Search

[cat] El càncer colorectal (CCR) representa una de les neoplàsies amb major incidència i mortalitat a escala global. Per aquest motiu els sistemes nacionals de salut europeus han posat en marxa programes de cribratge poblacionals amb l’objectiu d’augmentar la detecció precoç de lesions precursores o del càncer, i així, poder evitar l’aparició de CCR o disminuir-ne la mortalitat. Tanmateix, les modalitats dels programes de cribratge amb prova intermèdia, com la prova FIT (prova immunohistoquímica fecal), tendeixen a tenir un elevat nombre de falsos positius a causa de l’especificitat subòptima d’aquesta prova, el que es tradueix en colonoscòpies innecessàries. Per aquest motiu, és fonamental establir noves estratègies que millorin el rendiment de les actuals. La síndrome de poliposi serrada (SPS) és una entitat clínica caracteritzada per la presència de grans i/o múltiples lesions/pòlips serrats en el còlon i un alt risc a CCR. La causa de la SPS és desconeguda. No obstant una petita proporció de casos podrien ser resultat de factors genètics heretats, sobretot per la multiplicitat de les lesions, el ràpid desenvolupament d’un CCR i les edats joves de diagnòstic. Tanmateix, gran part de la predisposició germinal a la SPS està per determinar. En aquest sentit, pel CCR es coneix que variants genètiques comunes i de baixa penetrància contribueixen a la predisposició germinal a CCR, no obstant, encara no s’ha explorat el paper d’aquest tipus de variants en la predisposició germinal a la SPS. En aquest context, el primer objectiu proposat de la present tesi doctoral va ser identificar quines variants genètiques comunes i de baixa penetrància associades a la predisposició germinal a CCR estan també implicades en la predisposició germinal a SPS. Per contra, el segon objectiu, va ser avaluar si les variants genètiques comunes i de baixa penetrància associades a la predisposició germinal a CCR es poden aplicar en el programa de cribratge actual per optimitzar-lo. Per una banda, per tal d’avaluar si les variants genètiques comunes i de baixa penetrància associades a la predisposició germinal a CCR es poden aplicar en el programa de cribratge actual per optimitzar-lo, es van genotipar 65 variants genètiques germinals associades consistentment a la predisposició germinal del CCR en una cohort de 2.893 participants del programa de detecció precoç del CCR de Barcelona, amb una prova de sang oculta en femta positiva. Posteriorment, es va calcular el PRS per a cada individu. Els resultats obtinguts al comparar la mitjana dels valors del PRS entre casos i controls van assenyalar que els casos tenien valors de PRS més elevats en comparació amb els controls (OR 1,4; IC 95% 1,02-1,06; p-valor < 0,0001). Al comparar el PRS dels individus de l’últim decil amb els del primer decil, s’observava que els de l’últim decil tenien gairebé 2,5 vegades més risc de tenir un CCR o una lesió associada a risc de CCR (OR 2,22; IC 95% 1,59-3,12; p-valor, [eng] Colorectal cancer (CRC) has high incidence and associated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario. In the other hand serrated polyposis syndrome (SPS) is a clinical entity characterised by large and/or multiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. Accordingly, this thesis has two main purposes. The first one was to evaluate the potential of polygenic risk score to improve colorectal cancer screening while the second one was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility. To assess whether common genetic variants and low penetrance associated with germinal predisposition in CCR can be applied in the current screening program to optimize it, 65 germinal genetic variants associated consistent with the germinal predisposition of the CCR were genotyped in a cohort of 2,893 participants of the Barcelona CCR early detection program with a positive FIT. Subsequently, the PRS was calculated for each individual. To achieve the first objective, all the individuals included in the study were classified as cases when a high-risk lesion for colorectal cancer was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. 65 colorectal cancer risk genetic variants were genotyped. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value, and PRS were generated. To achieve the second objective a case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed. The results obtained by comparing the average PRS values between cases and controls noted that risk score was higher in cases compared with controls [per allele OR = 1.04; 95% confidence interval (CI), 1.02–1.06; P < 0.0001]. Moreover, a 2-fold increase in colorectal cancer risk was observed for subjects in the highest decile of risk alleles (≥65), compared with those in the first decile (≤54; OR = 2.22; 95% CI, 1.59–3.12; P < 0.0001). The results obtained by comparing the different risk models showed that the model combining sex, age, FIT value, and PRS reached the highest accuracy for identifying patients with a high-risk lesion [cross-validated area under the ROC curve (AUROC): 0.64; 95% CI, 0.62–0.66]. On the other hand, to identify which common genetic variants and low penetrance associated with germinal predisposition in CCR are also involved in germinal predisposition in SPS a case-control association study was conducted. Therefore, 65 germinal genetic variants associated consistent with germinal CCR predisposition in 219 patients diagnosed with SPS and 548 controls were genotyped. Subsequently, a PRS was calculated to assess whether people with SPS generally had a higher number of risk alleles than those in the control group. The results showed that seven genetic variants were significantly associated to SPS (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). Moreover, a 4-fold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50). Consequently, we could conclude that PRS has capacity for risk stratification of colorectal cancer suggesting its potential for optimizing screening strategies alongside with other biomarkers and that genetic variants for CRC risk are also involved in SPS susceptibility.