bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 730: Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up
Authors: Siraj Abdul K. , Parvathareddy Sandeep K. , Qadri Zeeshan , Azam Saud , De Vera Felisa , Al-Rasheed Maha , Haqawi Wael , AlDossari Hassan , Al-Kuraya Khawla S.
Published: July 2021

Predicting the pattern of recurrence is necessary to establish optimal surveillance and treatment strategies. We identified patient population that remain at risk for an event and clarify changes in the hazard rate (HR) for tumor recurrence overtime in Middle Eastern patients with Papillary Thyroid Cancer (PTC). Data for 1201 PTC patients from single institute with median follow-up of 9.5 years were analyzed. Estimated HR were plotted overtime for the entire cohort, as well as for radioactive iodine (RAI) ablation in patients separately. The changes in risk were further analyzed according to clinical variable and factors predictive of early (≤ 5years) and late (>5 years) recurrence were explored using Cox regression analysis. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 - 2 years (3.7%), with a second smaller peak between 13 - 14 years (3.2%). Patients receiving RAI therapy had a lower hazard of recurrence compared to those who did not receive RAI therapy (1.5% vs 2.7%, p = 0.0001). Importantly, this difference was significant even in the intermediate-risk PTC patients (0.7% vs 2.3%; p = 0.0001). Interestingly, PTC patients who were male, aged ≥ 55 years, with lymph node involvement and advanced stage disease were still at high risk for late recurrence. In conclusion, we confirmed the validity of double-peaked time-varying pattern for risk of recurrence in Middle-Eastern PTC patients. Furthermore, according to the time distribution of recurrence hazard, we could formulate individualized treatment and surveillance plans in PTC patients.

Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Zeeshan Qadri, Saud Azam, Felisa De Vera, Maha Al-Rasheed, Wael Haqawi, Hassan AlDossari, Khawla S. Al-Kuraya. Annual hazard rate of recurrence in Middle-Eastern papillary thyroid cancer over a long-term follow-up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 730.
Abstract 731: Neurotensin causes tyrosine phosphorylation of HER3
Authors: Moody Terry W. , Ramosalvarez Irene , Jensen Robert T.
Published: July 2021

Neurotensin (NTS) is an autocrine growth factor for non-small cell lung cancer cells. NTS stimulates and the NTSR1 antagonist SR48692 inhibits NSCLC growth (Moody et al., Life Sci 2014; 100: 25). NSCLC patients, whose tumors have high NTSR1, have significantly lower relapse-free survival than those with low NTSR1 (Younes et al., Oncotarget 2014; 5: 8252). NTS addition to NSCLC cells increases the tyrosine phosphorylation of the EGFR and HER2 (Moody et al., Eur J Pharmacol 2019; 865:172735). Activation of HER3 in NSCLC mediates aggressive growth and drug resistance. Therefore the ability of NTSR1 to regulate transactivation of HER3 was investigated. By RT-PCR, HER3 and NTSR1 but not NTSR2 mRNA was present in NSCLC cells. NTS addition to NCI-H358 or H441 cells increased HER3 and ERK tyrosine phosphorylation by 210% and 240%, respectively and the increase caused by NTS was antagonized by SR48692 or mAb3481 (HER3 mAb). The increase is phosphorylation of Tyr1289-HER3 caused by NTS or neuregulin-1 addition to NSCLC cells was due to the formation of HER2-HER3 and EGFR-HER3 heterodimers. NTSR1 regulation of HER3 or Akt phosphorylation was impaired by PP2 (Src inhibitor) or GM6001 (MMP inhibitor). Because N-acetylcysteine (antioxidant) or Tiron (superoxide scavenger) inhibited the ability of NTS to increase HER3 phosphorylation, reactive oxygen species (ROS) are essential. Using a clonogenic assay, NTS increased NSCLC colony number whereas SR48692 or mAb3481 reduced colony number. The results indicate that NTS increased HER3 tyrosine phosphorylation in a ROS-/Src-/MMP-dependent manner. In summary, NTSR1 transactivates HER3 resulting in ERK and Akt phosphorylation increasing the proliferation and survival of NSCLC cells.

Citation Format: Terry W. Moody, Irene Ramosalvarez, Robert T. Jensen. Neurotensin causes tyrosine phosphorylation of HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 731.
Abstract 733: Significance of PELP1/SETDB1 axis in endocrine therapy resistance
Authors: Liu Zexuan , Liu Junhao , Tang Weiwei , Pratap Uday P. , Altwegg Kristin A. , Ebrahimi Behnam , Li Xiaonan , Sareddy Gangadhara R. , Viswanadhapalli Suryavathi , Vadlamudi Ratna K.
Published: July 2021

BACKGROUND: PELP1 is commonly overexpressed in breast cancer (BCa) and is implicated in endocrine therapy resistance. However, the mechanism by which PELP1 contributes to therapy resistance remains elusive. Our ongoing studies using yeast two hybrid screen identified histone methyltransferase SETDB1 as a novel interactor of PELP1. The objective of this study is to determine the significance of PELP1 interaction with SETDB1 in BCa endocrine therapy resistance.

METHODS: We used two ER+ BCa cell lines (MCF7 and ZR75) and three endocrine therapy resistant cell lines (Tamoxifen resistant MCF7-TamR, Fulvestrant resistant MCF7-FR, Tamoxifen resistant MCF7-PELP1-cyto). Additional BCa models with stable overexpression and under expression of SETDB1 and PELP1 (MCF7-SETDB1-PELP1shRNA, ZR75-SETDB1-PELP1shRNA, ZR75-SETDB1, MCF7-SETDB1, MCF7-TamR-SETDB1shRNA, MCF7-FR-SETDB1shRNA) were generated using lentiviral transduction. Functional significance of cross-talk was tested using MTT, soft agar, and colony formation assays. Mechanistic studies were conducted using immunoprecipitation, Western blotting, and RT-qPCR.

RESULTS: Analyses of TCGA databases showed that SETDB1 expression is positively correlated with PELP1 expression in ER+ BCa (r=0.30, p<0.0001). Immunoprecipitation assays using multiple ER+ BCa cell lysates confirmed the interaction of SETDB1 with PELP1. Using ER+ BCa models with overexpression of SETDB1 or knockdown, we provided evidence that SETDB1 plays an important role in the proliferation of BCa cells. PELP1 knockdown attenuated SETDB1 mediated BCa cells proliferation. SETDB1 upregulation contributed to tamoxifen resistance, while PELP1 knockdown re-sensitized cells to tamoxifen therapy. Further, endocrine therapy resistant model cells (MCF7-TamR, MCF7-FR, MCF7-PELP1-cyto) showed increased expression of SETDB1, and its knockdown sensitized them to endocrine therapy. Mechanistic studies revealed that PELP1 is needed for SETDB1 mediated Akt phosphorylation and activation of its downstream targets such as S6, and Cyclin D1.

CONCLUSIONS: The results of study suggest that the PELP1/SETDB1 interactions contribute to endocrine therapy resistance via aberrant activation of Akt signaling. Targeting PELP1/SETDB1 axis could represent a new therapeutic avenue to mitigate endocrine resistance. Supported by VA grant I01BX004545 (R.K. Vadlamudi)

Citation Format: Zexuan Liu, Junhao Liu, Weiwei Tang, Uday P. Pratap, Kristin A. Altwegg, Behnam Ebrahimi, Xiaonan Li, Gangadhara R. Sareddy, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi. Significance of PELP1/SETDB1 axis in endocrine therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 733.
Abstract 734: Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer
Authors: El-Kenawi Asmaa , Viqueira William Dominguez , Liu Min , Awasthi Shivanshu , Dhillon Jasreman , Yamoah Kosj , Yu Xiaoqing , Koomen John , Gatenby Robert , Ruffell Brian
Published: July 2021

Castration-resistant prostate cancer (CRPC) is a lethal stage of disease. A wealth of clinical and experimental data supports the persistence of androgen receptor (AR) signaling in many cases of CRPC, despite androgen-deprivation therapy (ADT). Here we sought to determine the role of macrophage cholesterol in CRPC and androgen signaling using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of prostate tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid metabolism, indicating perturbation of cholesterol transport. Since cholesterol is the precursor of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

Citation Format: Asmaa El-Kenawi, William Dominguez Viqueira, Min Liu, Shivanshu Awasthi, Jasreman Dhillon, Kosj Yamoah, Xiaoqing Yu, John Koomen, Robert Gatenby, Brian Ruffell. Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 734.
Abstract 75: Determinants of tumor resistance to anti-angiogenic immunotherapy in mouse models of Kras-mutant NSCLC
Authors: Martinez-Usatorre Amaia , Kadioglu Ece , Cianciaruso Chiara , Guichard Alan , Torchia Bruno , Nassiri Sina , Schmittnaegel Martina , Ries Carola H. , Meylan Etienne , Keklikoglou Ioanna , De Palma Michele
Published: July 2021

Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC), often in combination with chemotherapy. However, only a minority of the patients respond and sustained remissions are rare. Anti-angiogenic therapy improves tumor response to ICB in mouse models of cancer and in patients with EGFR-mutant NSCLC, but the contribution of anti-angiogenic therapy to the clinical efficacy of ICB in patients with KRAS-mutant NSCLC remains unclear. We used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging of individual tumors to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and cisplatin chemotherapy. We found that anti-angiogenic blockade of VEGFA and angiopoietin-2 (ANGPT2) with the bispecific antibody A2V was superior to single VEGFA inhibition and markedly slowed tumor progression. But, contrary to findings in other tumor models, the addition of a PD1 antibody to A2V did not provide additive benefits and even accelerated growth of a fraction of the tumors. We implicated tumor-associated macrophages (TAMs) and PD-1+regulatory T cells (T-regs) in this growth-promoting response, and identified a pre-clinical strategy involving the differential targeting of two distinct TAM subsets that unleashed the therapeutic potential of anti-angiogenic immunotherapy and achieved regression of more than 80% of the lung tumors.

Citation Format: Amaia Martinez-Usatorre, Ece Kadioglu, Chiara Cianciaruso, Alan Guichard, Bruno Torchia, Sina Nassiri, Martina Schmittnaegel, Carola H. Ries, Etienne Meylan, Ioanna Keklikoglou, Michele De Palma. Determinants of tumor resistance to anti-angiogenic immunotherapy in mouse models of Kras-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 75.
Abstract 750: Race differences in telomere length in benign prostate and subsequent risk of prostate cancer
Authors: Rybicki Benjamin A. , Sadasivan Sudha M. , Chen Yalei , Loveless Ian , Gupta Nilesh S. , Chitale Dhananjay A. , Williamson Sean R. , Rundle Andrew G. , Tang Deliang
Published: July 2021

Telomere shortening is linked to aging and thought to be associated with increased risk for cancer. Most cancer studies have used leukocyte telomere length as a surrogate measure for telomere length with few focused upon telomeres in the target tissue of cancer origin. To determine whether telomere length in pre-malignant prostate tissue is associated with subsequent prostate cancer risk, we conducted a case-control study of 530 case-control pairs matched on date, age at cohort entry, and race nested within a historical cohort of 10,478 men with a benign prostate biopsy. Overall mean telomere length assessed using modified quantitative real-time PCR was not different in benign prostate biopsies of prostate cancer cases vs. matched controls (1.65 ± 0.35 vs. 1.64 ± 0.39; p=0.41). However, race was significantly associated with telomere length with African American (AA) men having shorter telomeres in benign prostate biopsy compared with white men (1.59 ± 0.37 vs. 1.70 ± 0.37; p<0.0001). In race-stratified analyses, telomere length only showed a suggestive association with prostate cancer risk in white men, wherein those with telomere length in the highest quartile had 1.5-fold greater risk of prostate cancer compared to men with prostate telomere lengths in the lowest quartile (OR=1.56; 95% CI = 0.89 - 2.73 ). In addition, white men in the highest prostate telomere length quartile had almost three-fold greater risk of aggressive prostate cancer, defined as Gleason group 3 and above, tumor stage 3 or above or PSA 20 ng/ml or higher , compared with men with telomere lengths in the lowest quartile (OR=2.73; 95% CI =1.05 - 7.15). In summary, white men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease.

Citation Format: Benjamin A. Rybicki, Sudha M. Sadasivan, Yalei Chen, Ian Loveless, Nilesh S. Gupta, Dhananjay A. Chitale, Sean R. Williamson, Andrew G. Rundle, Deliang Tang. Race differences in telomere length in benign prostate and subsequent risk of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 750.
Abstract 762: Clinical characteristics and prognostic value of the KRASmutation in Chinese colorectal cancer patients
Authors: Yuan Ye , Wang Wei , Zhao Jiemin , Zhang Junling , Chen Shiqing , Shen Chunti , Wu Changping , Hu Wenwei
Published: July 2021

Background: The KRAS mutation are high-frequency somatic mutations found in the colorectal cancer (CRC) patients both from Western and Asian countries, but except for exon 2 of KRAS, other prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutation of KRAS in Chinese CRC patients and to investigate their impact on prognosis.

Methods: 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing (NGS) for detection the KRAS mutation. All pathologic or likely pathologic mutations of KRAS were considered. In addition, clinical features and prognostic dates were collected from 145 patients at the third affliated Hospital of Soochow University (sCohort) and used ddPCR to detect KRAS mutations.

Results: In the iCohort, 2706 patients (37.6%) were confirmed harboring KRAS mutation. The most frequent mutations in KRAS were G12D (32.19%), G12V (17.96%) and G13D (17.59%). In the sCohort, 51 CRC patients (35.17%) had KRAS mutations, among which KRAS G12D (64.71%), G13D (29.41%) and G14D (3.92%) were high-frequency mutations. The KRAS mutation was associated with shorter median overall survival (OS) than wild-type tumors (mOS, 69 vs 55 months; HR, 1.80; 95% Cl 1.22-2.64; P=0.0003). In Cox multivariate analysis, age (HR, 1.562; 95% Cl 1.10-2.22; P=0.013), tumor differentiation (HR, 0.417; 95% Cl 0.19-0.90; P=0.026) and KRAS mutation (HR, 1.897; 95% Cl 0.19-0.90; P=0.001) remained independent predictor of shorter OS. Among the common KRAS mutations, G12D was significantly associated with shorter OS (HR, 2.17; 95% Cl 1.31-3.58; P < 0.0001) compared with KRAS wild-type patients.

Conclusions: Our findings indicate that KRAS genes are frequently mutated and over 30% harbored the KRAS G12D mutation subtype. Our finding that KRAS G12D mutation is associated with inferior survival and a biomarker of poor prognosis in Chinese patients. Our data emphasizes the importance of molecular features in CRC patients, which could potentially be improved by G12D-specific related inhibitors.

Citation Format: Ye Yuan, Wei Wang, Jiemin Zhao, Junling Zhang, Shiqing Chen, Chunti Shen, Changping Wu, Wenwei Hu. Clinical characteristics and prognostic value of the KRASmutation in Chinese colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 762.
Abstract 764: Circulating tumor cell-based mRNA scoring system for prognostication of hepatocellular carcinoma - Translating HCC tissue-based mRNA profiling into a non-invasive setting
Authors: Lee Yi-Te , Sun Na , Kim Minhyung , Wang Jasmine J. , Tran Benjamin V. , Zhang Ryan Y. , Zhang Ceng , Sadeghi Saeed , Finn Richard S. , Saab Sammy , Busuttil Ronald W. , Zhu Yazhen , Tseng Hsian-Rong , You Sungyong , Yang Ju Dong , Agopian Vatche G.
Published: July 2021

Background and Aims Numerous studies in hepatocellular carcinoma (HCC) have proposed tissue-based gene signatures for individualized prognostic assessments. In this study, we aim to develop the HCC circulating tumor cell (CTC) mRNA Scoring System and the HCC-CTC Risk Score (RS) panel to translate tissue-based mRNA signatures into a liquid biopsy setting for non-invasive HCC prognostication.

Methods We developed the HCC CTC mRNA Scoring System by combining the NanoVelcro CTC Assay for enriching HCC CTCs and the NanoString nCounter platform for quantifying the HCC-CTC RS panel in enriched HCC CTCs. The prognostic role of HCC-CTC RS was assessed in the Cancer Genome Atlas (TCGA) HCC cohort (n=362) and validated in an independent CTC cohort (n=40).

Results The HCC-CTC RS panel was developed from 8 HCC tissue-based prognostic gene signatures. Through our integrated data analysis framework, the top 10 prognostic genes highly expressed in HCC cells and lowly expressed in white blood cells were selected as the HCC-CTC RS panel. The panel accurately discriminated overall survival in TCGA HCC cohort (hazard ratio [HR]: 2.01, 95% confidence intervals [CI]: 1.39-2.91). In addition, the combined use of Scoring System and panel successfully distinguished artificial blood samples spiked with an aggressive HCC cell type, SNU-387, from those spiked with PLC/PRF/5 cells (P=0.02). Finally, the prognostic value of HCC-CTC RS was further validated in the CTC cohort (HR: 8.48, 95% CI: 1.89-38.03) by multivariable analysis.

Conclusions Our pilot study demonstrates a novel interdisciplinary approach to translate tissue-based gene signatures into a liquid biopsy setting. This non-invasive approach will allow real-time disease profiling and dynamical prognostication of HCC.

Citation Format: Yi-Te Lee, Na Sun, Minhyung Kim, Jasmine J. Wang, Benjamin V. Tran, Ryan Y. Zhang, Ceng Zhang, Saeed Sadeghi, Richard S. Finn, Sammy Saab, Ronald W. Busuttil, Yazhen Zhu, Hsian-Rong Tseng, Sungyong You, Ju Dong Yang, Vatche G. Agopian. Circulating tumor cell-based mRNA scoring system for prognostication of hepatocellular carcinoma - Translating HCC tissue-based mRNA profiling into a non-invasive setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 764.
Abstract 782: Exploring the contribution of introgressed ancient DNA to prostate cancer racial disparity
Authors: Useh Evi O. , Venugopal Suresh , Molokwu Chidi N.
Published: July 2021

Introduction: Prostate cancer is the most common cancer in men and there is racial disparity in prostate cancer incidence and mortality globally, with greater disease burden in men of African ancestry, followed by European ancestry and least in men of Asian ancestry. The etiology of prostate cancer is not fully understood, but includes genetic and environmental factors. Present day non-Africans are reported to have introgressed DNA from Neanderthal and Denisovan ancestors. Over 170 prostate cancer associated single nucleotide polymorphisms (SNPs) have been identified from several genome-wide association studies (GWAS), with SNPS on chromosomes 2, 8 and 22 reported as showing variation between African and non-African men with prostate cancer. We performed analysis of prostate cancer associated SNPs on chromosomes 2, 8 and 22 to determine if DNA introgression could explain the racial variation.

Methods: We obtained data on prostate cancer associated SNPs from the GWAS catalog (https://www.ebi.ac.uk/gwas) and from reports that were not included in the catalog. Using an Ancient Genome Browser provided by the Max Plank Institute (https://www.eva.mpg.de/genetics/genomeprojects/neandertal/index.html), we determined whether SNPs on chromosomes 2, 8 and 22 were present in African, Neanderthal or Denisovan genomes. Based on the results, we inferred that SNPs were introgressed if they were present in Neanderthal or Denisovan genomes but absent from African genomes.

Results: 49, 59 and 17 prostate cancer SNPs were reported in chromosomes 2, 8 and 22 respectively. 23/49 in ch2, 25/59 in ch8 and 9/17 in ch22 were present in Neanderthal and or Denisovan genomes. SNPs in ch2 (rs13403657, rs12621278) and ch8 (rs7825414) were present in Neanderthal or Denisovan genomes but absent in African genomes. These SNPs lie in regions that have previously been reported to harbor introgressed DNA.

Conclusion: Our analyses identified prostate cancer associated SNPs that are likely to have been introgressed into present day non-Africans by extinct Neanderthal and Denisovan ancestors. Phenotypic changes caused by introgressed DNA could be contributing to racial disparities in prostate cancer in present day humans.

Citation Format: Evi O. Useh, Suresh Venugopal, Chidi N. Molokwu. Exploring the contribution of introgressed ancient DNA to prostate cancer racial disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 782.
Abstract 793: Potential impact of time trend of lifestyle factors on burden of gastrointestinal cancer in China
Authors: Wu You , Li Yanping , Giovannucci Edward , Hu Frank B.
Published: July 2021

BACKGROUND: Colorectal, esophageal, stomach, and liver cancers are four major gastrointestinal (GI) cancers that have 2-3 times the age-standardized incidence rates in China compared to the global average. Examining the time trend of risk factors associated with GI cancer would help us project the future trend of GI cancer incidence in China and guide public health policymaking.

METHODS: We estimated the time trend of relevant dietary and lifestyle factors in China based on data from the China Health and Nutrition Survey 1991-2011. We applied the comparative risk assessment method to estimate the population attributable fraction (PAF%) and the absolute number of GI cancer events attributable to all non-optimal levels of each risk factor. We have also projected the lifestyle factors and the estimated burden of GI cancer in the next 30 years.

RESULTS: In 2011, the overall estimated PAF% by all risk factors under study is 73% for esophageal cancer, 59% for colorectal cancer, 47% for gastric cancer, and 35% for liver cancer. Smoking, low fruit intake, high red meat consumption, high body mass index (BMI), and high alcohol consumption were the top 5 contributors to GI cancer incidence in China; each accounted for 173, 134, 132, 125, and 91 thousand GI cancer cases, respectively. For specific cancer sites, high red meat consumption accounted for the most cases of colorectal cancer in 2011 (N = 51,405; PAF% = 19%) and is projected to have higher PAF% from 15% in 1997 to 23% in 2041. High BMI is responsible for the most liver cancer cases in 2011 (N = 55,244; PAF% = 17%) and has an increasing trend in expected PAF% from 7% in 1991 to 20% in 2041; low fruit intake is the top contributor for esophageal cancer in 2011 (N = 85,345; PAR% = 29%) with a downward trend in the next few decades (PAF% from 33% in 1997 to 23% in 2041); high sodium intake represented the highest PAF% for gastric cancer in 2011 (68,858 cases, PAF% = 17%), but is expected to be overpassed by smoking, high BMI, and red meat consumption in 2015-2025.

CONCLUSIONS: China has witnessed significant transitions in lifestyle, including diet, physical activity, and obesity. The impact of the lifestyle risk factors on the risk of GI cancer has been increasing from 1991 to 2011 and is projected to continue growing. High red meat consumption and high BMI call for extra attention as they are among the top contributors to GI cancer and are expected to have stronger impacts in the next 30 years in China.

Citation Format: You Wu, Yanping Li, Edward Giovannucci, Frank B. Hu. Potential impact of time trend of lifestyle factors on burden of gastrointestinal cancer in China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 793.
Abstract 796: Investigating incidence and survival patterns of cutaneous malignant melanoma in the United States from 2006-2017
Authors: Kye Yae , Alvarado Luis , Dwivedi Alok , Chacon Jessica
Published: July 2021

Introduction: Skin cancers are one of the most common cancers in the United States with melanoma being the fifth leading cause of cancer. Despite its increasing incidence, there are limited studies on how skin cancer affects different races and ethnicities. Here, we conduct a population-based registry study to derive incidence and survival patterns of cutaneous malignant melanoma (CMM) in the US from 2006-2017. 17 population-based cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were reviewed. A total of 58,666 cases with histologically confirmed cases of cutaneous malignant melanoma were evaluated. Surprisingly, the CMM subtype that was predominantly found in the non-Hispanic whites (56%) and Hispanic whites (45%) was acral lentiginous melanoma, while “other” melanomas were predominant in the Asian (54%) and Black (77%) populations. Superficial spreading and lentigo maligna melanomas presented more commonly in men (69% and 63%). In addition, nodular and lentigo maligna melanomas had the poorest survival rates and had a median survival of 26 and 21 months.

Methods: The Surveillance, Epidemiology, and End Results Program (SEER) of the National Cancer Institute was used to calculate the incidence, proportion, and survival data. 58,66 histologically confirmed CMM cases reported by the 17 cancer registries from 2006-2017 were used. The 17 registries include 14 states (Alaska, greater and California, Connecticut, Georgia, Hawaii, Idaho, Iowa, Kentucky, Louisiana, Massachusetts, New Mexico, New York, Utah, Washington) and 4 standard metropolitan areas (Los Angeles, San Francisco-Oakland, and San Jose-Monterey, California; and Seattle-Puget Sound, Washington). Cases of the 4 major CMM subtypes as well as the “other” subtypes were identified using the World Health Organization's International Classification of Diseases for Oncology (ICD-0-3) morphology code.

Conclusion and future direction: CMM has been steadily increasing in incidence within the US. Moreover, the incidence rate of CMM in the Hispanic population has been rising. It is important that we continue to assess the epidemiological characteristics and trends of CMM subtypes in the US and increase awareness of skin cancer and its preventative measures in the Hispanic population. In addition, future studies should analyze the genetic and environmental factors that may be contributing to observed incidence rates in the Hispanic population.

Citation Format: Yae Kye, Luis Alvarado, Alok Dwivedi, Jessica Chacon. Investigating incidence and survival patterns of cutaneous malignant melanoma in the United States from 2006-2017 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 796.
Abstract 799: Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers
Authors: ShKuligina Ekaterina , Romanko Alexandr A. , Jankevic Tatjana , Martianov Aleksandr S. , Sokolova Tatyana N. , Ivantsov Alexandr O. , Imyanitov Evgeny N.
Published: July 2021

Female carriers of germline BRCA1 mutation almost inevitably develop breast cancer (BC). However, the age of BRCA1-associated cancer onset varies widely. We hypothesize that age-related penetrance of BRCA1 mutations may depend on the inherited variability in the host immune system. We utilized high-throughput HLA-typing to describe 10 classical HLA class I/II loci for 90 young (<38 y.o.) and 73 elderly (>57 y.o.) BRCA1-mutated BC patients. 39% of young females were homozygous for two or more HLA-II loci; this was significantly higher than in the “elderly” cohort [OR = 3.23; p = 0.002]. In contrast, women who harboured identical alleles at HLA-B locus (class I) had increased chances to stay tumour-free to their older ages [OR = 3.02; p = 0.077]. Allele HLA-DBR1*11:03/04 was overtly overrepresented in elderly BRCA1-driven BC [11% vs. 3%, p = 0.006]. The frequencies of HLA-DRB1*01:01 and HLA-DQB1*05 were significantly higher in group of “young” patients [p = 0.020 and p = 0.011, correspondently]. The tumour immunogenicity was analyzed in early-onset and late-onset BC patients through the evaluation of the intratumoral density of cytotoxic T-lymphocytes (TILs) with anti-CD8 IHC staining. 5/10 carcinomas arisen in young BRCA1-carriers were classified as a “hot” phenotype with a high density of TILs across the tumour. Inversely, the BC developed in “elderly” women was characterized by the reduced levels of TILs. Conclusions: 1) the limited repertoire of HLA peptides caused by the homozygosity for HLA II loci may increase susceptibility to BC in BRCA1-carriers and manifest by early disease onset; 2) tumours from “elderly” BRCA1-associated patients have reduced levels of lymphocytic infiltration compared to “young” patients. The research is supported by RSF grant #19-15-00207

Citation Format: Ekaterina ShKuligina, Alexandr A. Romanko, Tatjana Jankevic, Aleksandr S. Martianov, Tatyana N. Sokolova, Alexandr O. Ivantsov, Evgeny N. Imyanitov. Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 799.
Abstract 802: Multi-cancer profiles in high-risk CLL families
Authors: Harris Nathan Scott
Published: July 2021

Discovery of novel etiological factors for B-cell malignancies is hindered by the heterogeneity of these diseases. The identification of important multi-cancer profiles provides a new avenue for discovery, but requires novel approaches and specific resources. The Utah Population Database (UPDB) includes extensive genealogy for 5 million Utahns (from three to 18 generations). The UPDB also includes over 360,000 cancer diagnoses from the NCI SEER Utah Cancer Registry, making it a unique and ideal resource for analyzing cancer patterns in families. Here we performed a multi-cancer clustering approach to identify patterns of familial clustering of cancers in high-risk CLL families. Other cancers considered in the cancer profiles were: Hodgkins lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma and 25 solid tumors. High risk CLL pedigrees were extracted from the UPDB. Based on cancer rates in UPDB, standardized incidence ratios were calculated for each pedigree for each of the 29 cancers. These vectors of cancer risks per pedigree were used as the basis for k-mediods clustering of the high-risk CLL families. Resulting clusters of families share similar co-aggregations of other B-cell malignancies and solid tumors. High-risk CLL families with similar multi-cancer profiles may be more etiologically homogeneous and provide improved power for the identification of underlying risk factors.

Citation Format: Nathan Scott Harris. Multi-cancer profiles in high-risk CLL families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 802.
Abstract 805: A germline mutation of gene ATM p.C1899* is associated with a family history of multiple cancers in a family in Yunnan province, China
Authors: Sun Xianghua , Zhang Hushan , Zhang Wanfu , Zhang Zhiping , Li Bo
Published: July 2021

Background: Ataxia-telangiectasia mutated (ATM) is a gene that plays role in cell cycle checkpoints and DNA damage response, heterozygous germline mutations in ATM are considered as one of risk factor of breast cancer (BC). There are also some reports that ATM mutations are related to other tumor types, such as prostate cancer. Several pathogenic germline mutations in ATM have been reported included missense mutations, nonsense mutations, frameshift deletions, in-frame deletion, large deletion. Here, we report a family history of multiple cancers related to germline mutation of ATM p.C1899* in a family in Yunnan province, China.

Methods: The proband is a 58-year old male patient with colon cancer. Both tumor tissue samples and peripheral blood sample of the proband was subjected to next generation sequencing (NGS) analysis by 3D Medicines Inc., Shanghai, China, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA). A novel germ-line mutation was identified, that was heterozygous ATM p.C1899* mutation (c.5697C>A). Peripheral blood sample of other family members have been collected and send to 3D Medicines Inc., for NGS analysis.

Results: In total of 6 members of the family underwent NGS analysis, results showed that these members were carry a germline mutation of gene ATM p.C1899*, one uncle was patient with gastric cancer, and one aunt was patient with pancreatic cancer, which means this germline mutation was related with three different cancer in a family.

Conclusion: The mutation of ATM, especially germline mutation, may associated with multiple cancers, such as gastric cancer, colorectal cancer and pancreatic cancer. Accurate genetic testing should be given more attention to better control the risk of familial cancer.

Citation Format: Xianghua Sun, Hushan Zhang, Wanfu Zhang, Zhiping Zhang, Bo Li. A germline mutation of gene ATM p.C1899* is associated with a family history of multiple cancers in a family in Yunnan province, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 805.
Abstract 81: Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms
Authors: Stoyanova Tanya Ivanova , Hsu En-Chi , Liu Shiqin , Marques Fernando Jose Garcia , Bermudez Abel , Aslan Merve , Shen Michelle , Pitteri Sharon , Brooks James D.
Published: July 2021

Background: The first line of treatment for men with advanced prostate cancer is androgen deprivation therapy. Although initial responses are observed, prostate cancer commonly relapses in its lethal metastatic form referred to as castration resistant prostate cancer (CRPC) with 1-2 years mean survival time. Neuroendocrine prostate cancer (NEPC) is highly aggressive, AR independent subtype and usually emerges post castration resistance. We recently identified that the cell surface receptor, Trop2, is a new driver of NEPC. Moreover, we demonstrated that Trop2 regulates prostate cancer growth and metastasis. In this study, we set out to delineate the molecular mechanisms through which Trop2 regulates prostate cancer growth and metastasis.

Methods: Proximity-dependent Biotin Identification (BioID) followed by mass spectrometry was performed to identify Trop2 interactome. Lentiviral infection was used to generate prostate cancer cell lines with over-expression of Trop2 and knock-down of NOTCH1, SLC4A7, PLEC, and OCLN shRNA to modulate gene expression levels. In vitro functional assays were performed including colony formation, and Matrigel drop 3D cell invasion assays.

Results: The Trop2 membrane interactome was identified utilizing Proximity-dependent Biotin Identification (BioID) in living cells and uncovered that Trop2-mediated prostate cancer growth and metastasis are orchestrated by distinct downstream pathways including Notch signaling (NOTCH1), control of intracellular pH (SLC4A7), exosome secretion (PLEC), and tight junctions (OCLN). Interaction of Trop2 binding partners including NOTCH1, SLC4A7, PLEC and OCLN with Trop2 were further validated by fluorescence resonance energy transfer (FRET) using confocal microscopy. Moreover, knocking down the Trop2 interacting partners in Trop2 over-expressing prostate cancer cells suppressed Trop2-driven growth and invasion ability.

Conclusions: In a previous study, we identified cell surface receptor, Trop2, as a novel driver of metastatic NEPC. Herein, our new findings reveal that Trop2 interacts with NOTCH1, SLC4A7, PLEC, and OCLN, which may highlight novel biological functions of Trop2 in prostate tumorigenesis and provide new understanding of the potential mechanism of neuroendocrine differentiation and metastasis to provide new therapeutic strategy for metastatic CRPC with neuroendocrine features.

Citation Format: Tanya Ivanova Stoyanova, En-Chi Hsu, Shiqin Liu, Fernando Jose Garcia Marques, Abel Bermudez, Merve Aslan, Michelle Shen, Sharon Pitteri, James D. Brooks. Trop2 regulates prostate cancer growth and metastasis through distinct molecular mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 81.
Abstract 817: Probing the diabetes - colorectal cancer link using gene - environment interaction analyses
Authors: Dimou Niki , Kim Andre E. , Flanagan Orlagh , Murphy Neil , Bouras Emmanouil , Campbell Peter T. , Casey Graham , Gallinger Steven , Gruber Stephen B. , Hsu Li , Jenkins Mark A. , Lin Yi , Moreno Victor , Qu Conghui , Ruiz-Narvaez Edward , Stern Mariana C. , Tian Yu , Tsilidis Kostas , Gauderman W. James , Gunter Marc J. , Peters Ulrike
Published: July 2021

Background: Type 2 diabetes mellitus (T2D) is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship are unclear and it is not known if the association is modified by genetic variants. To provide insights into the molecular pathways potentially linking diabetes and colorectal cancer, we undertook a large-scale gene-environment interaction analysis (GxE).

Methods: We tested multiplicative statistical interactions between approximately 7 million common (allele frequency >1%) genetic variants and T2D status in 31,529 colorectal cancer cases and 42,861 controls of European ancestry from 3 genetic consortia (GECCO/CCFR/CORECT). Statistical methods included traditional case-control logistic regression, case-only analyses, joint tests (2df/3df), and two-step approaches. We also explored additive and multiplicative interactions between polygenic risk score (PRS) of the known genome-wide significant loci for colorectal cancer and T2D. Results: Overall, T2D was positively associated with colorectal cancer risk [odds ratio [OR]: 1.25 (95% confidence interval [CI]: 1.14-1.36)]. A statistically significant interaction was identified between T2D status and an intronic variant in LRCH1 (rs9526201) and colorectal cancer risk using the 2-d.f. joint test (p-value:1.44x10-8). A statistically significant additive scale interaction between PRS for colorectal cancer and T2D was found (p-value: 1.8x10-10) such that the observed risk of developing colorectal cancer for individuals with T2D and a 1 standard deviation (SD) higher increment of PRS compared to non-diabetics with the lowest PRS was 0.184 more than if there was no interaction between T2D and PRS. Conclusion: These results suggest that variation in a gene related to immune function may modify the association of T2D with colorectal cancer and potentially provide novel insights into the biology underlying this relationship. Furthermore, our data show that genetic risk prediction models for CRC may need to consider non-genetic risk factors.

Citation Format: Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Emmanouil Bouras, Peter T. Campbell, Graham Casey, Steven Gallinger, Stephen B. Gruber, Li Hsu, Mark A. Jenkins, Yi Lin, Victor Moreno, Conghui Qu, Edward Ruiz-Narvaez, Mariana C. Stern, Yu Tian, Kostas Tsilidis, W. James Gauderman, Marc J. Gunter, Ulrike Peters. Probing the diabetes - colorectal cancer link using gene - environment interaction analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 817.
Abstract 828: Common genetic variants influence the composition of the tumor immune microenvironment and host anti-tumor responses
Authors: Pagadala Meghana , Kim Hyo , Castro Andrea , Gonzalez-Colin Cristian , Wu Victoria , Cao Steven , Schmiedel Benjamin , Salem Rany , Gutkind Silvio , Thompson Wes , Pandurangan Vijayanand , Carter Hannah
Published: July 2021

Developing effective therapies to intervene in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Germline variation is a major component of interindividual variability usually studied by large-scale genome-wide association studies (GWAS) in the context of disease risk; yet, there is still a gap in our understanding of germline variation specifically in the tumor immune microenvironment. To address this, we systematically characterized the immune effects of germline genetic polymorphisms across 33 human cancer types in the TCGA. Immune microenvironment phenotypes include immune infiltration levels as calculated by CIBERSORTx and expression of immunomodulator genes obtained through literature curation. PCA analysis reduced dimensionality of immune phenotypes, with macrophage regulation and EP300/Proteosome expression mediating most variability amongst individuals. We identified 482 SNP-immune gene associations, where a subset of SNPs affected multiple immune phenotypes. Using cell-type and epigenetic analyses, we further characterized immune microenvironment variants to act through macrophage and dendritic cell-specific manners and alter immune-cell specific epigenetic regions. Through burden analysis, we found several of these variants interact to have stronger immune microenvironment effects. Lastly, using ICB-trial cohorts, we found several variants affecting LILRB2, LILRB4, LAIR1, CCBL2, and CTSW modulate response to immune checkpoint blockade. Our results provide better understanding of how germline variation modifies tumor immune microenvironment dynamics and will set up further studies to identify predictive biomarkers of the tumor immune microenvironment.

Citation Format: Meghana Pagadala, Hyo Kim, Andrea Castro, Cristian Gonzalez-Colin, Victoria Wu, Steven Cao, Benjamin Schmiedel, Rany Salem, Silvio Gutkind, Wes Thompson, Vijayanand Pandurangan, Hannah Carter. Common genetic variants influence the composition of the tumor immune microenvironment and host anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 828.
Abstract 838: Sugar-sweetened beverage intake and risk of early-onset colorectal cancer
Authors: Hur Jinhee , Otegbeye Ebunoluwa , Joh Hee-Kyung , Nimptsch Katharina , Ng Kimmie , Ogino Shuji , Meyerhardt Jeffrey A. , Chan Andrew T. , Willett Walter C. , Wu Kana , Giovannucci Edward , Cao Yin
Published: July 2021

Background: The incidence of early-onset colorectal cancer (EO-CRC) diagnosed under age 50 continues to rise, and the pattern shows a strong birth cohort effect. Sugar-sweetened beverage (SSB) consumption had substantially increased across successive birth cohorts until 2000, and the population under age 50 has the highest level of consumption. Despite the well-documented, adverse metabolic effects of SSBs, their link with EO-CRC remains unexamined.

Methods: In the Nurses' Health Study II, consisting of US female registered nurses aged 25-42 in 1989, we prospectively investigated the association between SSB intake and risk of EO-CRC. A total of 95,621 women who had reported beverage intake using validated food frequency questionnaires every 4 years since 1991 were followed up through June 2015. Cox proportional hazards models were used to estimate relative risks (RRs) with 95% confidence intervals (CIs).

Results: We documented 109 EO-CRC cases over up to 24 years of follow-up (1,358,158 person-years). SSB consumption was associated with a higher risk of EO-CRC. Compared with individuals who consumed <1 serving/week of SSBs, women who consumed ≥2 servings/day had a more than doubled risk of EO-CRC (RR, 2.18; 95% CI, 1.10-4.35; P for trend=0.02). Each additional serving/day of SSB consumption was associated with a 16% higher risk of EO-CRC (RR, 1.16; 95% CI, 1.00-1.36). Replacing each serving/day of SSB intake with that of artificially sweetened beverages, coffee, reduced fat milk, or total milk was associated with a 17-36% lower risk of EO-CRC.

Conclusion: Higher SSB intake was associated with a higher risk of EO-CRC among women. Reduction of SSB consumption among young adults may serve as a potential strategy to alleviate the growing burden of EO-CRC.

Citation Format: Jinhee Hur, Ebunoluwa Otegbeye, Hee-Kyung Joh, Katharina Nimptsch, Kimmie Ng, Shuji Ogino, Jeffrey A. Meyerhardt, Andrew T. Chan, Walter C. Willett, Kana Wu, Edward Giovannucci, Yin Cao. Sugar-sweetened beverage intake and risk of early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 838.