There are unexplained geographical variations in the incidence of kidney cancer with the high rates reported in Baltic countries, as well as eastern and central Europe. Having access to a large and ...well-annotated collection of “tumor/non-tumor” pairs of kidney cancer patients from the Czech Republic, Romania, Serbia, UK, and Russia, we aimed to analyze the morphology of non-neoplastic renal tissue in nephrectomy specimens. By applying digital pathology, we performed a microscopic examination of 1012 frozen non-neoplastic kidney tissues from patients with renal cell carcinoma. Four components of renal parenchyma were evaluated and scored for the intensity of interstitial inflammation and fibrosis, tubular atrophy, glomerulosclerosis, and arterial wall thickening, globally called chronic renal parenchymal changes. Moderate or severe changes were observed in 54 (5.3%) of patients with predominance of occurrence in Romania (OR = 2.67, CI 1.07–6.67) and Serbia (OR = 4.37, CI 1.20–15.96) in reference to those from Russia. Further adjustment for comorbidities, tumor characteristics, and stage did not change risk estimates. In multinomial regression model, relative probability of non-glomerular changes was 5.22 times higher for Romania and Serbia compared to Russia. Our findings show that the frequency of chronic renal parenchymal changes, with the predominance of chronic interstitial nephritis pattern, in kidney cancer patients varies by country, significantly more frequent in countries located in central and southeastern Europe where the incidence of kidney cancer has been reported to be moderate to high. The observed association between these pathological features and living in certain geographic areas requires a larger population-based study to confirm this association on a large scale.
Background
Although early diagnosis and surgical resection of the tumor have been shown to be the most important predictors of lung cancer survival, long‐term survival for surgically‐resected ...early‐stage lung cancer remains poor.
Aims
In this prospective study we aimed to investigate the survival and prognostic factors of surgically‐resected early‐stage non‐small cell lung cancer (NSCLC) in Central and Eastern Europe.
Methods
We recruited 2052 patients with stage I‐IIIA NSCLC from 9 centers in Russia, Poland, Serbia, Czech Republic, and Romania, between 2007–2016 and followed them annually through 2020.
Results
During follow‐up, there were 1121 deaths (including 730 cancer‐specific deaths). Median survival time was 4.9 years, and the 5‐year overall survival was 49.5%. In the multivariable model, mortality was increased among older individuals (HR for each 10‐year increase: 1.31 95% CI: 1.21–1.42), males (HR:1.24 1.04–1.49), participants with significant weight loss (HR:1.25 1.03–1.52), current smokers (HR:1.30 1.04–1.62), alcohol drinkers (HR:1.22 1.03–1.44), and those with higher stage tumors (HR stage IIIA vs. I: 5.54 4.10 – 7.48). However, education, chronic obstructive pulmonary diseases (COPD), and tumor histology were not associated with risk of death. All baseline indicators of smoking and alcohol drinking showed a dose‐dependent association with the risk of cancer‐specific mortality. This included pack‐years of cigarettes smoked (p‐trend = 0.04), quantity of smoking (p‐trend = 0.008), years of smoking (p‐trend = 0.010), gram‐days of alcohol drank (p‐trend = 0.002), frequency of drinking (p‐trend = 0.006), and years of drinking (p‐trend = 0.016).
Conclusion
This study shows that the 5‐year survival rate of surgically‐resected stage I‐IIIA NSCLC is still around 50% in Central and Eastern Europe. In addition to non‐modifiable prognostic factors, lifetime patterns of smoking and alcohol drinking affected the risk of death and disease progression in a dose‐dependent manner in this population.
Chronic inflammation, which is suspected to play a role in the development of colorectal cancer (CRC), has rarely been studied in colorectal adenoma. We investigated the inter-relationships of serum ...levels of the inflammatory proteins CRP and in IL-6, single nucleotide polymorphisms (SNPs) in the CRP (rs1205, rs1130864, rs1800947) and IL6 (rs1800795) genes, and lifestyle factors with colorectal adenoma in a sigmoidoscopy-based case-control study of 271 adenoma cases and 539 age-, sex-, and race/ethnicity-matched controls in Hawaii. We found no association of serum CRP or IL-6 levels with the risk of adenoma. A multiple regression with stepwise selection identified elevated BMI, Caucasian and Native Hawaiian versus Japanese race/ethnicity, and current smoking as being associated with significantly higher serum CRP and IL-6 levels. Female versus male gender was also associated with higher CRP levels and older age with higher IL-6 levels. The C allele of rs1205 and the A allele of rs1130864 were significantly associated with higher serum CRP levels (p trend: 0.0002 and 0.01, respectively), as well as with a decreased adenoma risk rs1205: OR for CT and CC vs. TT = 0.69 (95% CI: 0.48-0.98) and 0.53 (0.34-0.83), respectively, p trend = 0.008; rs1130864: OR for GA and AA versus GG = 0.65 (0.45-0.93) and 0.74 (0.31-1.76), respectively, p trend = 0.04. The findings of lower serum CRP and IL-6 levels in Japanese (a group with a high CRC risk) and of a decreased adenoma risk observed for alleles associated with higher circulating CRP levels suggest a protective effect for CRP in early colorectal neoplasia that warrants further study.
Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic ...variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.
Background: Promoter hypermethylation of tumor suppressor genes presents promising markers for lung cancer diagnosis and prognosis. The purpose of this study was to determine the association between ...the promoter hypermethylation of multiple genes and 5-year survival rate in patients with Non-small cell lung cancer (NSCLC).
Materials and Methods: Primary tumor samples (n = 65), corresponding nonmalignant lung tissues (n = 65), and circulating blood were obtained from NSCLC patients who underwent curative surgery. Promoter methylation status in seven genes (RASSF1A, CDH13, MGMT, ESR1, DAPK, SOX1, and HOXA9) was quantified by using bisulfite pyrosequencing. Five-year survival data were obtained by a clinician. Cox proportional hazards models were used to analyze the associations between gene methylation status and overall patient survival.
Results: The 5-year survival of the patients with SOX1 aberrant tumor methylation was found to be statistically significantly shorter than for those patients without aberrant tumor methylation (P = 0.01). This effect was independent of TNM stage. No significant survival differences were associated with aberrant methylation in other genes tested in either of the two tissue types.
Conclusion: Our study shows that SOX1 promoter hypermethylation in NSCLC tumors is significantly associated with inferior survival, showing promise as a useful prognostic biomarker in patients with NSCLC.
Abstract
Background
Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking ...behaviors and DNA repair genes, but further work is required to identify susceptibility variants.
Methods
To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided.
Results
The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors.
Conclusions
This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
We performed an ...analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval CI:=1.70–2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36–2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50–2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01–3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78–7.17, p=0.13).
Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
This large Mendelian randomization study utilizes a risk score of telomere length associated genetic variants to demonstrate a strong association between longer predicted leukocyte telomere length and increased risk of developing common subtypes of renal cell carcinoma.
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Background: Fibrosarcoma (FS) is the second most common group of soft tissue sarcomas in children, however, most FS are diagnosed in adults. The goal of this study was to compare ...clinical features and outcomes of children and adults diagnosed with FS and identify predictors of survival. Methods: We have analyzed data from 569 children (≤ 19 years) and 5,508 adults (>19 years) diagnosed between 1973 and 2008 with FS (ICCC category IXb) available in the SEER database. Survival estimates were determined using survival time with end point death from any cause. Results: Comparison of two diagnostic periods, 1973-1989 vs. 1990-2008 showed that 5-year survival rates have improved in adults (48.4% vs 60.9%, P<0.0001), but not in children (72.3% vs. 73.9%, P=0.16). Children with FS had significantly better outcome compared to adults (5-year survival rates were 73.4% ± 2%, and 56.7% ± 0.7%, respectively, P<0.0001). Sites with survival rates higher than the median 5-year survival were grouped as favorable (extremities, head and neck, and genitourinary site); trunk, abdomen, and other sites were grouped as unfavorable. Cox proportional hazard regression model identified diagnosis in childhood, fibromyxosarcoma histologic subtype (ICD-O3 code 8811/3), favorable site, and localized stage as positive predictors of survival. Compared to fibromyxosarcoma, other histologic types had hazard ratio (HR) of 11.6 (95% CI= 1.6-83.2, P=0.01) in children, and HR of 1.8 (95%CI=1.5-2.1, P<0.0001) in adults. Diagnosis at unfavorable site was associated with HR=1.9 (95%CI=1.4-2.6) in children and HR=1.4 (95%CI=1.3-1.5) in adults. Compared to localized, distant disease had HR=4.2 in children and HR=5.1 in adults, both highly significant (P<0.0001). Conclusions: Adults diagnosed with FS had worse survival than children. Predictors of good outcome, including histiologic subtype, primary site, and stage, were valid in both children and adults.
Abstract Background: Colorectal cancers (CRC) have an important impact on both incidence and mortality worldwide, with varying rates in different parts of the world. Despite an overall decrease in ...incidence in the past years, an alarming increase in early onset colorectal cancer (CRC in patients under 50 years of age) rates has been observed. As part of the Cancer Research UK Grand Challenge Mutographs project, we aim to better understand the underlying mutagenic causes contributing to the differences in CRC incidence rates through mutational signatures. Methods: We collected epidemiological data and performed whole genome sequencing and mutational signature analysis on 981 CRC tumor samples from 11 countries with varying incidence rates, including intermediate incidence regions (Iran, Colombia, Thailand, and Brazil) and higher incidence regions (Argentina, Russia, Canada, Poland, Czechia, Serbia, and Japan). Results: The average mutational profiles were similar across the countries. Mutational signatures associated with DNA repair deficiencies, including POLE and POLD1 associated signatures (SBS10a/b/c/d and SBS28), MUTYH (SBS36), NTHL1 (SBS30), homologous recombination deficiency (SBS3), and a plethora of microsatellite instability (MSI) signatures, were found in 177 cancers (18% of all samples) and at comparable levels across all countries. Multiple signatures with known etiologies were found in 802 DNA repair proficient colorectal cancers including clock-like (SBS1 and SBS5), reactive oxygen species (SBS18), APOBEC (SBS2 and SBS13), and the microbiome-product colibactin (SBS88) signatures. The colibactin signature SBS88 was observed in 14% of samples overall, being more prevalent in distal and rectum tumors. SBS88 was significantly enriched in younger patients (33% <40y, 23% 40-49y, 20% 50-59y,10% 60-69y, 10% ≥70y; p-value = 0.0001). Tumors from early onset patients also showed higher prevalence of another mutational signature with unknown etiology (19% <40y, 16% 40-49y, 13% 50-59y, 6% 60-69y, 7% ≥70y, p-value = 0.005). Conclusions: These results indicate a potential association between SBS88 with early onset CRC, suggesting that the recent increase in incidence may be at least partially explained by the genotoxic compound colibactin, and associated bacteria. Citation Format: Wellington dos Santos, Marcos Diaz-Gay, Sarah Moody, Sergey Senkin, Behnoush Abedi-Ardekani, Mariya Kazachkova, Stephen Fitzgerald, Saamin Cheema, Valerie Gaborieau, Jingwei Wang, Christine Carreira, Thomas Cattiaux, Priscilia Chopard, Calli Latimer, David Zaridze, Riley Cox, Reza Malekzadeh, Miodrag Ognjanovic, Suleeporn Sangrajrang, Maria P. Curado, Rui M. Reis, Ivana Holcatova, Carlos Vaccaro, Beata Swiatkowska, Jolanta Lissowska, Carolina Wiesner, Tatsuhiro Shibata, Surasak Sangkhathat, Patricia Ashton-Prolla, Laura Humphreys, Sandra Perdomo, Ana C. de Caravalho, Mike Stratton, Paul Brennan, Ludmil Alexandrov. Mutational signatures in colorectal cancer from 11 countries reveal new insights in early-onset colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB134.
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