Carcinogenesis最新文献

Several decades ago a dramatic leap forward occurred in the development and application of statistical methods for modeling radiation risk at the Radiation Effects Research Foundation (RERF). Poisson regression analysis for grouped person-year cohort data and the linear excess relative risk model were introduced, and subsequently a devoted software system, Epicure® (https://www.hirosoft.com), was developed by researchers at RERF and at the U.S. National Cancer Institute. Numerous advancements in understanding radiation effects on humans were made possible with these methods, which are still the state-of-the-art for risk assessment at RERF and have remained part of the standard toolbox for radiation-and other environmental-epidemiological studies worldwide. Nevertheless, as our understanding of radiation risk has increased, so have the breadth and depth of questions that require answers based on emerging data that are not amenable to these conventional methods. This overview briefly recounts the conventional methods and then describes our recent diversification into the use or development of new statistical approaches to meet the challenges of burgeoning biological data and emerging mechanistic information. We briefly discuss the development and application of new methods, current and planned, that are part of the RERF Statistics Department's role in supporting institution-wide research, especially in our collaborations involving the Life Span Study, Adult Health Study, and First-generation Offspring Clinical Study. Some approaches to modeling and assessing radiation risk with newer methods mentioned herein have already been published, while some are still in development or are only beginning at the proposal stage.

This paper concludes the third comprehensive report on radiation effects on solid cancer incidence within the Life Span Study (LSS) cohort of Japanese atomic bomb survivors, adding 11 years of follow-up. Over 1958-2009, 22 538 solid cancer cases and 3.1 million person-years were identified among 105 444 individuals. The study utilized improved radiation doses (DS02R1), updated migration probabilities, and adjustments for smoking and lifestyle factors. Poisson regression was used to model excess relative risk (ERR) and excess absolute rate (EAR) per 1 Gy for all-solid cancers combined and specific sites. Among females, a linear dose-response model best described all-solid cancer risk [ERR = 0.64 Gy-1, 95% confidence interval (CI): 0.52-0.77], whereas among males, a linear-quadratic model with upward curvature provided the best fit (ERR = 0.20 at 1 Gy, 95% CI: 0.12-0.28). Radiation-associated ERR declined with attained age, more rapidly in males than in females, while EAR increased with age. Independently, radiation-associated ERR and EAR decreased with age at exposure. A significant dose-response was identified for prostate cancer for the first time; for brain and central nervous system tumors, female pancreatic, and uterine corpus cancers dose-response reached statistical significance. A new age-at-exposure pattern emerged for female breast and uterine corpus cancers, suggesting that radiation-associated risk increased as exposure age approached menarche (∼age 15), decreasing at older exposure ages. Most cancers exhibited linear dose-response, except non-melanoma skin, bone and joint, esophageal, and kidney parenchyma cancers in males. Sixty-four years post-exposure, solid cancer risks remain elevated, reinforcing the LSS's critical role in unraveling lifetime cancer effects of a-bomb radiation after exposure at various ages.

Radiation exposure is a well-established risk factor for leukemia. Clonal hematopoiesis (CH), the expansion of mutated hematopoietic cells, is also associated with increased leukemia risk and its frequency is higher in cancer patients following radiotherapy and chemotherapy. We investigated whether low to moderate environmental ionizing radiation determined by state-of-the-art dosimetric analysis was associated with CH in the Chornobyl Family Study (CFS). Our study conducted targeted high-depth sequencing and array genotyping to identify and characterize clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) in 882 participants from 292 CFS families. Fathers had mean bone marrow radiation doses of 0.24 Gy (range: 0-3.86) and mothers had mean doses of 0.009 Gy (range: 2 × 10-5-0.63). The expected relationship between increasing age and CHIP was observed. No detectable effect of red bone marrow radiation dose was observed for CHIP risk (Fathers: Excess OR (EOR)/Gy = 0.41; 95% confidence interval (CI) = -0.57,1.39; P-value = .42; Mothers (categorical model due to limited dose range): odds ratio (OR)0.01-0.09 versus <0.001 Gy = 0.73; 95% CI = 0.39,1.38; P-value = .33) and the distribution and types of CHIP and mCAs detected in CFS participants did not differ from that seen in previously published studies of unexposed populations. No transgenerational effect of parental gonadal radiation exposure was detected in the children (Fathers: P-value = .08; Mothers: P-value = .67). Our findings suggest the type and levels of radiation exposure investigated in CFS families are unlikely to be strong contributors to CH risk, which could have important implications for public health concerns following environmental exposure to low to moderate ionizing radiation.

Neuroblastoma (NB) is a pediatric tumor with diverse outcomes and unknown underlying mechanisms. The core transcriptional regulatory circuit (CRC) and N6-methyladenosine (m6A) are key factors that control cell identity and fate. IGF2BP3 is an m6A reader protein that is transcriptionally regulated by CRC transcription factors (TFs). In NB, this molecule is abundantly expressed, and there is a clear correlation between its expression and a bad prognosis. We mechanistically demonstrated that IGF2BP3 promotes E2F2 mRNA expression through m6A, which is correlated with high risk and poor prognosis in NB patients. We showed that the CRC TF-IGF2BP3-E2F2 regulatory axis forms an oncogenic network that drives NB development and progression. Overall, we investigated the molecular mechanism by which IGF2BP3, a m6A-reading protein that is regulated by CRC TFs, regulates E2F2 mRNA expression in an m6A-dependent manner. This study highlights the therapeutic potential of disrupting this axis with m6A-targeted interventions.

During space missions, astronauts are continuously exposed to extraterrestrial radiation that differs in quality and dose rate compared with terrestrial radiation. As such, astronauts are considered special radiation workers and are subject to a unique set of standards in place of the Occupational Safety and Health Administration standards that cover terrestrial radiation workers. To accurately estimate and communicate the risk of cancer from space radiation to astronauts and mission managers to facilitate decision-making, the NASA Space Cancer Risk (NSCR) model was developed and has been used operationally at NASA since 2013. The Life Span Study (LSS) of the atomic bomb survivor cohort serves as a key foundational dataset for NSCR that enables quantification of health risks from space radiation. Here, we provide a description of how LSS data and models are currently used within the NSCR model and discuss future perspectives for utilizing this robust dataset to improve risk estimation.

Previous studies have linked liver diseases to lung cancer (LC) risk; however, few studies evaluated the associations of circulating liver enzyme levels with LC risk. We conducted a study of 353 incident LC cases and 646 matched controls with baseline serum alanine aminotransferase (ALT) and of 548 cases and 1032 matched controls with baseline serum alkaline phosphatase (ALP) nested within the Southern Community Cohort Study. Conditional logistic regression and generalized linear models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among all study participants and by stratification of potential effect modifiers. Most participants had clinically normal liver enzyme levels. Higher serum ALT levels were associated with reduced LC risk. Compared with the lowest tertile, participants in the second and third tertiles had OR (95% CI) of 0.74 (0.48-1.14) and 0.47 (0.28-0.78) (Ptrend < .01), respectively. The inverse association was observed in African Americans (AAs) and European Americans, which was especially prominent among men, and was seen in both those diagnosed within [ORT3 versus T1 = 0.41 (0.19-0.88)] and beyond [ORT3 versus T1 = 0.35 (0.17-0.73)] a median follow-up time of 39 months. Higher serum ALP levels were associated with increased LC risk among AA men only [ORT3 versus T1 = 2.01 (1.19-3.39)] (Ptrend < .01). Our results indicate that in a predominantly low-income American population, higher serum ALT levels may be related to lower LC risk. Further studies are warranted to confirm our findings and elucidate the potential underlying biological mechanisms of the associations.

Gastric cancer (GC) is globally recognized as one of the most widespread malignant tumors. As the symptoms of patients with early GC are ambiguous, the majority of patients are given a diagnosis of advanced GC. Therefore, this necessitates the search for new biomarkers to be utilized in the early diagnosis and screening of GC. Enhancer RNA (eRNA) is a non-coding RNA in transcription by enhancers that is tumor-specific and has a critical function in cancer progression. Our research investigates new eRNAs as bio-diagnostic markers for GC. Four eRNAs with good differential expression in GC were screened by TCGA and University of California, Santa Cruz databases. Quantitative real-time PCR was utilized for testing the level of RASSF8-AS1. The diagnostic effect of RASSF8-AS1 was evaluated using the receiver operating characteristic (ROC). Functional experiments were used to detect the ability of RASSF8-AS1 to affect the metastasis and proliferation in GC cells. The expression of RASSF8-AS1 was obviously elevated in both GC tissues and serum, whereas it was decreased in the serum levels of postoperative GC patients. ROC showed that RASSF8-AS1 was more diagnostically efficient than common diagnostic biomarkers for GC and that diagnostic effectiveness could be better than combining them. The findings of in vitro experiments showed that knocking down the level of RASSF8-AS1 clearly suppressed the ability of growth and metastasis in GC cells. Studies have shown that serum RASSF8-AS1 has the potential to contribute to the progression of GC as a biomarker for diagnosis and prognostic monitoring of GC.

CKLF-like MARVEL transmembrane domain-containing (CMTM) proteins play pivotal roles in tumorigenesis and cancer progression across various malignancies. However, their expression profiles and regulatory mechanisms in distinct subtypes of breast cancer remain largely undefined. In this study, we systematically analysed the expression of all nine CMTM family members across major molecular subtypes of breast cancer, including Luminal A, Luminal B, HER2-positive (HER2+), and triple-negative breast cancer (TNBC). Among these, CMTM3 was uniquely downregulated in Luminal B and HER2+ breast cancer cells and functioned as a tumor suppressor. Overexpression of HER2 in normal breast epithelial cell lines led to the phosphorylation of CMTM3. Molecular and biochemical analyses revealed that HER2 overexpression activated the downstream phosphoinositide 3-kinase (PI3K)/protein kinase B (also known as RAC-Alpha Serine/Threonine-Protein Kinase, AKT) signaling pathway in Luminal B and HER2+ breast cancer cells. AKT1 directly phosphorylated CMTM3 at serine 181 (Ser181), a modification that facilitated its recognition and ubiquitination by the E3 ligase HECT domain E3 ubiquitin protein ligase 3 (HECTD3), ultimately targeting CMTM3 for proteasomal degradation. Functional assays demonstrated that either knockdown of HECTD3 or pharmacological inhibition of PI3K/AKT signaling stabilized CMTM3 protein levels. Moreover, reintroducing a nonphosphorylatable CMTM3 mutant (CMTM3S181A) into CMTM3 knockout breast cancer cells resulted in significantly reduced proliferation, colony formation, invasive capacity, and in vivo tumor growth compared with cells expressing wild-type CMTM3 (CMTM3WT). Collectively, these findings reveal a previously unrecognized posttranslational regulatory mechanism of CMTM3 and suggest that targeting the PI3K/AKT-HECTD3-CMTM3 axis may offer a promising therapeutic approach for treating HER2+ breast cancers.