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Background Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from colorectal cancer patients. Methods We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 colorectal cancer patients and 2,952 healthy controls. DNA was extracted with Phenol/Chloroform, PureGene or QIAamp. Results We observed differences in RTL depending on DNA extraction method (p<0.001). Phenol/Chloroform extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01-6.54) ) compared to PureGene extracted DNA (mean RTL of 0.75; range 0.00-12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02-3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17-0.58-) was smaller than from either PureGene or Phenol/Chloroform (ranges:0.04-2.67 and 0.32-2.81, respectively). Conclusions RTL measured by qPCR from QIAamp-extracted DNA was smaller than from either PureGene or Phenol/Chloroform (p<0.001). Impact Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL.

Background: Rapid, preoperative identification of patients with the highest risk for medical complications is necessary to ensure that limited infrastructure and human resources are directed towards those most likely to benefit. Existing risk scores either lack specificity at the patient level or utilise the American Society of Anesthesiologists (ASA) physical status classification, which requires a clinician to review the chart. Methods: We report on the use of machine learning algorithms, specifically random forests, to create a fully automated score that predicts postoperative in-hospital mortality based solely on structured data available at the time of surgery. Electronic health record data from 53 097 surgical patients (2.01% mortality rate) who underwent general anaesthesia between April 1, 2013 and December 10, 2018 in a large US academic medical centre were used to extract 58 preoperative features. Results: Using a random forest classifier we found that automatically obtained preoperative features (area under the curve [AUC] of 0.932, 95% confidence interval [CI] 0.910e0.951) outperforms Preoperative Score to Predict Postoperative Mortality (POSPOM) scores (AUC of 0.660, 95% CI 0.598e0.722), Charlson comorbidity scores (AUC of 0.742, 95% CI

Background Telomeres, the ends of chromosomes, are critical for maintaining genomic stability and grow shorter with age. Shortened telomeres in pancreatic tissue play a key role in the pathogenesis of pancreatic cancer, and shorter telomeres in peripheral blood leukocytes (PBLs) have been associated with increased risk for several cancer types. We hypothesized that shorter blood telomeres are associated with higher risk for pancreatic cancer. Methods Telomere length was measured in PBLs using quantitative real-time PCR in 499 cases with pancreatic cancer and 963 cancer-free controls from the Mayo Clinic. Odds ratios and confidence intervals were computed using logistic generalized additive models adjusting for multiple variables. Results: In multivariable adjusted models we observed a significant non-linear association between telomere length in peripheral blood samples and the risk for pancreatic cancer. Risk was lower among those with longer telomeres compared to shorter telomeres across a range from the 1%ile to 90%ile of telomere length. There was also some evidence for higher risk among those with telomeres in the longest extreme. Conclusions Short telomeres in peripheral blood are associated with an increased risk for pancreatic cancer across most of the distribution of length, but extremely long telomeres may also be associated with higher risk. Impact Although the temporality of this relationship is unknown, telomere length may be useful as either a marker of pancreatic cancer risk or of the presence of undetected pancreatic cancer. If telomere shortening precedes cancer incidence, interventions to preserve telomere length may be an effective strategy to prevent pancreatic cancer.

The majority of colorectal cancer (CRC) arises from precursor lesions known as polyps. The molecular determinants that distinguish benign from malignant polyps remain unclear. To molecularly characterize polyps, we utilized Cancer Adjacent Polyp (CAP) and Cancer Free Polyp (CFP) patients. CAPs had tissues from the residual polyp of origin and contiguous cancer; CFPs had polyp tissues matched to CAPs based on polyp size, histology and dysplasia. To determine whether molecular features distinguish CAPs and CFPs, we conducted Whole Genome Sequencing, RNA-seq, and RRBS on over 90 tissues from 31 patients. CAPs had significantly more mutations, altered expression and hypermethylation compared to CFPs. APC was significantly mutated in both polyp groups, but mutations in TP53, FBXW7, PIK3CA, KIAA1804 and SMAD2 were exclusive to CAPs. We found significant expression changes between CAPs and CFPs in GREM1, IGF2, CTGF, and PLAU, and both expression and methylation alterations in FES and HES1. Integrative analyses revealed 124 genes with alterations in at least two platforms, and ERBB3 and E2F8 showed aberrations specific to CAPs across all platforms. These findings provide a resource of molecular distinctions between polyps with and without cancer, which have the potential to enhance the diagnosis, risk assessment and management of polyps.

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Peripheral blood telomere length has been associated with age-related conditions including Alzheimer’s disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1 years, [range 70.9–90.8]; 49.6% men) by age and sex to 137 cognitively normal controls. We measured telomere length (T/S ratio) at baseline and follow-up using quantitative PCR. Compared to the middle T/S quintile (Q3), the risk of aMCI was elevated for subjects with the shortest (Q1: HR, 2.85, 95% Confidence interval [CI] 0.98, 8.25; p = 0.05) and the longest telomere lengths (Q5: HR, 5.58, 95%CI, 2.21, 14.11; p = 0.0003). In this elderly cohort, short and long telomeres were associated with increased risk of aMCI. Our findings suggest that both long and short telomere lengths may play a role in the pathogenesis of aMCI, and may be markers of increased risk of aMCI.

IntroductionColorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition. Experimental DesignMSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH. ResultsTumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949).ConclusionsMSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.