Power-law scaling in intratumoral microbiota of colorectal cancer.

It has recently been proposed that the study of microbial dynamics in humans may gain insights from island biogeographical theory. Here, we test whether the diversity of the intratumoral microbiota of colorectal cancer tumors (CRC) follows a power law with tumor size akin to the island species-area relationship. We confirm a direct correlation between the quantity of Amplicon Sequence Variants (ASVs) within CRC tumors and tumor sizes, following a (log)power model, explaining 47% of the variation. Understanding the processes involved, potentially through the analogy of tumors and islands, may ultimately contribute to future clinical and therapeutic strategies.

Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10-5). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association.

Perioperative nutritional assessment and management of patients undergoing gastrointestinal surgery.

Malnutrition is a major issue in gastrointestinal perioperative situations, as only 40% of malnourished patients are finally treated. This literature review investigates the inconsistencies regarding the diagnostic approach to both preoperative and postoperative patients and the various underlying causes, as well as the efficiency of the various therapeutic regimens. A literature search was conducted until August 2023 in MEDLINE and Scopus. Clinical studies involving perioperative nutritional assessment in adult gastrointestinal surgery patients during the last 10 years were included in the present review. Finally, 19 articles were included in the study. Preoperative nutritional therapy is increasingly recognized as a key component of surgical care. Malnourished patients who are hospitalized and operated on, have significantly worse clinical results. Gastrointestinal postoperative malnutrition coexists with metabolic stress, as patients usually suffer from minor chronic inflammations; therefore, postoperative malnutrition is the result of a combination of the effects of inflammation and a lack of food intake. Postoperative malnutrition leads to prolonged hospitalizations and hospital complications and therefore the need to treat it is essential. There are many recognized tools for detecting malnutrition. However, all tools showed inconsistent results regarding their validity. Per os feeding after surgery, and dietary supplements when necessary, have been recommended. Therefore, it is very important to reduce malnutrition and define clear strategies towards that direction.

The Impact of Mechanical Bowel Preparation and Oral Antibiotics in Colorectal Cancer Surgery (MECCA Study): A Prospective Randomized Clinical Trial.

Background: Colorectal cancer surgery has been associated with surgical site infections (SSIs), leading to an increase in postoperative morbidity, length of stay and total cost. The aim of the present randomized study was to investigate the relationship between the preoperative administration of oral antibiotic therapy and SSI rate, as well as other postoperative outcomes in patients undergoing colorectal cancer surgery. Material and Methods: Patients who underwent colorectal cancer surgery in a university surgical department were included in the present study. Patients were randomized into two groups using the "block randomization" method. The intervention group received three doses of 400 mg rifaximin and one dose of 500 mg metronidazole per os, as well as mechanical bowel preparation the day before surgery. The control group underwent only mechanical bowel preparation the day before surgery. The study has been registered in ClinicalTrials.gov (NCT03563586). Results: Two hundred and five patients were finally included in the present study, 97 of whom received preoperative antibiotic therapy per os (intervention group). Patients of this group demonstrated a significantly lower SSI rate compared with patients who did not receive preoperative antibiotic therapy (7% vs. 16%, p = 0.049). However, preoperative antibiotic administration was not correlated with any other postoperative outcome (anastomotic leak, overall complications, readmissions, length of stay). Conclusions: Preoperative antibiotic therapy in combination with mechanical bowel preparation seemed to be correlated with a lower SSI rate after colorectal cancer surgery.

Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Malignant Bowel Obstruction: A Retrospective Multicenter Cohort Study.

BACKGROUND: Malignant bowel obstruction (MBO) is a serious clinical entity that requires surgical intervention in almost 50% of cases. However, overall survival remains low even for operable cases. The aim of the present study was to investigate the correlation between patients' characteristics, perioperative details, histopathological results and postoperative outcomes of patients who were operated on due to MBO. METHODS: A retrospective search of patients who were operated on due to MBO in a university and a rural hospital was conducted. Patients' characteristics, perioperative details, histopathological results and postoperative outcomes were reported. Univariable and multivariable analysis was performed. RESULTS: Seventy patients were included with a mean age of 76.1 ± 10.6 years. The 30-day mortality rate was 18.6%, the Intensive Care Unit (ICU) admission rate was 17.1% and the mean length of stay (LOS) was 12.4 ± 5.7 days. Postoperative 30-day mortality was associated with increased age, known malignant recurrence, microscopically visible metastatic foci and defunctioning stoma creation. Colorectal malignancy type, sigmoid obstruction and primary anastomosis were correlated with decreased 30-day mortality. In addition, operation at the university hospital led to increased LOS, while stoma creation led to decreased LOS. Finally, ICU admission rates were increased for operations at university hospitals, at least one comorbidity, known malignant recurrence and longer preoperative waiting interval, whereas they were decreased for colorectal primary malignancy type. CONCLUSIONS: Surgery due to MBO leads to increased morbidity and mortality. Therefore, prospective studies are needed to highlight inter-patient differences regarding the best individualized therapeutic strategy.

A Strict Patient Selection Protocol Could Be the Key to Success for Transanal Minimally Invasive Surgery (TAMIS).

OBJECTIVES: In recent years, the local excision of benign rectal lesions or early-stage rectal cancers using minimally invasive surgical techniques has replaced radical interventions that caused impairment in patients' quality of life. The aim of the present study was to investigate the feasibility of transanal minimally invasive surgery (TAMIS), as well as its excision quality, its oncologic outcomes, and its impact on anorectal function. METHODS: Patients who underwent TAMIS at a single colorectal unit of a tertiary university hospital from 2015 until 2020 for benign rectal lesions or early-stage malignant rectal lesions, along with unsuitable patients for radical interventions, were included in the present study. RESULTS: Twenty-five patients underwent TAMIS for rectal lesions. Their median distance from the anal verge was 7 cm (range 4-12 cm) and their median size was 3.8 cm (range 2-6 cm). The median operative duration was 75 minutes (range 30-150 minutes) and the median hospitalization interval was 2 days (range 1-6 days). In addition, the negative resection rate was 100% and the recurrence rate was 4% during an average follow-up period of 30 months (range 3-36 months). Two patients (8%) presented short-term complications, and in 1 patient (4%) a hybrid technique was required. Seventeen patients (68%) reported moderate incontinence symptoms 6 weeks postoperatively that subsided in all patients 3 months postoperatively. CONCLUSIONS: TAMIS seemed to be a feasible technique with adequate oncologic outcomes and high excision quality, which preserved patients' quality of life. The impact of TAMIS on anorectal function after neoadjuvant chemoradiotherapy for rectal cancer should be further investigated, however.

The PANcreatic Disease ReseArch (PANDoRA) consortium: Ten years' experience of association studies to understand the genetic architecture of pancreatic cancer.

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies.

Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer.

BACKGROUND: The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production. METHODS: Co-culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class, IDO1/TDO2 dual inhibitor AT-0174 at 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated. RESULTS: CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8+ T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8+ T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved immunity in CR tumors which in turn extended overall survival in mice. CONCLUSION: Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

BACKGROUND: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. METHODS: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. RESULTS: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). CONCLUSIONS: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

The effect of anastomotic leak on postoperative pelvic function and quality of life in rectal cancer patients.

AIM: The aim of this review was to collect all available literature data analysing the effects of the anastomotic leak (AL) on post-sphincter preserving rectal cancer surgery bowel and urogenital function as well as to quality of life (QoL) dimensions. METHODS: A literature search of the PubMed and Embase electronic databases was conducted by two independent investigators and all studies using either functional parameters or QoL as a primary or secondary endpoint after a rectal cancer surgery AL were included. RESULTS: Amongst the 13 identified studies focusing on the post-AL neorecto-anal function, 3 case-matched studies,3 comparative studies and 1 population-based study supported the deleterious effects of the AL on bowel function, with disturbances of the types of high bowel movement frequency, urgency and increased incontinent episodes to predominate. At one case-matched study the Low Anterior Resection Syndrome (LARS) score was inferior in the AL patients. At limited under-powered studies, urinary frequency, reduced male sexual activity and female dyspareunia may be linked to a prior AL. According to two QoL-targeted detailed studies, QoL disturbances, such as physical and emotional function difficulties may persist up to 3 years after the AL occurrence. CONCLUSIONS: AL may have adverse effects on postoperative pelvic function and QoL in rectal cancer patients. As evidenced by this literature review, the limited reports on this intriguing topic may trigger the initiative for planning and undertaking larger, multicentre studies on rectal cancer patients with varying degrees of AL severity.

UEG and EAES rapid guideline: Systematic review, meta-analysis, GRADE assessment and evidence-informed European recommendations on TaTME for rectal cancer.

BACKGROUND: Evidence and practice recommendations on the use of transanal total mesorectal excision (TaTME) for rectal cancer are conflicting. OBJECTIVE: We aimed to summarize best evidence and develop a rapid guideline using transparent, trustworthy, and standardized methodology. METHODS: We developed a rapid guideline in accordance with GRADE, G-I-N, and AGREE II standards. The steering group consisted of general surgeons, members of the EAES Research Committee/Guidelines Subcommittee with expertise and experience in guideline development, advanced medical statistics and evidence synthesis, biostatisticians, and a guideline methodologist. The guideline panel consisted of four general surgeons practicing colorectal surgery, a radiologist with expertise in rectal cancer, a radiation oncologist, a pathologist, and a patient representative. We conducted a systematic review and the results of evidence synthesis by means of meta-analyses were summarized in evidence tables. Recommendations were authored and published through an online authoring and publication platform (MAGICapp), with the guideline panel making use of an evidence-to-decision framework and a Delphi process to arrive at consensus. RESULTS: This rapid guideline provides a weak recommendation for the use of TaTME over laparoscopic or robotic TME for low rectal cancer when expertise is available. Furthermore, it details evidence gaps to be addressed by future research and discusses policy considerations. The guideline, with recommendations, evidence summaries, and decision aids in user-friendly formats can also be accessed in MAGICapp: https://app.magicapp.org/#/guideline/4494 . CONCLUSIONS: This rapid guideline provides evidence-informed trustworthy recommendations on the use of TaTME for rectal cancer.

Primary Squamous Cell Carcinoma of Colon and Rectum: A Systematic Review of the Literature.

Background - Objective: Primary colorectal squamous cell carcinoma is an extremely rare neoplasm with an incidence of 0.1 to 0.25 per 1,000 diagnosed colorectal carcinomas.The objective of this study was to evaluate its biological behavior and highlight the role of a surgical approach for its management.MethodsPubMed and Cohrane databases were independently searched (last search: April 10th, 2020) for articles concerning colorectal squamous cell carcinoma in adult population.Results: Seventy-one studies met predefined inclusion criteria and involved 99 patients (54.5% females) with an age of 56.98 ± 12.19 years (mean ± SD). The most frequent site of occurrence was the rectum (63.5%). Open surgery was conducted at 95% of patients, while 21.4% and 30.3% received neoadjuvant and adjuvant therapy respectively.Postoperative complications were developed in 31.3% of patients, while 6.1% died withing the first month following operation. Five-years survival rate was 49.5% (95% CI: 33.7%-63.4%). Female sex (HR: 0.24; 95% CI: 0.11-0.54; p-value: 0.001) and presence of postoperative complications (HR: 4.10; 95%CI: 1.47-1.46; p-value: 0.007) significantly affected the survival.Conclusions Colorectal Squamous Cell Carcinoma is a rare tumor with an aggressive behavior. Surgery is the standard of treatment for the colontumors, while the role of chemoradiotherapy is promising especially for rectal tumors. Further clinical trials are necessary to determine the preferred treatment approach.

Temporal Changes of Low Anterior Resection Syndrome Score after Sphincter Preservation: A Prospective Cohort Study on Repetitive Assessment of Rectal Cancer Patients.

Background: There is a relative shortage of studies directly addressing the postoperative rectal cancer patients' evacuatory dysfunction, as estimated by the low anterior resection syndrome (LARS) score at repeated assessment time-points. The aim of the present study was to prospectively evaluate the incidence of LARS at predefined time intervals during the first 3 years after sphincter preserving rectal cancer surgery and to enlighten the effect of identified risk factors.Materials and methods: Seventy-eight patients, who remained alive and recurrence-free 2 years after (ultra-) low anterior resection were prospectively assessed at 6, 12, 18, 24, 30 and 36 months postoperatively, using the LARS score as bowel dysfunction outcome measure. All patients have completed the 2-year follow-up functional assessment, while 56 and 37 of them have been evaluated up to the 30th and the 36th postoperative month, respectively.Results: The proportion of patients with "major and minor" LARS significantly decreased during the first 3 evaluations (up to 18 months) (74% vs 62% vs 35%, p = 0.0001). The tumor distance from the anal verge and the neoadjuvant radiotherapy were identified as risk factors for high LARS score at 6 months (p < 0.03). The tumor distance remained as risk factor throughout the entire follow-up. All patients with high tumors were alleviated from symptoms reflecting "major" or "minor" LARS at 18 months. Most patients (90%) after radiotherapy showed a high LARS score in the first semester, but improved afterwards.Conclusion: Overall, the LARS score improves in the majority of patients after 18 months, with low tumor height and radiation adversely affecting them. Our results may be useful in more accurately define the postoperative "functional course" of rectal cancer patients and in aiding their consultation on expected functional outcome.

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk.

BACKGROUND: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. METHODS: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. RESULTS: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10-5). CONCLUSIONS: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. IMPACT: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk.

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

Cisplatin Resistance and Redox-Metabolic Vulnerability: A Second Alteration.

The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.