title: Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome.
abstract: Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative riskLSca<45_AA=2.90; 95% confidence interval=1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Bellido
authors.forename: Elisabet
authors.initials: E
authors.lastname: Guinó
authors.forename: Shantie
authors.initials: S
authors.lastname: Jagmohan-Changur
authors.forename: Nuria
authors.initials: N
authors.lastname: Seguí
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.forename: Matilde
authors.initials: M
authors.lastname: Navarro
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Laura
authors.initials: L
authors.lastname: Valle
mesh_terms: D000328:Adult; D000367:Age Factors; D001665:Binding Sites / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D019295:Computational Biology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics; D012307:Risk Factors; D013030:Spain; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics
chemical_list: D047490:Retinoid X Receptor alpha; D019098:Telomerase