Previous genomic studies have identified two mutually exclusive molecular subtypes of large-cell neuroendocrine carcinoma (LCNEC): the
mutated (mostly comutated with
) and the
wild-type groups. We ...assessed whether these subtypes have a predictive value on chemotherapy outcome.
Clinical data and tumor specimens were retrospectively obtained from the Netherlands Cancer Registry and Pathology Registry. Panel-consensus pathology revision confirmed the diagnosis of LCNEC in 148 of 232 cases. Next-generation sequencing (NGS) for
and
genes, as well as IHC for RB1 and P16 was performed on 79 and 109 cases, respectively, and correlated with overall survival (OS) and progression-free survival (PFS), stratifying for non-small cell lung cancer type chemotherapy including platinum + gemcitabine or taxanes (NSCLC-GEM/TAX) and platinum-etoposide (SCLC-PE).
mutation and protein loss were detected in 47% (
= 37) and 72% (
= 78) of the cases, respectively. Patients with
wild-type LCNEC treated with NSCLC-GEM/TAX had a significantly longer OS 9.6; 95% confidence interval (CI), 7.7-11.6 months than those treated with SCLC-PE 5.8 (5.5-6.1);
= 0.026. Similar results were obtained for patients expressing RB1 in their tumors (
= 0.001). RB1 staining or P16 loss showed similar results. The same outcome for chemotherapy treatment was observed in LCNEC tumors harboring an
mutation or lost RB1 protein.
Patients with LCNEC tumors that carry a wild-type
gene or express the RB1 protein do better with NSCLC-GEM/TAX treatment than with SCLC-PE chemotherapy. However, no difference was observed for
mutated or with lost protein expression.
.
A dramatic increase in the incidence of papillary thyroid carcinoma (PTC) after childhood exposure to ionizing radiation from the Chernobyl nuclear accident has been described as the largest number ...of tumors of one type due to one cause that have ever occurred. inter‐individual variations in response to radiation have been documented and the role of genetics in sporadic PTC is well established, suggesting that genetic factors may also affect the risk of radiation‐related PTC. To investigate how environmental and host factors interplay to modify PTC risk, we genotyped 83 cases and 324 matched controls sampled from children living in the area contaminated by fallout from the Chernobyl power plant accident for 19 polymorphisms previously associated with PTC, thyroid biology or radiation‐induced second primary tumors. Significant association with PTC was found for rs1801516 (D1853N) in ATM (odds ratio (OR) = 0.34, 95% confidence interval (CI) 0.16, 0.73) and rs1867277 in the promoter region of FOXE1 (OR = 1.55, 95% CI 1.03, 2.34). Analysis of additional polymorphisms confirmed the association between these two genes and PTC. Our findings suggest that both DNA double‐strand break repair pathway and thyroid morphogenesis pathway or dysregulation of thyroid differentiated state maintenance are involved in the etiology of PTC, and that the studied genetic polymorphisms and radiation dose appear to act as independent multiplicative risk factors for PTC.
What's new?
Children who were exposed to ionizing radiation from the Chernobyl nuclear accident suffered a dramatic rise in cases of papillary thyroid carcinoma (PTC). In this study of genetic risk factors, the authors found a significant correlation between single nucleotide polymorphisms (SNPs) in ATM and FOXE1 genes and PTC in children exposed to the radiation. The results suggest that the aetiology of PTC may involve a DNA repair pathway, a thyroid morphogenesis pathway, and/or dysregulation of the differentiated state in the thyroid.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
This study was done to determine the representation of minorities, women, and the elderly in National Cancer Institute (NCI) clinical trials.
Methods
This is an analysis in the NCI ...Clinical Data Update System. Patients were evaluated in breast, colorectal, lung, and prostate cancer trials from 2000 to 2019. Representation in a trial was determined by race/ethnicity, sex, and age. Secondarily, the change in trial participation by multivariable analysis by comparing years 2000 through 2004 to 2015 through 2019 was evaluated.
Results
The cohort included 242,720 participants: 197,320 Non‐Hispanic White (81.3%), 21,190 Black (8.7%), 11,587 Hispanic (4.8%), and 6880 Asian/Pacific Islander (2.8%). Black and Hispanic patients were underrepresented for colorectal (odds ratio OR, 0.58; 95% confidence interval CI, 0.50‐0.67; P < .001 and OR, 0.74; 95% CI, 0.64‐0.87; P < .001, respectively), lung (OR, 0.83; 95% CI, 0.76‐0.91; P < .001 and 0.66; 95% CI, 0.57‐0.77; P < .001, respectively), and prostate cancer trials (OR, 0.85; 95% CI, 0.79‐0.92; P < .001 and OR, 0.58; 95% CI, 0.51‐0.66; P < .001) between 2015 and 2019. The odds of participation in 2015 to 2019 increased among Black patients in breast (OR, 2.19; 95% CI, 2.07‐%2.32; P < .001), lung (OR, 1.54; 95% CI, 1.38‐1.73; P < .001), and prostate cancer trials (OR, 1.14; 95% CI, 1.04‐1.26; P < .001). The odds of participation in a trial among Hispanic patients increased for breast (OR, 3.32; 95% CI, 3.09‐3.56; P < .001), colorectal (OR, 2.46; 95% CI, 2.04‐2.96; P < .001), lung (OR, 3.88; 95% CI, 3.20‐4.69; P < .001), and prostate cancer (OR, 1.70; 95% CI, 1.42‐2.04; P = .005).
Conclusions
This study identified that Black and Hispanic patients remain underrepresented in trials, but in recent years, participation has increased. These findings indicate that minority participation has increased over time, but further efforts are needed.
Minorities, women, and the elderly have remained underrepresented in clinical trials in recent years. However, some minority participation has increased in recent years.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung ...cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.
•CtDNA may play a crucial role in the detection of pre-clinical cancer.•TP53 mutations are detectable in the cfDNA of SCLC patients with early-stage tumors.•Detection of TP53 mutations in non-cancer controls poses serious challenges for the development of ctDNA screening tests.
Cell-free DNA (cfDNA) has potential for monitoring response to treatment and relapse, but also for early detection. This is the first study reporting the detection of circulating-tumor DNA (ctDNA) in cases diagnosed with small-cell lung cancer (SCLC). Our results show that TP53 mutations are detectable in the cfDNA of SCLC patients including those with early-stage tumors. Importantly, we also provide evidence that cancer-like TP53 mutations are present in non-cancer controls, which poses serious challenges for the development of ctDNA screening tests.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate‐to‐severe plaque psoriasis. It is unclear whether recent safety concerns ...(ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss‐of‐function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non‐Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta‐analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non‐Hodgkin lymphoma risk were obtained from a GWAS meta‐analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09‐1.23, P = 2.29 × 10−6) and non‐Hodgkin lymphoma (OR 1.18, 95% CI 1.05‐1.33, P = 5.25 × 10−3). Our analyses using an established partial loss‐of‐function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non‐Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development.
What's new?
Increased rates of lymphoma and lung cancer associated with Janus kinase (JAK) inhibitors used in the treatment of chronic inflammatory conditions have raised significant concern. A promising alternative, particularly for the treatment of plaque psoriasis, is deucravacitinib, a selective inhibitor of JAK family member TYK2. Here, the authors explored possible carcinogenic effects of TYK2 inhibition by genetic proxy based on a partial loss‐of‐function variant in TYK2 that provides protection against psoriasis. Analyses show that genetically proxied TYK2 inhibition increases lung cancer and non‐Hodgkin lymphoma risk. The findings could impact safety assessments of deucravacitinib and future novel TYK2 inhibitors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Population‐based studies demonstrate that Black men in the United States have an increased risk of death from prostate cancer. Determinants of racial disparities are multifactorial, ...including socioeconomic and biologic factors.
Methods
The authors conducted a pooled analysis of patients derived from 152 centers within the Veterans Health Administration. The cohort included men who had nonmetastatic prostate diagnosed between 2001 and 2015 and received definitive radiation therapy. The primary endpoint was prostate cancer‐specific mortality (PCSM). Secondary endpoints included all‐cause mortality (ACM) and the time from a prostate‐specific antigen level ≥4 ng/mL to biopsy and radiation therapy. A Cox regression model was performed to adjust for differences between clinical parameters.
Results
Among the 31,131 patients included in the cohort, 9584 (30.8%) were Black. The 10‐year cumulative incidence of death from prostate cancer was lower in Black men compared with White men (4.0% vs 4.8%; P = .004). In a competing risk model, Black race was associated with a decreased risk of PCSM (subdistribution hazard ratio, 0.79; 95% CI, 0.69‐0.92; P = .002). Similarly, the 10‐year cumulative incidence of death from any cause was lower in Black men (27.6% vs 31.8%; P < .001). In multivariable analysis, Black men had a 10% decreased risk of ACM (hazard ratio, 0.90; 95% CI, 0.85‐0.95; P < .001).
Conclusions
The current results indicate relatively lower PCSM and ACM among Black men who were included in a large Veterans Health Administration cohort and received radiation therapy as primary treatment for nonmetastatic prostate cancer. There is an ongoing need to continue to understand and mitigate the factors associated with disparities in health care outcomes.
In this pooled analysis from multiple Veterans Health Administration medical centers, an association is observed between race and both prostate cancer‐specific and all‐cause mortality in men who receive curative‐intent radiation therapy. However, when care is delivered in a system with improved access, mortality decreases among Black men with prostate cancer who receive radiation therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Corneal fibrosis develops in response to injury, infection, postsurgical complications, or underlying systemic disease that disrupts the homeostasis of the tissue leading to irregular extracellular ...matrix deposition within the stroma. The mechanisms that regulate corneal scarring are focused heavily on the canonical transforming growth factor-β pathway and relevant activators, and their role in promoting myofibroblast differentiation. In this paper, we discuss the biochemical pathways involved in corneal fibrosis in the context of different injury models-epithelial debridement, superficial keratectomy, and penetrating incision. We elaborate on the interplay of the major pro-fibrotic factors involved in corneal scar development (e.g., transforming growth factor-β1, thrombospondin-1, and ανβ6), and explore a novel role for extracellular vesicles secreted by the wounded epithelium and the importance of the basement membrane.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We investigated how somatic changes in HNSCC interact with environmental and host risk factors and whether they influence the risk of HNSCC occurrence and outcome. 180-paired samples diagnosed as ...HNSCC in two high incidence regions of Europe and South America underwent targeted sequencing (14 genes) and evaluation of copy number alterations (SCNAs). TP53, PIK3CA, NOTCH1, TP63 and CDKN2A were the most frequently mutated genes. Cases were characterized by a low copy number burden with recurrent focal amplification in 11q13.3 and deletion in 15q22. Cases with low SCNAs showed an improved overall survival. We found significant correlations with decreased overall survival between focal amplified regions 4p16, 10q22 and 22q11, and losses in 12p12, 15q14 and 15q22. The mutational landscape in our cases showed an association to both environmental exposures and clinical characteristics. We confirmed that somatic copy number alterations are an important predictor of HNSCC overall survival.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mid-Holocene (6000 years ago) is a standard time period for the evaluation of the simulated response of global climate models using palaeoclimate reconstructions. The latest mid-Holocene ...simulations are a palaeoclimate entry card for the Palaeoclimate Model Intercomparison Project (PMIP4) component of the current phase of the Coupled Model Intercomparison Project (CMIP6) – hereafter referred to as PMIP4-CMIP6. Here we provide an initial analysis and evaluation of the results of the experiment for the mid-Holocene. We show that state-of-the-art models produce climate changes that are broadly consistent with theory and observations, including increased summer warming of the Northern Hemisphere and associated shifts in tropical rainfall. Many features of the PMIP4-CMIP6 simulations were present in the previous generation (PMIP3-CMIP5) of simulations. The PMIP4-CMIP6 ensemble for the mid-Holocene has a global mean temperature change of −0.3 K, which is −0.2 K cooler than the PMIP3-CMIP5 simulations predominantly as a result of the prescription of realistic greenhouse gas concentrations in PMIP4-CMIP6. Biases in the magnitude and the sign of regional responses identified in PMIP3-CMIP5, such as the amplification of the northern African monsoon, precipitation changes over Europe, and simulated aridity in mid-Eurasia, are still present in the PMIP4-CMIP6 simulations. Despite these issues, PMIP4-CMIP6 and the mid-Holocene provide an opportunity both for quantitative evaluation and derivation of emergent constraints on the hydrological cycle, feedback strength, and potentially climate sensitivity.
Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.
We conducted a stratified multi-population (European, East Asian, ...and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer.
Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior.
We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies.
Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.
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