Hormone-dependent Cancer Research Articles

Use of personal care product mixtures and incident hormone-sensitive cancers in the Sister Study: A U.S.-wide prospective cohort

BackgroundPersonal care products (PCPs), a source of endocrine-disrupting chemical exposure, may be associated with the risk of hormone-sensitive cancers. Few studies have investigated associations for PCP use with the incidence of hormone-sensitive cancers or considered the joint effect of multiple correlated PCPs. We examined associations between frequently used, or “everyday”, PCPs and incident cancers of the breast, ovary, and uterus with a fucus on the joint effect of multiple product exposure. MethodsSister Study participants (n=49 899) self-reported frequency of use in the year before enrollment (2003–2009) for 41 PCPs. Using five-level frequency categories based on questionnaire options, hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the associations between multiple PCP use and incident breast, ovarian, and uterine cancer using quantile-based g-computation with Cox proportional hazards regression as the underlying model. Multiple PCP use was examined using groupings (beauty, hygiene, and skincare products) determined by both a priori knowledge and Spearman correlation coefficients for co-occurring product use. Associations between individual PCPs and the three cancers were also examined using Cox proportional hazards models coupling with Benjamini-Hochberg procedure for multiple comparisons. ResultsOver an average of 11.6 years, 4 226 breast, 277 ovarian, and 403 uterine cancer cases were identified. Positive associations were observed between the hygiene mixture and ovarian cancer (HR=1.35, 95%CI=1.00, 1.83) and the beauty mixture with postmenopausal breast cancer (HR=1.08, 95%CI=1.01, 1.16). Additionally, we observed an inverse association between the skincare mixture and breast cancer (HR=0.91, 95%CI=0.83, 0.99). No significant associations were observed for individual products after corrected for multiple comparison. ConclusionsFindings from this multi-product, joint-effect approach contribute to the growing body of evidence for associations between PCPs and breast cancer and provides novel information on ovarian and uterine cancer.

Predictive model for identifying new CYP19A1 ligands on the KNIME analytical platform

The purpose of this study was to create a database of the chemical compounds – ligands of human steroid-hydroxylating cytochrome CYP19A1 (aromatase) in order to build a predictive model. The idea was to create a model on the basis of the machinery learning method such as random forest for two types of ligands – with steroidal (I type) and non-steroidal structure (II type). Two predictive models were built with the help of the KNIME analytical platform. Topological descriptors of the chemical structure were used as training data when building a model that takes into account their correlation between the structure of the molecule and the biological effect. The selection of the feature importance of the descriptors, optimal parameters of random forest and the definition of applicability domain of the models were carried out. The assessment of the ability to predict the results of a test sample was performed for each model. The quality marks of the obtained models indicated a rather high predictive ability of the models and the prospects of their use for identification of new human CYP19A1 ligands as potential drugs for treatment of hormone-dependent tumors.

Discovery of RET as an endocrine cancer gene

Discovery of RET as an endocrine cancer gene

Risk Stratification of Differentiated Thyroid Cancer: A Single-Center Study in Basrah.

Background Differentiated thyroid cancer is a common endocrine cancer; most of it has an indolent course and favorable outcomes, with a subset of patients having the risk of disease recurrence, which can be assessed using the fixed American Thyroid Association (ATA) risk stratification system or the dynamic response to therapy risk stratification that can be modified during patients follow-up. Aim The aim of this article is to assess the risk stratification of patients having differentiated thyroid cancer. Methods This is aretrospective cross-sectional study in which we evaluated medical records of 75 patients having differentiated thyroid cancer to assess the baseline ATA risk of recurrence and compared it to the results of dynamic risk stratification in response to therapy at 6-12 months post-surgery and at the last visit. Thyroglobulin level, anti-thyroglobulin antibody, thyroid ultrasound, and cytopathological examination were used to determine dynamic response to therapy and divided subjects into four groups: excellent response (ER), biochemical incomplete response (BIR), structural incomplete response (SIR), and indeterminate response (IR). Results At baseline, 55 patients had low risk, 14 patients had intermediate risk, and six patients had high risk. At 6-12 months post-surgery, in the low-risk group, ER, BIR, and IR responses were observed in 56.4%, 5.5%, and 38.2% of patients, respectively, and none of them exhibited SIR. In the intermediate-risk group, ER, BIR, and IR responses were observed in 57.1%, 21.4%, and 21.4% of patients, respectively, and none exhibited SIR. Among the high-risk group, two patients had ER, two patients had BIR, one patient had IR, and one patient had SIR. At the last visit, ER, BIR, and IR were observed in 65.5%, 9.1%, and 25.5% of low-risk patients, respectively, and no patient developed SIR. In the intermediate-risk group, ER, BIR, and IR were observed in 50%, 21.4%, and 28.6% of patients, respectively, and no patients developed SIR. Among the high-risk group, three patients achieved ER, one had BIR, one had IR, and one had SIR. Conclusion Most of the differentiated thyroid cancers in this study are low-risk. Dynamic risk stratification appears to be an effective tool in the follow-up of this population of patients having differentiated thyroid cancer.

Uterine fibroids associated with pregnancy – is myomectomy during pregnancy feasible? Review and case presentation

Uterine myomas affect 2-10% of pregnant women. They are hormone-dependent tumors, and 30% of them will increase in response to hormonal changes during pregnancy. Therefore, significant growth is expected in pregnancy, but, actually, most of them do not change in size. They are usually asymptomatic, but they may be associated with severe abdominal pain and adverse pregnancy outcomes. Conservative management is the first option. If the conservative treatment fails and the symptoms are severe, a myomectomy can be performed, with serious risks of severe hemorrhage, uterine rupture, miscarriage and preterm labor. We present the case of a 31-year-old primigravida presenting in our service for severe abdominal pain, pollakiuria and constipation. The ultrasound examination revealed a 13-week pregnancy, with no ultrasound signs of fetal structural abnormalities, and several fibroids, in contact with each other, developed as one fibroid mass, intramural and subserous, in the lower uterine segment and into both parametria, with a diame­ter of 100/95/87 mm. During the following weeks, the symptoms progressed, and the fibroid volume almost doubled. At 17 weeks of pregnancy, due to the severity of the symptoms, rapidly growing myomas and suggestive ultrasound aspect of degeneration, we performed a myomectomy. The surgery was uneventful. The patient was monitored weekly. Detailed second-trimester and third-trimester scans confirmed the normal pregnancy evolution. Doppler evaluation of both uterine arteries showed a normal spectrum. The fetal growth was favorable, at a percentile of 50 at 32 weeks of pregnancy. No short-term or long-term complications of the surgery have been noted so far. Myomectomy during pregnancy should be considered in cases of symptomatic uterine fibroids not responding to conservative management or in large or rapidly growing myomas, large or medium myomas located in the lower uterine segment, or deforming the placental site, following appropriate counseling of the patient regarding the associated risks.

Thyroid Cancer Knowledge and Awareness in Saudi Arabia: A Cross-Sectional Study.

Background Thyroid cancer incidence has been increasing worldwide over the last few decades. It is the most common endocrine cancer and is most common among females. The study contributes to filling the knowledge gap among Saudi people regarding thyroid cancer. Objectives This research aims to investigate the level of thyroid cancer knowledge and awareness in Saudi Arabia, identify potential knowledge gaps, and develop targeted strategies for enhancing public awareness and education. Methods A cross-sectional, voluntary online survey was conducted from 1st August 2023 to 1st October 2023 among residents living in Saudi Arabia over 18 years of age. The participants included were 2030 respondents. Data analysis was performed using RStudio (R version 4.3.0; R Foundation for Statistical Computing, Vienna, Austria). Results Among the participants, the majority were female (60.4%). A total of 49.7% of the individuals reported having a moderate to high level of knowledge about thyroid cancer. While 63.9% knew the association of a lump in the neck to thyroid cancer, 82.6% affirmed to consult a doctor upon discovering a lump, 72.1% knew that regular monitoring of neck lumps is crucial for early diagnosis and treatment of precancerous conditions, 38.7% were aware of females being prone to thyroid cancer, and 59.2% were aware of the link between lifestyle and increased risk. Higher awareness scores were positively associated with female gender, previously having thyroid function tests done, and previously undergoing a US scan of the thyroid. Conclusion In this study, Saudi individuals are reported to lack some aspects of knowledge and perception of thyroid cancer. This study emphasizes filling the existing knowledge gap in thyroid cancer awareness in the Saudi population.

Multi-view progression diagnosis of thyroid cancer by integrating platelet transcriptomes and blood routine tests

Thyroid cancer is the most common type of endocrine system cancer. The pre-cancer and early stages are usually benign or slowly growing, and do not need invasive treatments. This study investigated the challenging classification task of four classes of samples, i.e., normal controls (N), thyroid adenomas (TA), papillary thyroid cancers (PTC) and metastasized papillary thyroid cancers (MPTC). We proposed a multi-view progression diagnosis framework ThyroidBloodTest to integrate the two views of RNAseq platelet transcriptomes (View-T) and blood routine (View-B) features. Platelet transcriptome represented the molecular-level information, while the blood routine features were easy to obtain in the clinical practice. Eleven feature selection algorithms and seven classifiers were evaluated for both views. The experimental data suggested the importance of choosing appropriate data analysis algorithms and feature engineering techniques like principal component analysis (PCA). The best ThyroidBloodTest model achieved Acc = 0.8750 for the four-class classification of the N/TA/PTC/MPTC samples based on the integrated feature space of View-T and View-B. The cellular localization cytosol and three post-translational modification types acetylation/phosphorylation/ubiquitination were observed to be enriched in the proteins encoded by the View-T biomarkers. The numbers of different immune cells also contributed positively to the progression diagnosis of thyroid cancer. The proposed multi-view prediction model demonstrated the necessity of integrating both platelet transcriptomes and blood routine tests for the progression diagnosis of thyroid cancer.

Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.

Rational Design, Synthesis and Binding Affinity Studies of Anthraquinone Derivatives Conjugated to Gonadotropin-Releasing Hormone (GnRH) Analogues towards Selective Immunosuppression of Hormone-Dependent Cancer.

Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone-GnRH conjugates (con1-con8) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (con2-con7) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, con3 and con7 show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.

The role of the tumor microenvironment in endocrine therapy resistance in hormone receptor-positive breast cancer.

Endocrine therapy is the prominent strategy for the treatment of hormone-positive breast cancers. The emergence of resistance to endocrine therapy is a major health concern among hormone-positive breast cancer patients. Resistance to endocrine therapy demands the design of newer therapeutic strategies. The understanding of underlying molecular mechanisms of endocrine resistance, components of the tumor microenvironment (TME), and interaction of resistant breast cancer cells with the cellular/acellular components of the intratumoral environment are essential to formulate new therapeutic strategies for the treatment of endocrine therapy-resistant breast cancers. In the first half of the article, we have discussed the general mechanisms (including mutations in estrogen receptor gene, reregulated activation of signaling pathways, epigenetic changes, and cell cycle alteration) responsible for endocrine therapy resistance in hormone-positive breast cancers. In the latter half, we have emphasized the precise role of cellular (cancer-associated fibroblasts, immune cells, and cancer stem cells) and acellular components (collagen, fibronectin, and laminin) of TME in the development of endocrine resistance in hormone-positive breast cancers. In sum, the article provides an overview of the relationship between endocrine resistance and TME in hormone-positive breast cancers.

The Act of Diminishing the RTRAF Expression in Benign Thyroid Tissues Represents a Potential Method for Impeding the Progression of Malignancy in Cells

Background: Thyroid cancer is the most common endocrine cancer, and women are almost three times more likely to develop it than men. Objectives: The etiology of thyroid cancer at the genetic level remains elusive. However, a potential involvement of the RNA Transcription, Translation, and Transport Factor (RTRAF) gene in the pathogenesis of this malignancy has been postulated. This gene has been shown to govern the expression of proteins that exert regulatory effects on the transition from the G1 to S phase of the cell cycle. Methods: For this study, 22 papillary thyroid carcinoma (PTC) tissues and 22 healthy tissues were collected. Additionally, 10 benign goiter tissues and 10 healthy tissues were gathered. RNA molecules were fixed, and complementary DNA (cDNA) was produced. Specific primers were used to measure the RTRAF gene expression. Statistical analysis was conducted using REST 2009 software. Results: Upon assessing the quality and quantity of RNA, it was ascertained that the extracted RNA molecules exhibited minimal damage and were found to be appropriately concentrated for cDNA production. The amplification of the RTRAF gene was carried out accurately, as evidenced by the melting curve. A noteworthy decline in the RTRAF gene expression was detected in the benign goiter tissue compared to the adjacent healthy tissue, with a relative expression of 0.154 and a statistical value of P = 0.002. Conversely, there was no significant difference in the RTRAF gene expression between PTC and the adjacent healthy tissue, with a P-value of 0.808. Conclusions: The reduced RTRAF gene expression in benign thyroid tumors may hinder cancer cell growth, as no difference was observed between malignant PTC tumor tissues and their healthy tissues.

SAT621 Hemorrhage After Treatment: A Case Of Pituitary Apoplexy In Metastatic Prostate Cancer After Leuprolide

Abstract Disclosure: M. Dillon: None. S. Shteyman: None. W. Rashid: None. B.P. Ramchandani: None. A.G. Samat: None. Introduction: Hormone-sensitive cancers, including prostate and breast cancer, and some gynecological conditions can be treated with GnRH agonists, including leuprolide. However, pituitary apoplexy is a rare potential complication after administration. Case Description: 71-year-old gentleman with metastatic hormone-sensitive prostate cancer presented with an acute headache after receiving a dose of leuprolide. This was his first GnRH agonist dose after prior Degarelix treatment. After two hours, the patient developed a constant throbbing headache, palpitations, left eye tearing and non-bilious non-bloody vomiting. Vitals were within normal ranges, and initial lab work showed low serum cortisol of 4.6. CT scan of the head showed exophthalmos and a mildly enlarged sella. Subsequent MRI demonstrated pituitary hemorrhage and optic chiasm impingement from resulting swelling. Hormone levels remained normal. Since the patient did not develop visual field defects or other ocular complaints, the decision was to manage the patient medically rather than with surgery. The day after admission, he developed hypotension requiring high dose steroids. After discharge, outpatient repeat MRI showed interval resolution of hemorrhage into a predominantly cystic pituitary macroadenoma. Discussion: With continued stimulation, GnRH agonists desensitize the pituitary and cause a downregulation of hormonal induced cancer growth. However, there is an initial transient burst of stimulation that can induce pituitary apoplexy in patients who already have a large adenoma. The hemorrhage and subsequent swelling cause a sudden severe headache and possible visual loss or hypopituitarism. This is life-threatening due to hypotension from catecholamine insensitive blood vessels in the absence of cortisol. Treatment involves high dose steroids, frequent sodium checks and possible emergency neurosurgery for decompression. It is important with GnRH agonists to watch out for this rare complication, whether the hormonal axis is being suppressed for metastatic cancer treatment or for hormonally driven gynecological conditions. Sources: Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P. Pituitary Apoplexy. Endocr Rev. 2015 Dec;36(6):622-45. doi: 10.1210/er.2015-1042. Epub 2015 Sep 28. PMID: 26414232. Tanios G, Mungo NA, Kapila A, Bajaj K. Pituitary apoplexy: a rare complication of leuprolide therapy in prostate cancer treatment. BMJ Case Rep. 2017 Jul 14; 2017:bcr2016218514. doi: 10.1136/bcr-2016-218514. PMID: 28710301; PMCID: PMC5534692. Presentation: Saturday, June 17, 2023

OR11-02 Structural Determinants of Pure Antiestrogenic Activity

Abstract Disclosure: A. Vallet: None. M. Diennet: None. K. Thiombane: None. A. Vivet: None. S. Weber: None. M. El Ezzy: None. F. Shaikh: None. J. Poupart: None. R. Mendoza-Sanchez: None. D. Schuetz: None. A. Marinier: None. G.L. Greene: None. S.W. Fanning: None. S.N. Mader: None. Inhibitory activities of antiestrogens on estrogen receptor alpha (ERα) range from mixed antagonism/agonism (selective ER modulators; SERMs) to complete antiestrogenicity associated with accelerated ERα turnover (selective ER degraders; SERDs). Using a panel of SERMs, SERDs and PROTACs, we show that antiestrogens induce variable degrees of SUMOylation of ERα and that efficient induction of SUMOylation, rather than increased suppression of coactivator recruitment or accelerated ERα degradation, correlates with suppression of ERα basal and induced transcriptional activity in reporter assays. Antiestrogens did not induce SUMOylation of ERβ and did not suppress its basal transcriptional activity in the same assays. Chimeras between the two receptors identified ERα-specific residues required for induction of SUMOylation by antiestrogens and revealed differences according to the antiestrogen structure. In addition, induction of ERα SUMOylation by antiestrogens depended on the hydrophobicity of N-terminal residues of ligand binding domain (LBD) helix H12. L536 mutations, including those occurring in endocrine therapy-resistant breast cancer, abolished both induction of ERα SUMOylation and pure antiestrogenicity. Structures of the L536S human ERα LBD bound to fulvestrant analogs and molecular dynamics simulations revealed dynamic side chain interactions with ERα H12 in the coactivator-binding groove, and predict the impact of SUMOylation-suppressing L536 mutations on these interactions. Together, our results show that antiestrogen-induced ERα SUMOylation is associated with complete suppression of its transcriptional activity and provide insights into the structural determinants of pure antiestrogenicity. Presentation Date: Friday, June 16, 2023

OR05-02 Silencing Of Adenylosuccinate Lyase Impairs Growth And Perturbs Mitochondrial Function Of Endocrine Therapy Resistant Breast Cancer Cells

Abstract Disclosure: A.K. Yadav: None. L. Jin: None. R. Clarke: None. S. Sengupta: None. The estrogen receptor positive (ER+) subtype comprises of ∼80% of all breast cancers and is the major contributor to cancer related deaths in women. While ER+ breast cancers respond to treatment with endocrine therapies (ET) such as tamoxifen, Fulvestrant and aromatase inhibitors, a major limitation is emergence of resistance to ET resulting from adaptive pathways that promote relapse and disease progression. Hence, there is an urgent need for identification and validation of new molecular targets for potential therapeutic treatment of ET resistant-ER+ breast cancer. Here, we have determined the role of adenylosuccinate lyase (ADSL), a crucial enzyme involved in the de novo purine synthesis pathway, as a potential molecular target for ER+ breast cancer cells. ADSL enzyme catalyzes two non-sequential steps in de-novo purine synthesis pathway that produces aminoimidazole carboxamide ribonucleotide (AICAR) and adenosine monophosphate (AMP); fumarate is generated as a byproduct. We observed higher protein expression of ADSL in LCC9 (endocrine therapy crossresistant cells) when compared with LCC1 or MCF-7 (antiestrogen sensitive) cells. Additionally, T47D-4HT cells (also endocrine therapy resistant) also expressed modestly higher ADSL protein level in comparison to its parental endocrine therapy sensitive T47D-A18 cells. Notably, siRNA-mediated knockdown of ADSL in both LCC9 and T47D-4HT cells leads to strong inhibition of cell proliferation, long-term colony, and spheroid formation. Furthermore, ADSL depletion in LCC9 increased the accumulation of cells in G0/G1 phase along with elevated protein expression of cyclin D1. In T47D-4HT cells, ADSL knockdown caused cells to accumulate in S-phase, with a reduction of total cyclin D1 protein levels. Further investigation revealed that ADSL knockdown decreased ATP levels and mitochondrial membrane potential in both LCC9 and T47D-4HT cells and significantly reduced the basal oxygen consumption rate (OCR) and maximal respiration capacity. Notably, addition of AICAR (100 µM) to ADSL deficient LCC9 cells partially rescued cell proliferation, colony formation, and restored the mitochondrial membrane potential. In clinical datasets higher expression of ADSL transcripts correlates with poor relapse free survival in ER+ breast cancer patients treated with endocrine therapies. Overall, our results indicate that ADSL-mediated de novo purine synthesis plays an important role in growth and proliferation of endocrine therapy resistant ER+ breast cancer cells through mitochondrial function. Therefore, targeting ADSL is a novel potential therapeutic approach for ER+ endocrine resistance breast cancer. Presentation: Thursday, June 15, 2023

Endocrine Disrupting Chemicals and their Role in Cancer-A review

Endocrine-disrupting chemicals (EDCs), which are environmentally prevalent compounds, have the ability to interact with the body's endocrine system and thus exert detrimental effects on human health. Despite persistent concerns over public health, endocrine-disrupting chemicals (EDCs) remain integral components of commonplace consumer products, rendering them ubiquitous pollutants for individuals. In light of the numerous epidemiological and experimental studies that have established a connection between endocrine-disrupting chemicals and adverse effects on human health, there has been an increased emphasis on mitigating human exposure to these compounds. There exists a correlation between endocrine-disrupting drugs and adverse impacts on human health, as well as an elevated susceptibility to hormone-sensitive cancers such as breast, uterine, ovarian, prostate, and thyroid cancers. The objective of this study was to provide a comprehensive overview of previous studies investigating the relationship between endocrine-disrupting chemicals and the development of cancer.

SAT527 The Management Of Thyroid Cancer: Where We Started And Where We Are Heading? A Five-decades Text Mining Analysis

Abstract Disclosure: I. Tessler: None. N.A. Gecel: None. G. Avior: None. E. Klang: None. E. Alon: None. T. Kolitz: None. Aim: Thyroid cancer prevalence rate continues to increase, being the most common endocrine cancer. During the years, significant progress in methods for diagnosis, risk-stratification and management were developed, with the recent advance of molecular testing. Here we explore the evolution of thyroid cancer management over the past five decades through a text-mining analysis. Materials and methods: We have queried PubMed for all available 'thyroid cancer' related entries published during 1970-2022. The following data were extracted for each entry: year of publication, publishing journal, title, keywords, and abstract text. Search terms belonged to demographics, histology, diagnosis methods, treatment, and follow-up. Annual trends of publications were plotted. The slopes of publication trends were calculated by fitting regression lines to the yearly number of publications. We also retrieved the number of citations per publication and analyzed the most impactful papers on each topic.Results: Our search yielded 95,931 papers published during the study period. Publications regarding diagnosis (39,490) outnumbered all other topics, in which molecular testing has significantly sharpest raise (slope p=34.1±3.3). Most publication focused on females (n=56,198) and differentiated thyroid cancer (n=45,953). Surgery remains the most studied treatment method during the whole study period, with recent raise in studies regarding active-surveillance (slope 14.2±1.3). Studies concerning shared decision-making and patient experience emerged in 2000, with a sharp increase in recent years (slope 3.8±0.3, p < .001).Conclusions: Our study provides an overview of the trends in thyroid cancer research over the past five decades. Publications regarding molecular testing outnumbered all other diagnosis methods, identified as the primary trend of the current era. Publications on active surveillance have rapidly risen in recent years, highlighting this method's role in thyroid cancer. Keywords: Machine learning; artificial intelligence; Thyroid cancer; Molecular-tests Presentation Date: Saturday, June 17, 2023

Comprehensive analysis of BTNL9 as a prognostic biomarker correlated with immune infiltrations in thyroid cancer

BackgroundThyroid cancer (THCA) is the most common type of endocrine cancers, and the disease recurrences were usually associated with the risks of metastasis and fatality. Butyrophilin-like protein 9 (BTNL9) is a member of the immunoglobulin families. This study investigated the prognostic role of BTNL9 in THCA.MethodsGene enhancers of BTNL9 were identified by interrogating H3K27ac ChIP-seq and RNA-seq data of papillary thyroid cancer (PTC) and benign thyroid nodule (BTN) tissues. Meanwhile, BTNL9 expression level was verified by qRT-PCR in 30 pairs of primary THCA and adjacent normal tissues. Clinicopathological and RNA sequencing data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) to analyze the relations between BTNL9 expression and immune cell infiltration, chemokines/cytokines, immune checkpoint genes, clinical parameters and prognosis values. Besides, survival analysis combining BTNL9 expression and immune cell infiltration scores was conducted. Functional enrichment analysis was performed to investigate the potential biological mechanisms. Cox regression analyses were used to explore independent clinical indicators, and a nomogram model incorporating BTNL9 expression with clinical parameters was established.ResultsBTNL9 showed significantly stronger H3K27ac modifications in BTN than PTC tissues at the promoter region (chr5: 181,035,673–181,047,436) and gene body (chr5: 181,051,544–181,054,849). The expression levels of BTNL9 were significantly down-regulated in THCA samples compared to normal tissues, and were strongly associated with different tumor stages, immune cell infiltrations, chemokines/cytokines and immune checkpoint genes in THCA. Functional enrichment analyses indicated that BTNL9 was involved in immune-related and cancer-related pathways. The Kaplan–Meier analysis showed lower BTNL9 expression was associated with poorer progression-free interval (PFI). BTNL9 expression and pathologic stages were independent prognostic indicators of PFI in THCA.ConclusionsThe results implied an important role of BTNL9 in the tumor progression, with the possibility of serving as a novel prognostic biomarker and a potential therapeutic target for THCA.

An Endocrine Perspective on Lynch Syndrome

"Background: A germline mutation of the MisMatch Repairgene that causes a malfunctioning DNA system is the defining feature of the hereditary illness known as Lynch syndrome. This review will discuss the endocrine aspects of LS and highlight current advancements in the area. Methods: We searched the available literature of the last 10 years for terms such as endocrine tumors and LS. Our goal is to provide a summary of the most recent information available on the endocrine perspective in Lynch syndrome. Results: The hormonal chemoprevention methods cited are the use of combined oral contraceptives, the use of progestogen-releasing intrauterine devices, and the use of progesterone-only drugs. In addition, after surgical exclusion of the uterus and ovaries, a method frequently adopted for LS patients, it is necessary to start hormonal menopausal therapy, taking into account certain age-specific features. In addition, numerous LS-associated endocrine tumor types have been described. Conclusions: Many hormonal variants are available that are useful in the chemoprevention involved in the treatment of LS. Menopausal hormone therapy is imperative for LS patients who need it. Clinicians need to be aware of the possible association of certain types of aggressive endocrine cancers associated with LS."

Time-specific impact of mono-benzyl phthalate (MBzP) and perfluorooctanoic acid (PFOA) on breast density of a Chilean adolescent Cohort

IntroductionHigh mammographic density is among the strongest and most established predictors for breast cancer risk. Puberty, the period during which breasts undergo exponential mammary growth, is considered one of the critical stages of breast development for environmental exposures. Benzylbutyl phthalate (BBP) and perfluorooctanoic acid (PFOA) are pervasive endocrine disrupting chemicals that may increase hormone-sensitive cancers. Evaluating the potential impact of BBP and PFOA exposure on pubertal breast density is important to our understanding of early-life environmental influences on breast cancer etiology. ObjectiveTo prospectively assess the effect of biomarker concentrations of monobenzyl phthalate (MBzP) and PFOA at specific pubertal window of susceptibility (WOS) on adolescent breast density. MethodThis study included 376 Chilean girls from the Growth and Obesity Cohort Study with data collection at four timepoints: Tanner breast stages 1 (B1) and 4 (B4), 1- year post- menarche (1YPM) and 2-years post-menarche (2YPM). Dual-energy X-ray absorptiometry was used to assess the absolute fibroglandular volume (FGV) and percent breast density (%FGV) at 2YPM. We used concentrations of PFOA in serum and MBzP in urine as an index of exposure to PFOA and BBP, respectively. Parametric G-formula was used to estimate the time-specific effects of MBzP and PFOA on breast density. The models included body fat percentage as a time-varying confounder and age, birthweight, age at menarche, and maternal education as fixed covariates. ResultsA doubling of serum PFOA concentration at B4 resulted in a non-significant increase in absolute FGV (β:11.25, 95% confidence interval (CI): −0.28, 23.49)), while a doubling of PFOA concentration at 1YPM resulted in a decrease in % FGV (β:-4.61, 95% CI: −7.45, −1.78). We observed no associations between urine MBzP and breast density measures. ConclusionIn this cohort of Latina girls, PFOA serum concentrations corresponded to a decrease in % FGV. No effect was observed between MBzP and breast density measures across pubertal WOS.

Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation?

Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name "Over-Expression by Degradation Rescue" (OEDR), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an OEDR-regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer.