bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance in pancreatic cancer
Authors: Su Jiachun , Li Rui , Chen Ziming , Liu Shaoqiu , Zhao Hongzhe , Deng Shuang , Zeng Lingxing , Xu Zilan , Zhao Sihan , Zhou Yifan , Li Mei , He Xiaowei , Liu Ji , Xue Chunling , Bai Ruihong , Zhuang Lisha , Zhou Quanbo , Zhang Shaoping , Chen Rufu , Huang Xudong , Lin Dongxin , Zheng Jian , Zhang Jialiang
Published: September 2024

Abstract
The therapeutic options for treating pancreatic ductal adenocarcinoma (PDAC) are limited, and resistance to gemcitabine, a cornerstone of PDAC chemotherapy regimens, remains a major challenge. N6-methyladenosine (m6A) is a prevalent modification in mRNA that has been linked to diverse biological processes in human diseases. Herein, by characterizing the global m6A profile in a panel of gemcitabine-sensitive and gemcitabine-insensitive PDAC cells, we identified a key role for elevated m6A modification of the master G0/G1 regulator FZR1 in regulating gemcitabine sensitivity. Targeting FZR1 m6A modification augmented the response to gemcitabine treatment in gemcitabine-resistant PDAC cells both in vitro and in vivo. Mechanistically, GEMIN5 was identified as a novel m6A mediator that specifically bound to m6A-modified FZR1 and recruited the eIF3 translation initiation complex to accelerate FZR1 translation. FZR1 upregulation maintained the G0/G1 quiescent state and suppressed gemcitabine sensitivity in PDAC cells. Clinical analysis further demonstrated that both high levels of FZR1 m6A modification and FZR1 protein corresponded to poor response to gemcitabine. These findings reveal the critical function of m6A modification in regulating gemcitabine sensitivity in PDAC and identify the FZR1/GEMIN5 axis as a potential target to enhance gemcitabine response.
Data from Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression
Authors: Adaku Nneoma , Ostendorf Benjamin N. , Mei Wenbin , Tavazoie Sohail F.
Published: September 2024

Abstract
The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer’s disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing anti-tumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The LRP1 receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer’s disease.
Data from Mutant KRAS mediates circARFGEF2 biogenesis to promote lymphatic metastasis of pancreatic ductal adenocarcinoma
Authors: Kong Yao , Luo Yuming , Zheng Shangyou , Yang Jiabin , Zhang Dingwen , Zhao Yue , Zheng Hanhao , An Mingjie , Lin Yan , Ai Le , Diao Xiarao , Lin Qing , Chen Changhao , Chen Rufu
Published: September 2024

Abstract
Circular RNAs (circRNAs) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis.
Data from Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma
Authors: Gulay Kevin Christian Montecillo. , Zhang Xinlian , Pantazopoulou Vasiliki , Patel Jay , Esparza Edgar , Pran Babu Deepa Sheik. , Ogawa Satoshi , Weitz Jonathan , Ng Isabella , Mose Evangeline S. , Pu Minya , Engle Dannielle D. , Lowy Andrew M. , Tiriac Hervé
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
Data from CD25high Effector Regulatory T Cells Hamper Responses to PD-1 Blockade in Triple-Negative Breast Cancer
Authors: Fattori Stéphane , Le Roy Aude , Houacine Jemila , Robert Lucie , Abes Riad , Gorvel Laurent , Granjeaud Samuel , Rouvière Marie-Sarah , Ben Amara Amira , Boucherit Nicolas , Tarpin Carole , Pakradouni Jihane , Charafe-Jauffret Emmanuelle , Houvenaeghel Gilles , Lambaudie Eric , Bertucci Francois , Rochigneux Philippe , Gonçalves Anthony , Foussat Arnaud , Chrétien Anne-Sophie , Olive Daniel
Published: September 2024

Abstract
Regulatory T cells (Tregs) impede effective antitumor immunity. However, the role of Tregs in clinical outcomes of patients with triple-negative breast cancer (TNBC) remains controversial. Here, we found that an immunosuppressive TNBC microenvironment is marked by an imbalance between effector αβCD8+ T cells and Tregs harboring hallmarks of highly suppressive effector Tregs (eTregs). Intratumoral eTregs strongly expressed PD-1 and persisted in patients with TNBC resistant to PD-1 blockade. Importantly, CD25 was the most selective surface marker of eTregs in primary TNBC and metastases compared with other candidate targets for eTreg depletion currently being evaluated in trials for patients with advanced TNBC. In a syngeneic TNBC model, the use of Fc-optimized, IL-2 sparing, anti-CD25 antibodies synergized with PD-1 blockade to promote systemic antitumor immunity and durable tumor growth control by increasing effector αβCD8+ T cell/Treg ratios in tumors and in the periphery. Together, this study provides the rationale for clinical translation of anti-CD25 therapy to improve PD-1 blockade responses in patients with TNBC.
Data from LncRNA AGPG confers endocrine resistance in breast cancer by promoting E2F1 activity
Authors: Yu Shiyi , Wang Ying , Gong Xue , Fan Zhehao , Wang Zheng , Liang Zhengyan , Wu Rui , Cao Binjie , Wang Ning , Bi Caili , Lv Dan , Sun Haibo
Published: September 2024

Abstract
Resistance to endocrine therapy represents a major concern for patients with estrogen receptor α positive (ERα+) breast cancer. Endocrine therapy resistance is commonly mediated by activated E2F signaling. A better understanding of the mechanisms governing E2F1 activity in resistant cells could reveal strategies for overcoming resistance. Here, we identified the long non-coding RNA (lncRNA) actin gamma 1 pseudogene 25 (AGPG) as a regulator of E2F1 activity in endocrine resistant breast cancer. Expression of EGPG was increased in endocrine-resistant breast cancer cells, which was driven by epigenomic activation of an enhancer. AGPG was also abnormally upregulated in patient breast tumors, especially in the luminal B subtype, and high AGPG expression was associated with poor survival of ERα+ breast cancer patients receiving endocrine therapy. The upregulation of AGPG mediated resistance to endocrine therapy and CDK4/6 inhibition in breast cancer cells. Mechanistically, AGPG physically interacted with PURα, thus releasing E2F1 from PURα and leading to E2F1 signaling activation in ERα+ breast cancer cells. In breast cancer patients, E2F1 target genes were positively and negatively correlated with expression of AGPG and PURα, respectively. Co-administration of chemically modified AGPG siRNA and tamoxifen strongly suppressed tumor growth in endocrine resistant cell line-derived xenografts. Together, these results demonstrate that AGPG can drive endocrine therapy resistance and indicate that it is a promising biomarker and potential therapeutic target in breast cancer.
Data from Targeting the immunoglobulin IGSF9 enhances anti-tumor T cell activity and sensitivity to anti-PD-1 immunotherapy
Authors: Liu Yifan , Wang Hongying , Zhao Xinyu , Zhang Jiashen , Zhao Zhiling , Lian Xia , Zhang Juan , Kong Feng , Hu Tao , Wang Ting , Li Xiaohua , Wang Lei , Wang Dapeng , Li Chunling , Luan Huiwen , Liu Xiaoli , Wang Chunyan , Jiang Yun , Li Xiaomin , Li Fangmin , Ji Shuhao , Wang Yaopeng , Li Zunling
Published: September 2024

Abstract
Immune checkpoints modulate the immune response and represent important immunotherapy targets for cancer treatment. However, as many tumors are resistant to current immune checkpoint inhibitors, the discovery of novel immune checkpoints could facilitate the development of additional immunotherapeutic strategies to improve patient responses. Here, we identified increased expression of the adhesion molecule immunoglobulin superfamily member 9 (IGSF9) in tumor cells and tumor-infiltrating immune cells across multiple cancer types. IGSF9 overexpression or knockout in tumor cells did not alter cell proliferation in vitro or tumor growth in immunocompromised mice. Alternatively, IGSF9 deficient tumor cells lost the ability to suppress T cell proliferation and exhibited reduced growth in immunocompetent mice. Similarly, growth of tumor cells was reduced in IGSF9 knockout syngeneic and humanized mice, accompanied by increased tumor-infiltrating T cells. Mechanistically, the extracellular domain (ECD) of IGSF9 bound to T cells and inhibited their proliferation and activation, and the tumor promoting effect of IGSF9 ECD was reversed by CD3+ T cell depletion. Anti-IGSF9 antibody treatment inhibited tumor growth and enhanced the anti-tumor efficacy of anti-PD-1 immunotherapy. Single-cell RNA sequencing revealed tumor microenvironment remodeling from tumor-promoting to tumor-suppressive following anti-IGSF9 treatment. Together, these results indicate that IGSF9 promotes tumor immune evasion and is a candidate immune checkpoint target.
Data from Histone methyltransferase NSD2 activates PKCα to drive metabolic reprogramming and lenalidomide resistance in multiple myeloma
Authors: Chong Phyllis S.Y. , Chooi Jing-Yuan , Lim Julia S.L. , Leow Aaron C.Y. , Toh Sabrina Hui Min. , Azaman Irfan , Koh Mun Yee , Teoh Phaik Ju , Tan Tuan Zea , Chung Tae-Hoon , Chng Wee Joo
Published: September 2024

Abstract
Multiple myeloma (MM) cells undergo metabolic reprogramming in response to the hypoxic and nutrient-deprived bone marrow microenvironment. Primary oncogenes in recurrent translocations might be able to drive metabolic heterogeneity to survive the microenvironment that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase NSD2 that promotes plasma cell transformation through a global increase in H3K36me2. Here, we identified PKCα as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA-sequencing of t(4;14) MM cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. Additionally, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production. Metabolomics analysis indicated lactate as a differential metabolite associated with PKCα. As a result, PKCα conferred resistance to the immunomodulatory drugs (IMiD) lenalidomide in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Clinically, t(4;14) MM patients had elevated plasma lactate levels and did not benefit from lenalidomide-based regimens. Altogether, this study provides insights into the epigenetic-metabolism crosstalk in MM and highlights the opportunity for therapeutic intervention that leverages the distinct metabolic program in t(4;14) myeloma.
Data from Breast cancer-secreted factors promote lung metastasis by signaling systemically to induce a fibrotic pre-metastatic niche
Authors: Cohen Noam , Mundhe Dhanashree , Deasy Sarah K. , Adler Omer , Ershaid Nour , Shami Tamar , Levi-Galibov Oshrat , Wassermann Rina , Scherz-Shouval Ruth , Erez Neta
Published: September 2024

Abstract
Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAFs) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at pre-metastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGFβ superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of pro-fibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung pre-metastatic niche. ActA signaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human breast cancer patients were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanism by which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis.
Data from Bi-allelic Dicer1 mutations in the gynecologic tract of mice drive lineage-specific development of DICER1 syndrome-associated cancer
Authors: Wang Yemin , Chen Shary Yuting , Ta Monica , Senz Janine , Tao Lan Valerie. , Thornton Shelby , Tamvada Nirupama , Yang Winnie , Moscovitz Yana , Li Eunice , Guo Jingjie , Shen Cindy , Douglas J. Maxwell , El-Naggar Amal M. , Kommoss Felix K. F. , Underhill T. Michael , Singh Naveena , Gilks C. Blake , Morin Gregg B. , Huntsman David G.
Published: September 2024

Abstract
DICER1 is an RNase III enzyme essential for microRNA (miRNA) biogenesis through cleaving pre-miRNA hairpins. Germline loss-of-function DICER1 mutations underlie the development of DICER1 syndrome, a rare genetic disorder that predisposes children to cancer development in organs such as lung, gynecologic tract, kidney, and brain. Unlike classical tumor suppressors, the somatic “second hit” in DICER1 syndrome-associated cancers does not fully inactivate DICER1 but impairs its RNase IIIb activity only, suggesting a noncanonical two-hit hypothesis. Here, we developed a genetically engineered conditional compound heterozygous Dicer1 mutant mouse strain that fully recapitulates the bi-allelic DICER1 mutations in DICER1 syndrome-associated human cancers. Crossing this tool strain with tissue-specific Cre strains that activate Dicer1 mutations in gynecologic tract cells at two distinct developmental stages revealed that embryonic bi-allelic Dicer1 mutations caused infertility in females by disrupting oviduct and endometrium development and ultimately drove cancer development. These multicystic tubal and intra-uterine tumors histologically resembled a subset of DICER1 syndrome-associated human cancers. Molecular analysis uncovered accumulation of additional oncogenic events (e.g. aberrant p53 expression, Kras mutation, and Myc activation) in murine Dicer1 mutant tumors and validated miRNA biogenesis defects in 5P miRNA strand production, of which loss of let-7 family miRNAs was identified as a putative key player in transcriptomic rewiring and tumor development. Thus, this DICER1 syndrome-associated cancer model recapitulates the biology of human cancer and provides a unique tool for future investigation and therapeutic development.
Data from Crosstalk between myeloid and B cells shapes the distinct microenvironments of primary and secondary liver cancer
Authors: Chen Zhihang , Zhang Guopei , Ren Xiaoxue , Yao Zhijia , Zhou Qian , Ren Xuxin , Chen Shuling , Xu Lixia , Sun Kaiyu , Zeng Qianwen , Kuang Ming , Kuang Dong-Ming , Peng Sui
Published: September 2024

Abstract
The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC while IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted pro-tumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, while increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.
Supplementary Table 1 from Updated Review of Major Cancer Risk Factors and Screening Test Use in the United States, with a Focus on Changes During the COVID-19 Pandemic
Authors: Star Jessica , Bandi Priti , Nargis Nigar , Islami Farhad , Yabroff K Robin , Minihan Adair K. , Smith Robert A. , Jemal Ahmedin
Published: September 2024

Weighted population estimates of major cancer risk factors, preventive behaviors and services, and up-to-date cancer screening.
Figure S2 from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

Early- (age 20-54 years) and later-onset (55-99 years) esophagogastric adenocarcinoma incidence rate (IR) per 100,000 person-years over years 1993-2019, comparing empirical estimates (dots), modeled linear predictions with no breakpoint (blue solid line), together with linear predictions including one breakpoint year (red solid line) identified using piecewise linear regression.
Supplementary Table S1 from Associations of race and ethnicity with hepatocellular carcinoma, decompensation, and mortality in US Veterans with cirrhosis
Authors: VoPham Trang , Cravero Anne , Feld Lauren D. , Green Pamela , Feng Ziding , Berry Kristin , Kim Nicole J. , Vutien Philip , Mendoza Jason A. , Ioannou George N.
Published: September 2024

Supplementary Table S1. ICD-9 and ICD-10 codes for cirrhosis, decompensated cirrhosis, liver transplantation, and hepatocellular carcinoma
Supplementary Materials and Methods from Field synopsis of environmental and genetic risk factors of sporadic early-onset colorectal cancer and advanced adenoma
Authors: Zhang Rongqi , Boakye Daniel , Yang Nan , Zhou Xuan , Zhou Yajing , Jiang Fangyuan , Yu Lili , Wang Lijuan , Sun Jing , Yuan Shuai , Chen Jie , Hamilton Ashleigh C. , Coleman Helen G. , Larsson Susanna C. , Little Julian , Dunlop Malcolm G. , Giovannucci Edward L. , Theodoratou Evropi , Li Xue
Published: September 2024

Supplementary Materials and Methods shows the literature search strategy, selection criteria, evidence credibility grading criteria, and PRISMA 2020 Checklist.
Table S3 from Associations between etiologic or prognostic tumor tissue markers and neighborhood contextual factors in male health professionals diagnosed with prostate cancer
Authors: Iyer Hari S. , Kensler Kevin H. , Vaselkiv Jane B. , Stopsack Konrad H. , Roscoe Charlotte , Bandera Elisa V. , Qin Bo , Jang Thomas L. , Lotan Tamara L. , James Peter , Hart Jaime E. , Mucci Lorelei A. , Laden Francine , Rebbeck Timothy R.
Published: September 2024

Table S3. Odds Ratios and 95% Confidence Intervals for Association Between Neighborhood Contextual Factors at Diagnosis and Somatic Alterations in Tumor Tissue Among US Male Health Professionals with Prostate Cancer Using Inverse Probability of Censoring Weights
Supplementary Table S4 from Development of a breast cancer risk prediction model incorporating polygenic risk scores and non-genetic risk factors for Korean women
Authors: Choi Jihye , Ha Tae-woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2024

Association between PRS38_ASN+PRS190_EB and breast cancer risks in different age groups
Supplementary Figure S6 from Characteristics of Cancer Epidemiology Studies that Employ Metabolomics: A Scoping Review
Authors: Yu Catherine T. , Farhat Zeinab , Livinski Alicia A. , Loftfield Erikka , Zanetti Krista A.
Published: September 2024

Supplementary Figure S6 shows pie chart displaying breakdown of studies that used an LC-MS semi-targeted approach.
Supplemental Table 3 from Germline mutations in 12 genes and risk of ovarian cancer in three population-based cohorts
Authors: Kotsopoulos Joanne , Hathaway Cassandra A. , Narod Steven A. , Teras Lauren R. , Patel Alpa V. , Hu Chunling , Yadav Siddhartha , Couch Fergus J. , Tworoger Shelley S.
Published: September 2024

Supplemental Table 3: Mutation frequencies in invasive ovarian cancer cases and controls and risk of ovarian cancer in the NHS, NHSII, and CPSII
Data from Associations between MICA and MICB genetic variants, protein levels, and colorectal cancer: Atherosclerosis Risk in Communities (ARIC)
Authors: Wang Shuo , Onyeaghala Guillaume C. , Pankratz Nathan , Nelson Heather H. , Thyagarajan Bharat , Tang Weihong , Norby Faye L. , Ugoji Chinenye , Joshu Corinne E. , Gomez Christian R. , Couper David J. , Coresh Josef , Platz Elizabeth A. , Prizment Anna E.
Published: September 2024

Abstract
Background: The major histocompatibility complex class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer (CRC), but have not been examined in CRC development.

Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies. SNPs were genotyped by the Affymetrix Genome-Wide Human SNP Array. We applied linear and Cox proportional hazards regressions to examine the associations of pre-selected SNPs with sMICA and sMICB levels and CRC risk (236 CRCs, 8,609 participants) and of sMICA and sMICB levels with CRC risk (312 CRCs, 10,834 participants). In genetic analyses, estimates adjusted for ancestry markers were meta-analyzed.

Results: Rs1051792-A, rs1063635-A, rs2516448-C, rs3763288-A, rs2596542-T, and rs2395029-G were significantly associated with decreased sMICA levels. Rs2395029-G, in the vicinity of MICA and MICB, was also associated with increased sMICB levels. Rs2596542-T was significantly associated with decreased CRC risk. Lower sMICA levels were associated with lower CRC risk in males (HR=0.68, 95%CI 0.49-0.96) but not in females (p-interaction=0.08).
Conclusions: Rs2596542-T associated with lower sMICA levels was associated with decreased CRC risk. Lower sMICA levels were associated with lower CRC risk in males.

Impact: These findings support an importance of immunosurveillance in CRC.
Data from Survival of Middle Eastern and North African Individuals Diagnosed with Colorectal Cancer: A Population-Based Study in California
Authors: Zaki Timothy A. , Ziogas Argyrios , Chang Jenny , Murphy Caitlin C. , Anton-Culver Hoda
Published: September 2024

Abstract
Background: Literature on colorectal cancer (CRC) outcomes in individuals of Middle Eastern and North African (MENA) descent is limited. To address this gap, we estimated five-year CRC-specific survival by race and ethnicity, including MENA individuals, in a diverse, population-based sample in California.

Methods: We identified adults (ages 18-79 years) diagnosed with a first or only CRC in 2004 – 2017 using the California Cancer Registry, including non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, Hispanic, and MENA individuals. For each racial/ethnic group, we calculated five-year CRC-specific survival and used Cox proportional hazards regression models to examine the association of race/ethnicity and survival, adjusting for clinical and sociodemographic factors.

Results: Of 110,192 persons diagnosed with CRC, five-year CRC-specific survival was lowest in Black (61.0%) and highest in MENA (73.2%) individuals. Asian (72.2%) individuals had higher survival than White (70.0%) and Hispanic (68.2%) individuals. In adjusted analysis, MENA (aHR 0.82, 95% CI 0.76, 0.89), Asian (aHR 0.86, 95% CI 0.83, 0.90), and Hispanic (aHR 0.94, 95% CI 0.91, 0.97) race/ethnicity were associated with higher, and Black (aHR 1.13, 95% CI 1.09, 1.18) race/ethnicity was associated with lower, survival compared to non-Hispanic White race/ethnicity.

Conclusion: To our knowledge, this is the first study to report CRC survival in MENA individuals in the U.S. We observed higher survival of MENA individuals compared to other racial/ethnic groups, adjusting for sociodemographic and clinical factors.

Impact: Future studies are needed to identify factors contributing to cancer outcomes in this unique population.

Keywords: colorectal cancer; survival; Middle Eastern; race/ethnicity; population-based
Data from Incidence trends and survival in early-onset esophagogastric adenocarcinoma: A Swedish population-based cohort study
Authors: Radkiewicz Cecilia , Asplund Johannes , Lagergren Jesper
Published: September 2024

Abstract
Background: Early-onset adenocarcinomas of different sites are increasing in high-income countries, data on esophagogastric adenocarcinoma are sparse.
Methods: We performed a Swedish population-based cohort study over 1993-2019 to delineate differences in incidence and survival in early-onset (age 20-54 years) compared to later-onset (55-99 years) esophageal, cardia, and non-cardia gastric adenocarcinoma. Temporal incidence trends were quantified as annual percentage changes (APC) and survival differences as excess mortality rate ratios (EMRR) using Poisson regression and including 95% confidence intervals (CI).
Results: Among 27,854 esophagogastric adenocarcinoma patients, 2576 were early-onset whereof 470 were esophageal, 645 were cardia, and 1461 were non-cardia gastric. Except non-cardia gastric, the male predominance was larger in early- compared to later-onset disease. Advanced stage and signet ring cell morphology were more common among early-onset patients. Early- and later-onset APC estimates were comparable and esophageal adenocarcinoma incidence increased, cardia remained stable, and non-cardia gastric decreased. Early-onset patients had better survival than later-onset, which was amplified when adjusting for prognostic factors including stage (adjusted EMRR 0.73 [95% CI 0.63-0.85] in esophageal, 0.75 [95% CI 0.65-0.86] in cardia, and 0.67 [95% CI 0.61-0.74] in non-cardia gastric adenocarcinoma). The early-onset survival advantage was more pronounced in localized stages 0-II (all sites) and women (esophageal and non-cardia gastric).
Conclusions: We found no major differences in incidence trends comparing early- and later-onset esophagogastric adenocarcinoma. Despite unfavorable prognostic features, early-onset esophagogastric adenocarcinoma survival was better than later-onset, particularly in localized stages and women.
Impact: Our findings suggest delayed diagnosis in younger individuals and especially men.
Data from Estimated ovulatory years prior to menopause and postmenopausal endogenous hormone levels
Authors: Cramer Daniel W. , Vitonis Allison F. , Huang Tianyi , Shafrir Amy L. , Eliassen A Heather. , Barbieri Robert L. , Hankinson Susan E.
Published: September 2024

Abstract
Background
Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex-hormone levels in postmenopausal women with at least one intact ovary not using hormones.
Methods
Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate (DHEAS), prolactin, and sex-hormone-binding globulin (SHBG) were measured in 1,976 postmenopausal women from the Nurses’ Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t-tests and ANOVA. Linear regression was used to assess multivariable-adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated.

Results
Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI<25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI.

Conclusions

This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone.

Impact
A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.
Data from Development and Demonstration of Tobacco Treatment Measures for Cancer Registries:
Novel Metrics for Quality Improvement
Authors: Hutcheson Tresza D. , Metcalf Tim , Ellerbeck Edward F. , Sanderson Cox Lisa , Hu Jinxiang , Chen Xi , Richter Kimber P.
Published: September 2024

Abstract
Background. Individuals undergoing cancer treatment have better outcomes when they discontinue tobacco use. Few cancer centers systematically provide evidence-based cessation services. As part of a national quality improvement initiative (Cancer Center Cessation Initiative, (C3i)), we collaborated with our cancer registry to develop and implement two tobacco treatment metrics for tracking the provision of behavioral support and pharmacotherapy.
Methods. Post-development, the tobacco treatment metrics were integrated into the registry for all future patients. We used means and frequencies to summarize tobacco treatment for cases treated between 2017-2019, coinciding with the timeframe of C3i participation.
Results. Of 17,735 cancer cases reviewed, both measures were captured on 17,654 (99.5%) of patients, with 3,091 (17.4%) identified as users of tobacco. Across the 3 years, 557 (18%) of individuals who used tobacco received either tobacco cessation pharmacotherapy or behavioral support; with 478 (15.5%) receiving behavioral counseling, 352 (11.4%) receiving pharmacotherapy, and 273 (8.8%) receiving both—considered gold standard care. Tobacco treatment varied substantially across cancer types. The odds of receiving gold standard care were 2.37 times greater in 2019 compared to 2017. (OR=2.37, 95% CI=1.63–3.46, p<0.0001).
Conclusions. The new metrics demonstrated high completion rates and their potential to track quality improvement efforts over time. They identified suboptimal treatment reach, but a potential increase in treatment over time and greater treatment among tobacco-related versus non-tobacco-related cancers.
Impact. Continued tobacco use worsens cancer care outcomes. Integrating measures into cancer registries is a viable option for tracking tobacco treatment and cessation in the context of cancer care.
Data from Associations of Dietary Patterns with Colorectal Adenomas in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Cohort
Authors: Nepal Sushma , Aslani Zahra , Shi Ni , Tabung Fred K.
Published: September 2024

Abstract
Background: Most Colorectal cancers arise from adenomas, and though insulinemic and inflammatory dietary patterns have been associated with colorectal cancer risk, these dietary patterns have not been studied in relation to adenoma risk.
Methods: Using data from 21,192 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening cohort, we calculated the Empirical Dietary Index for Hyperinsulinemia (EDIH), Empirical Dietary Inflammatory Pattern (EDIP) and overall dietary quality measured via the Healthy Eating Index (HEI-2015), from food frequency questionnaires (FFQ). In multivariable-adjusted logistic regression, we investigated associations of these dietary indices with adenoma (any adenoma, advanced adenoma, n=19,493), and recurrent adenoma (n=1,699).
Results: EDIH was not associated with adenoma or advanced adenoma but was marginally associated with recurrent adenoma. The OR (95%CI) comparing highest (lowest insulinemic) versus lowest (most hyperinsulinemic) quintiles was 0.76 (0.55, 1.05) after multivariable adjustment including BMI. EDIP and HEI-2015 were not associated with any of the three outcomes.
Conclusions: In the PLCO cohort, we did not observe substantial associations between dietary patterns and risk of colorectal adenomas.
Impact: Pending confirmation in larger prospective studies, our findings suggest that these dietary patterns may not substantially affect colorectal cancer risk via the adenoma-carcinoma sequence.
Data from Elevated EVL methylation level in the normal colon mucosa is a potential risk biomarker for developing recurrent adenomas
Authors: Yu Ming , Carter Kelly T. , Baker Kelsey K. , Redman Mary W. , Wang Ting , Vickers Kathy , Li Christopher I. , Cohen Stacey A. , Krane Mukta , Ose Jennifer , Gigic Biljana , Figueiredo Jane C. , Toriola Adetunji T. , Siegel Erin M. , Shibata David , Schneider Martin , Ulrich Cornelia M. , Dzubinski Lynda Ann. , Schoen Robert E. , Grady William M.
Published: September 2024

Abstract
Background: Individuals with adenomatous colorectal polyps undergo repeated
colonoscopy surveillance to identify and remove metachronous adenomas. However, many patients with adenomas do not develop recurrent adenomas. Better methods to evaluate who benefits from increased surveillance are needed. We evaluated the use of altered EVL methylation as a potential biomarker for risk of recurrent adenomas.
Methods: Patients with ≥1 colonoscopy had EVL methylation (mEVL) measured with an ultra-accurate methylation-specific droplet digital PCR assay on normal colon mucosa. The association between EVL methylation levels and adenoma or colorectal cancer (CRC) was evaluated using three case/control definitions in three models: unadjusted (model 1), adjusting for baseline characteristics (model 2), and an adjusted model excluding patients with CRC at baseline (model 3).
Results: Between 2001 and 2020, 136 patients were included; 74 healthy patients and 62 patients with a history of CRC. Older age, never smoking and baseline CRC were associated with higher levels of mEVL (p≤0.05). Each log10 difference in mEVL was associated with an increased risk of adenoma(s) or cancer at/after baseline for model 1(OR: 2.64 95% CI: 1.09-6.36), and adenoma(s) or cancer after baseline for models 1(OR: 2.01, 95% CI: 1.04-3.90) and model 2 (OR: 3.17, 95% CI: 1.30-7.72).
Conclusion: Our results suggest that EVL methylation level detected in the normal colon mucosa has the potential to be a biomarker for monitoring the risk for recurrent adenomas.
Impact: These findings support the potential utility of EVL methylation for improving the accuracy for assigning risk for recurrent colorectal adenomas and cancer.
Data from Development of a breast cancer risk prediction model incorporating polygenic risk scores and non-genetic risk factors for Korean women
Authors: Choi Jihye , Ha Tae-woong , Choi Hye-Mi , Lee Han-Byoel , Shin Hee-Chul , Chung Woosung , Han Wonshik
Published: September 2024

Abstract
Background:To develop a breast cancer prediction model for Korean women using published polygenic risk scores (PRSs) combined with non-genetic risk factors (NGRFs).

Methods:Thirteen PRS models generated from single or multiple combinations of the Asian and European PRSs were evaluated among 20,434 Korean women. The area under the curve (AUC) and increase in odds ratio (OR) per standard deviation (SD) were compared for each PRS. The PRSs with the highest predictive power were combined with NGRFs; then, an integrated prediction model was established using the iCARE tool. The absolute breast cancer risk was stratified for 18,142 women with available follow-up data.

Results:PRS38_ASN+PRS190_EB, a combination of Asian and European PRSs, had the highest AUC (0.621) among PRSs, with an OR per SD increase of 1.45 (95% CI: 1.31-1.61). Compared with the average risk group (35-65%), women in the top 5% had a 2.5-fold higher risk of breast cancer. Incorporating NGRFs yielded a modest increase in the AUC of women aged >50 years. For PRS38_ASN+PRS190_EB+NGRF, the average absolute risk was 5.06%. The lifetime absolute risk at age 80 years for women in the top 5% was 9.93%, whereas that of women in the lowest 5% was 2.22%. Women at higher risks were more sensitive to NGRF incorporation.

Conclusions:Combined Asian and European PRSs were predictive of breast cancer in Korean women. Our findings support the use of these models for personalized screening and prevention of breast cancer.

Impact:Our study provides insights into genetic susceptibility and NGRFs for predicting breast cancer in Korean women.
Data from Diabetes and prostate cancer outcomes in men with nonmetastatic castrate-resistant prostate cancer: Results from the SEARCH Cohort
Authors: Sergeyev Andrei , Gu Lin , De Hoedt Amanda M. , Amling Christopher L. , Aronson William J. , Cooperberg Matthew R. , Kane Christopher J. , Klaassen Zachary , Terris Martha K. , Guerrios-Rivera Lourdes , Freedland Stephen J. , Csizmadi Ilona
Published: September 2024

Abstract
Background: The prognosis of diabetic men with advanced prostate cancer (PC) is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, PC-specific mortality (PCSM) and all-cause mortality (ACM) in men with non-metastatic castrate-resistant PC (nmCRPC).
Methods: Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between diabetes and outcomes. Men with diabetes were classified according to (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men ((i) and (ii) combined).
Results: Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR= 0.67; 95%CI: 0.48-0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR=1.41; 95%CI: 1.16-1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR=0.93; 95%CI: 0.88-0.98).
Conclusion: In men with late-stage PC, ICD-9/10 code identified diabetes is associated with better overall survival than ‘undiagnosed’ diabetes identified by high HbA1c values only.
Impact: Our data suggest that better diabetes detection and management may improve survival in late-stage PC.
Data from HSA Adductomics Reveals Sex Differences in NHL Incidence and Possible Involvement of Microbial Translocation
Authors: Grigoryan Hasmik , Imani Partow , Sacerdote Carlotta , Masala Giovanna , Grioni Sara , Tumino Rosario , Chiodini Paolo , Dudoit Sandrine , Vineis Paolo , Rappaport Stephen M.
Published: September 2024

Abstract
Background: The higher incidence of non-Hodgkin’s lymphoma (NHL) in males is not well understood. Although reactive oxygen species (ROS) have been implicated as causes of NHL, they cannot be measured directly in archived blood.

Methods: We performed untargeted adductomics of stable ROS adducts in human serum albumin (HSA) from 67 incident NHL cases and 82 matched controls from the EPIC-Italy cohort. Regression and classification methods were employed to select features associated with NHL in all subjects and in males and females separately.

Results: Sixty seven HSA-adduct features were quantified by liquid chromatography-high-resolution mass spectrometry at Cys34 (n=55) and Lys525 (n=12). Three features were selected for association with NHL in all subjects, while seven were selected for males and five for females with minimal overlap. Two selected features were more abundant in cases and seven in controls, suggesting that altered homeostasis of ROS may affect NHL incidence. Heatmaps revealed differential clustering of features between sexes, suggesting differences in operative pathways.

Conclusions: Adduct clusters dominated by Cys34 oxidation products and disulfides further implicate ROS and redox biology in the etiology of NHL. Sex differences in dietary and alcohol consumption also help to explain the limited overlap of feature selection between sexes. Intriguingly, a disulfide of methanethiol from enteric microbial metabolism was more abundant in male cases, thereby implicating microbial translocation as a potential contributor to NHL in males.

Impact: Only two of the ROS adducts associated with NHL overlapped between sexes and one adduct implicates microbial translocation as a risk factor.
Data from Sex-specific associations between body mass index and thyroid cancer incidence among Korean adults
Authors: Kim Kyoung-Nam , Kim Kyungsik , Lee Sangjun , Park Sue K.
Published: September 2024

Abstract
Background: The potential differences by sex in the association between body mass index (BMI) and thyroid cancer risk remain unconfirmed.
Methods: Data from the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) (2002–2015; population size = 510,619) and the Korean Multi-center Cancer Cohort (KMCC) data (1993–2015; population size = 19,026) were used. We constructed Cox regression models, adjusted for potential confounders, to evaluate the association between BMI and thyroid cancer incidence in each cohort, and assessed the consistency of the results.
Results: In the NHIS-HEALS, 1,351 and 4,609 incident thyroid cancer cases occurred during the follow-up among men and women, respectively. Compared to BMI of 18.5–22.9 kg/m2, BMI of 23.0–24.9 (N of cases = 410, hazard ratio [HR] = 1.25, 95% confidence interval [CI]: 1.08–1.44), 25.0–29.9 (N of cases = 522, HR = 1.32, 95% CI: 1.15–1.51), and ≥30.0 kg/m2 (N of cases = 48, HR = 1.93, 95% CI: 1.42–2.61) were associated with an increased risk of incident thyroid cancer among males. Among females, BMI of 23.0–24.9 (N of cases = 1,300, HR = 1.17, 95% CI: 1.09–1.26) and 25.0–29.9 (N of cases = 1,406, HR = 1.20, 95% CI: 1.11–1.29) were associated with incident thyroid cancer. The analyses using the KMCC demonstrated results consistent with wider CIs.
Conclusions: Sex-differences in the associations between BMI and thyroid cancer incidence were observed in Korean cohorts.
Impact: BMI <23 kg/m2 may help prevent incident thyroid cancer, especially among men.
Data from Predicted proteome association studies of breast, prostate, ovarian, and endometrial cancers implicate plasma protein regulation in cancer susceptibility
Authors: Gregga Isabelle , Pharoah Paul DP. , Gayther Simon A. , Manichaikul Ani , Im Hae Kyung , Kar Siddhartha P. , Schildkraut Joellen M. , Wheeler Heather E.
Published: September 2024

Abstract
Background: Predicting protein levels from genotypes for proteome-wide association studies (PWAS) may provide insight to the mechanisms underlying cancer susceptibility.

Methods: We performed PWAS of breast, endometrial, ovarian, and prostate cancers and their subtypes in several large European ancestry discovery consortia (effective sample size: 237,483 cases/317,006 controls) and tested the results for replication in an independent European ancestry GWAS (31,969 cases/410,350 controls). We performed PWAS using the cancer GWAS summary statistics and two sets of plasma protein prediction models, followed by colocalization analysis.

Results: Using Atherosclerosis Risk in Communities (ARIC) models, we identified 93 protein-cancer associations (FDR < 0.05). We then performed a meta-analysis of the discovery and replication PWAS, resulting in 61 significant protein-cancer associations (FDR < 0.05). Ten of 15 protein-cancer pairs that could be tested using Trans-omics for Precision Medicine (TOPMed) protein prediction models replicated with the same directions of effect in both cancer GWAS (p<0.05). To further support our results, we applied Bayesian colocalization analysis and found colocalized SNPs for SERPINA3 protein levels and prostate cancer (Posterior Probability, PP=0.65) and SNUPN protein levels and breast cancer (PP=0.62).

Conclusions: We used proteome-wide association studies (PWAS) to identify potential biomarkers of hormone-related cancer risk. SNPs in SERPINA3 and SNUPN did not reach genome-wide significance for cancer in the original GWAS, highlighting the power of PWAS for novel locus discovery, with the added advantage of providing directions of protein effect.

Impact: PWAS and colocalization are promising methods to identify potential molecular mechanisms underlying complex traits.