mammary and salivary tumorigenesis in mice expressing an activated erbB2 oncogene under the endogenous erbB2 promoter. Significantly, the majority of tumors bearing a single conditional 14-3-3σ allele lose expression of the remaining 14-3-3σ allele, which is associated with epigenetic methylation of the 14-3-3σ locus. In addition to accelerated tumor onset, in a mouse mammary tumor virus-driven ErbB2 tumor model, loss of 14-3-3σ results in enhanced metastatic phenotype that is correlated with loss of cellular junctions. Taken together, these results provide compelling evidence that 14-3-3σ is a potent tumor suppressor involved in ErbB2-driven breast cancer initiation and metastasis.

Significance: 14-3-3σ has been identified as a normal mammary epithelial cell marker frequently downregulated during neoplastic development. Consistent with its potential role as a tumor suppressor, we demonstrate that targeted disruption of 14-3-3σ in a number of epithelial tissues can profoundly impact both the initiation and metastatic phases of ErbB2-mediated tumor progression through modulation of a number of distinct signaling networks. Cancer Discovery; 2(1); 68–81. ©2011 AACR.

Read the Commentary on this article by Hynes and Smirnova, p. 19

This article is highlighted in the In This Issue feature, p. 1
Data from Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis
Authors: Geis Abby L. , Fan Hongni , Wu Xinqun , Wu Shaoguang , Huso David L. , Wolfe Jaime L. , Sears Cynthia L. , Pardoll Drew M. , Housseau Franck
Published: March 2024

Abstract
Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity can inhibit inflammation-associated cancers. Paradoxically, we show that colonic Tregs initiate IL17-mediated carcinogenesis in multiple intestinal neoplasia mice colonized with the human symbiote enterotoxigenic Bacteroides fragilis (ETBF). Depletion of Tregs in ETBF-colonized C57BL/6 FOXP3DTR mice enhanced colitis but diminished tumorigenesis associated with shifting of mucosal cytokine profile from IL17 to IFNγ; inhibition of ETBF-induced colon tumorigenesis was dependent on reduced IL17 inflammation and was independent of IFNγ. Treg enhancement of IL17 production is cell-extrinsic. IL2 blockade restored Th17 responses and tumor formation in Treg-depleted animals. Our findings demonstrate that Tregs limit the availability of IL2 in the local microenvironment, allowing the Th17 development necessary to promote ETBF-triggered neoplasia, and thus unveil a new mechanism whereby Treg responses to intestinal bacterial infection can promote tumorigenesis.

Significance: Tregs promote an oncogenic immune response to a common human symbiote associated with inflammatory bowel disease and colorectal cancer. Our data define mechanisms by which mucosal Tregs, despite suppressing excessive inflammation, promote the earliest stages of immune procarcinogenesis via enhancement of IL17 production at the expense of IFNγ production. Cancer Discov; 5(10); 1098–109. ©2015 AACR.

See related commentary by Irrazabal and Martin, p. 1021.

This article is highlighted in the In This Issue feature, p. 1005
Data from A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity
Authors: Grabiner Brian C. , Nardi Valentina , Birsoy Kıvanç , Possemato Richard , Shen Kuang , Sinha Sumi , Jordan Alexander , Beck Andrew H. , Sabatini David M.
Published: March 2024

Abstract
Genes encoding components of the PI3K–AKT–mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.

Significance: We report that a diverse set of cancer-associated MTOR mutations confer increased mTORC1/2 pathway activity and that cells harboring these mutations are highly sensitive to rapamycin in culture and in vivo. These findings are clinically relevant as the MTOR mutations characterized herein may serve as biomarkers for predicting tumor responses to mTOR inhibitors. Cancer Discov; 4(5); 554–63. ©2014 AACR.

See related commentary by Rejto and Abraham, p. 513

This article is highlighted in the In This Issue feature, p. 495
Data from Autophagy Opposes p53-Mediated Tumor Barrier to Facilitate Tumorigenesis in a Model of PALB2-Associated Hereditary Breast Cancer
Authors: Huo Yanying , Cai Hong , Teplova Irina , Bowman-Colin Christian , Chen Guanghua , Price Sandy , Barnard Nicola , Ganesan Shridar , Karantza Vassiliki , White Eileen , Xia Bing
Published: March 2024

Abstract
Hereditary breast cancers stem from germline mutations in susceptibility genes such as BRCA1, BRCA2, and PALB2, whose products function in the DNA damage response and redox regulation. Autophagy is an intracellular waste disposal and stress mitigation mechanism important for alleviating oxidative stress and DNA damage response activation; it can either suppress or promote cancer, but its role in breast cancer is unknown. Here, we show that similar to Brca1 and Brca2, ablation of Palb2 in the mouse mammary gland resulted in tumor development with long latency, and the tumors harbored mutations in Trp53. Interestingly, impaired autophagy, due to monoallelic loss of the essential autophagy gene Becn1, reduced Palb2-associated mammary tumorigenesis in a Trp53–wild-type but not conditionally null background. These results indicate that, in the face of DNA damage and oxidative stress elicited by PALB2 loss, p53 is a barrier to cancer development, whereas autophagy facilitates cell survival and tumorigenesis.

Significance: Our findings directly show a tumor-promoting role of autophagy in a new model of hereditary breast cancer. Given the close functional relationship and the genetic similarity between PALB2 and BRCA1/2, our results further suggest that inhibition of autophagy may represent a new avenue to the prevention or treatment of a significant portion of hereditary breast cancers, namely those associated with DNA damage and oxidative stress. Cancer Discov; 3(8); 894–907. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 826
Data from Measuring Residual Estrogen Receptor Availability during Fulvestrant Therapy in Patients with Metastatic Breast Cancer
Authors: van Kruchten Michel , de Vries Elisabeth G. , Glaudemans Andor W. , van Lanschot Meta C. , van Faassen Martijn , Kema Ido P. , Brown Myles , Schröder Carolien P. , de Vries Erik F. , Hospers Geke A.
Published: March 2024

Abstract
It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) antagonist, is sufficient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/computed tomography (PET/CT) at baseline (scan 1), day 28 (scan 2), and day 84 (scan 3) to monitor tumor [18F]fluoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefined as <75% decrease in median tumor FES uptake and a residual standardized uptake value (SUVmax) of ≥1.5. In total, 131 FES-positive lesions were identified (median SUVmax of 2.9; range, 1.7–6.5). The median change in patients during fulvestrant treatment was −85% at scan 2, but varied widely (−99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 (38%) of the 16 patients, which was associated with early progression.

Significance: Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER. FES-PET showed significant residual ER availability in tumors during fulvestrant therapy in 38% of patients, which was associated with early progression. Cancer Discov; 5(1); 72–81. ©2014 AACR.

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Data from Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction
Authors: Curry Natasha L. , Mino-Kenudson Mari , Oliver Trudy G. , Yilmaz Ömer H. , Yilmaz Vedat O. , Moon Jade Y. , Jacks Tyler , Sabatini David M. , Kalaany Nada Y.
Published: March 2024

Abstract
PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss.

Significance: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway. Cancer Discov; 3(8); 908–21. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 826
Data from Linking Tumor Mutations to Drug Responses via a Quantitative Chemical–Genetic Interaction Map
Authors: Martins Maria M. , Zhou Alicia Y. , Corella Alexandra , Horiuchi Dai , Yau Christina , Rakhshandehroo Taha , Gordan John D. , Levin Rebecca S. , Johnson Jeff , Jascur John , Shales Mike , Sorrentino Antonio , Cheah Jaime , Clemons Paul A. , Shamji Alykhan F. , Schreiber Stuart L. , Krogan Nevan J. , Shokat Kevan M. , McCormick Frank , Goga Andrei , Bandyopadhyay Sourav
Published: March 2024

Abstract
There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic–lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical–genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT–PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies.

Significance: Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation. Cancer Discov; 5(2); 154–67. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 97
Data from MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition
Authors: Wagle Nikhil , Van Allen Eliezer M. , Treacy Daniel J. , Frederick Dennie T. , Cooper Zachary A. , Taylor-Weiner Amaro , Rosenberg Mara , Goetz Eva M. , Sullivan Ryan J. , Farlow Deborah N. , Friedrich Dennis C. , Anderka Kristin , Perrin Danielle , Johannessen Cory M. , McKenna Aaron , Cibulskis Kristian , Kryukov Gregory , Hodis Eran , Lawrence Donald P. , Fisher Sheila , Getz Gad , Gabriel Stacey B. , Carter Scott L. , Flaherty Keith T. , Wargo Jennifer A. , Garraway Levi A.
Published: March 2024

Abstract
Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2Q60P). MEK2Q60P conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal–regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

Significance: This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in BRAF-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant BRAF-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms. Cancer Discov; 4(1); 61–8. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

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