Hyperbilirubinemia: Does It Matter?

Serum bilirubin concentrations are increased in several hematological and hepatic disorders; however, hyperbilirubinemia, often of familial origin, may occur without overt signs of hemolysis or evident liver disease. The authors review briefly the main steps of hepatic bilirubin metabolism, then discuss the pathogenetic mechanisms of the different forms of familial hyperbilirubinemia. The knowledge of these conditions is increasingly important because orthotopic liver transplantation may be a therapeutic choice for some severe forms. Furthermore, early diagnosis is necessary to avoid unnecessary medical investigations for the otherwise relatively common, benign unconjugated hyperbilirubinemia. Finally, individuals with unmasked defective bilirubin handling may be potential liver donors; thus, unexplained jaundice occurring after orthotopic liver transplantation may be related to this disorder

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in this study. We conducted a multi-phase study analysing 7,745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14,666 PDAC cases and 221,897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR=1.11, 95%CI=1.07-1.15, P=5.25×10-9 ). CDKN2B-AS1/ANRIL is a long non-coding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases. This article is protected by copyright. All rights reserved

Association of polyps with early-onset colorectal cancer and throughout surveillance: Novel clinical and molecular implications

Early-onset colorectal cancer (EOCRC) is an increasing and worrisome entity. The aim of this study was to analyze its association with polyps concerning prognosis and surveillance. EOCRC cases were compared regarding the presence or absence of associated polyps (clinical and molecular features), during a minimum of 7 years of follow-up. Of 119 cases, 56 (47%) did not develop polyps (NP group), while 63 (53%) did (P group). The NP group showed a predominant location of the CRC in the rectum (50%), of sporadic cases (54%), and diagnosis at advanced stages: Only P53 and SMARCB1 mutations were statistically linked to this group. The P group, including mainly early-diagnosed tumors, was linked with the most frequent and differential altered chromosomal regions in the array comparative genomic hybridization. The two most frequent groups according to the follow-up were the NP group (40%), and patients developing polyps in the first 5 years of follow-up (P 5FU) showed a mucinous component (50%). Our results show that the absence or presence of polyps in EOCRC is an important prognostic factor with differential phenotypes. The development of polyps during surveillance shows that it is necessary to extend the follow-up time, also in those cases with microsatellite-stable EOCRCThis work was funded by the Spanish Ministry of Health and ConsumerA airs and FEDER, grant number PI10/00683 and PI16/01650 to J.P.G., PI16/01920 to R.G.S., and PI14/00459 to M.U., and by the National Cancer Institute, National Institutes of Health, grant number R01 CA72851, CA18172, CA184792 and U01 CA187956 to A.G

Increased Number of Colorectal Interval Cancers in Lynch Syndrome after the SARS-CoV-2 Pandemic: A Survey-Based Study

Background: Hereditary colorectal cancer syndromes require timely endoscopic surveillance. Methods: This study evaluated the approach of Italian gastroenterologists to the management of such patients. It then assessed the impact of SARS-CoV-2. All members affiliated with the leading Italian gastroenterology societies (AIGO, SIED, and SIGE) received an online questionnaire. Results: One hundred and twenty-one clinicians from 96 centers answered, not necessarily experts in the field (mean age 50.26 +/- 11.22 years). Many collected family history for genetic risk assessment (74.4%), but only 14.0% used an online predictive software. 65.6% discussed cases in multidisciplinary units. Genetic analysis was available to most centers, but only a few hospitals offered dedicated endoscopy (19.0%), outpatient clinics (33.9%), or surgeries (23.1%). Since the start of the SARS-CoV-2 pandemic, the number of clinicians with a high volume of patients decreased (from 38.8% to 28.1%). Almost half of the responders (45.5%) reported a delay in the surveillance (median: 4-12 months). Ultimately, 30.6% detected one interval colorectal cancer in at least one of their patients. Conclusion: The SARS-CoV-2 pandemic directly affected the surveillance of hereditary colorectal cancer syndromes in Italy. Endoscopic surveillance should resume in all centers to avoid the possible long-term consequences of its interruption, especially for inherited colorectal cancer syndromes

Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients

No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.Fil: Dominguez Valentin, Mev. St Mark’s Hospital; Reino Unido. The Norwegian Radium Hospital; Noruega. European Hereditary Tumour Group; Reino UnidoFil: Plazzer, John Paul. St Mark’s Hospital; Reino Unido. The Royal Melbourne Hospital; AustraliaFil: Sampson, Julian R.. European Hereditary Tumour Group; Reino Unido. Cardiff University; Reino UnidoFil: Engel, Christoph. European Hereditary Tumour Group; Reino Unido. Universitat Leipzig; AlemaniaFil: Aretz, Stefan. Universitat Bonn; AlemaniaFil: Jenkins, Mark A.. University of Melbourne; AustraliaFil: Sunde, Lone. Aalborg University; DinamarcaFil: Bernstein, Inge. Aalborg University; DinamarcaFil: Capella, Gabriel. European Hereditary Tumour Group; Reino Unido. St Mark’s Hospital; Reino Unido. Institut Català d’Oncologia; EspañaFil: Balaguer Prunés, Francesc. Universidad de Barcelona; EspañaFil: Macrae, Finlay. European Hereditary Tumour Group; Reino Unido. The Royal Melbourne Hospital; AustraliaFil: Winship, Ingrid M.. University of Melbourne; AustraliaFil: Thomas, Huw. Imperial College London; Reino UnidoFil: Evans, Dafydd Gareth. University of Manchester; Reino UnidoFil: Burn, John. Universidad de Newcastle; Australia. The Royal Melbourne Hospital; Australia. St Mark’s Hospital; Reino UnidoFil: Greenblatt, Marc. University of Vermont; Estados UnidosFil: de Vos tot Nederveen Cappel, Wouter H.. Isala Clinics; Países BajosFil: Sijmons, Rolf H.. University of Groningen; Países Bajos. St Mark’s Hospital; Reino Unido. European Hereditary Tumour Group; Reino UnidoFil: Nielsen, Maartje. Leids Universitair Medisch Centrum; Países BajosFil: Bertario, Lucio. Fondazione IRCCS Istituto Nazionale dei Tumori; ItaliaFil: Bonanni, Bernardo. Fondazione IRCCS Istituto Nazionale dei Tumori; ItaliaFil: Tibiletti, Maria Grazia. Università dell’Insubria; ItaliaFil: Cavestro, Giulia Martina. Vita-Salute San Raffaele University; ItaliaFil: Lindblom, Annika. Karolinska Huddinge Hospital; SueciaFil: Della Valle, Adriana. Hospital Fuerzas Armadas; UruguayFil: Lopez Kostner, Francisco. Clínica Universidad de los Andes; ChileFil: Alvarez, Karin. Clínica Universidad de los Andes; ChileFil: Gluck, Nathan. Universitat Tel Aviv; IsraelFil: Katz, Lior. Sheba Medical Center; IsraelFil: Heinimann, Karl. University Hospital Basel; SuizaFil: Piñero, Tamara Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; Argentin

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender

Risk-Reducing Gynecological Surgery in Lynch Syndrome : Results of an International Survey from the Prospective Lynch Syndrome Database

Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (similar to 90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.Peer reviewe

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.</p

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.</p