Telomere Length as a New Risk Marker of Early-Onset Colorectal Cancer.

Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (hTERT, TERC, DKC1, TERF1, TERF2, TERF2IP, TINF2, ACD, and POT1) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb; p < 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of hTERT (rs79662648), POT1 (rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354), TERF2 (rs251796 and rs344152214), and TERF2IP (rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.

Familial component of early-onset colorectal cancer: opportunity for prevention.

BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Biliary Complications After Liver Transplantation From Uncontrolled Donors After Circulatory Death: Incidence, Management, and Outcome.

The utilization of livers from donation after uncontrolled circulatory death (uDCD) increases the availability of liver grafts, but it is associated with a higher incidence of biliary complications (BCs) and lower graft survival than those organs donated after brain death. From January 2006 to December 2016, we performed 75 orthotopic liver transplantations (OLTs) using uDCD livers. To investigate the relationship of BCs with the use of uDCD OLT, we compared patients who developed BCs (23 patients) with those who did not (non-BC group, 43 patients) after excluding cases of hepatic artery thrombosis (a known cause of BC) and primary nonfunction. The groups had similar uDCD donor maintenance, donor and recipient characteristics, and perioperative morbidity/mortality rates, but we observed a higher rate of hepatocellular carcinoma and hepatitis C virus in the non-BC group. Percutaneous transhepatic biliary dilation, endoscopic retrograde cholangiopancreatography dilation, Roux-en-Y hepaticojejunostomy (HJ), a T-tube, and retransplantation were used for BC management. In the BC group, 1-, 3-, and 5-year patient survival rates were 91.3%, 69.6%, and 65.2%, respectively, versus 77.8%, 72.9%, and 72.9%, respectively, in the non-BC group (P = 0.89). However, 1-, 3-, and 5-year graft survival rates were 78.3%, 60.9%, and 56.5%, respectively, in the BC group versus 77.8%, 72.9%, and 72.9%, respectively, in the non-BC group (P = 0.38). Multivariate analysis did not indicate independent risk factors for BC development. In conclusion, patient and graft survival rates were generally lower in patients who developed BCs but not significantly so. These complications were managed in the majority of patients through radiological dilation, endoscopic dilation, or Roux-en-Y HJ. Retransplantation is necessary in rare cases after the failure of biliary dilation or surgical procedures.

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) (34%) (these last groups predominantly diagnosed at the earliest stage and with adenomatous polyps (45%)). EOCRC with polyps that developed during the entire follow-up (PDFU group) were mainly located in the right colon (53%), diagnosed in earlier stages, and 75% had a familial history of CRC. Patients developing polyps after the first 5 years (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 EOCRC.

Clinical and Molecular Comparative Study of Colorectal Cancer Based on Age-of-onset and Tumor Location: Two Main Criteria for Subclassifying Colorectal Cancer.

Our aim was to characterize and validate that the location and age of onset of the tumor are both important criteria to classify colorectal cancer (CRC). We analyzed clinical and molecular characteristics of early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and we compared each tumor location between both ages-of-onset. In right-sided colon tumors, early-onset cases showed extensive Lynch syndrome (LS) features, with a relatively low frequency of chromosomal instability (CIN), but a high CpG island methylation phenotype. Nevertheless, late-onset cases showed predominantly sporadic features and microsatellite instability cases due to BRAF mutations. In left colon cancers, the most reliable clinical features were the tendency to develop polyps as well as multiple primary CRC associated with the late-onset subset. Apart from the higher degree of CIN in left-sided early-onset cancers, differential copy number alterations were also observed. Differences among rectal cancers showed that early-onset rectal cancers were diagnosed at later stages, had less association with polyps, and more than half of them were associated with a familial LS component. Stratifying CRC according to both location and age-of-onset criteria is meaningful, not only because it correlates the resulting categories with certain molecular bases, but with the confirmation across larger studies, new therapeutical algorithms could be defined according to this subclassification.

DNA copy number profiling reveals different patterns of chromosomal instability within colorectal cancer according to the age of onset.

Chromosomal instability resulting in copy number alterations is a hallmark of colorectal cancer (CRC). However, few studies have attempted to characterize the chromosomal changes occurring in early-onset CRC in order to compare them with those taking place within the more extensively studied late-onset CRC subset. Our aim was to characterize the genomic profiles of these two groups of colorectal tumors and to compare them to each other. Array comparative genomic hybridization profiling of 146 colorectal tumors (60 early-onset and 86 late-onset) in combination with an unsupervised analysis was used to define common and specific copy number alterations. We found a number of important differences between the chromosomal instability profiles of each age subset. Thus, losses at 1p36, 1p12, 1q21, 9p13, 14q11, 16p13, and 16p12 were significantly more frequent in younger patients, whereas gains at 7q11 and 7q22 were more frequent in older patients. Moreover, the unsupervised analysis stratified the tumors into two clusters, each one of which was enriched in patients from one of the age subsets. Our findings confirm the existence of substantial differences between the chromosomal instability profiles of the two groups which are more important from a qualitative point of view. Further studies are needed to understand the clinicopathological implications of these dissimilarities.

Age at onset should be a major criterion for subclassification of colorectal cancer.

An important proportion of early-onset colorectal cancer (CRC) does not show a hereditary component with limited knowledge about its molecular basis and features. We analyzed a subset of patients with early-onset CRC and compared them with patients with late-onset CRC. We analyzed the microsatellite instability and CpG island methylator phenotype (CIMP) in both populations and classified them into four molecular subtypes. We analyzed the differential features between groups. Only 12 of 81 early-onset cases (15%) showed microsatellite instability, 10 of which (83%) were Lynch syndrome cases; microsatellite instability cases in elderly patients were sporadic. Early-onset microsatellite-stable cases showed different tumor locations and more family history of cancer than the elderly. Microsatellite instability/CIMP-high early-onset CRC was associated with Lynch syndrome, whereas the elderly cases were associated with BRAF mutations. Early-onset microsatellite-stable/CIMP-high CRCs were more frequently mucinous and right sided than elderly cases, with a high incidence of Lynch syndrome neoplasms; early-onset microsatellite stable/CIMP-low/0 differed from elderly cases in location, stages, incidence of multiple primary neoplasms, and the familial component. The clinical and familial differences observed between early- and late-onset CRC when considering the different carcinogenetic pathways underline that the age at onset criterion should be considered when classifying CRC.

Early-onset colorectal cancer is an easy and effective tool to identify retrospectively Lynch syndrome.

BACKGROUND AND OBJECTIVES: Early age of onset is a marker of a possible hereditary component in colorectal cancer (CRC). We evaluated whether early age of onset is a good marker to identify Lynch syndrome, especially retrospectively, and if there is any other feature that could improve this identification. METHODS: We selected patients with CRC aged 45 years or younger from the pathological reports of three different institutions and different periods of time. Clinical information, family history, and tumor samples were obtained. Cases were classified according to mismatch repair (MMR) proficiency. RESULTS: Of 133 tumors, 22 showed microsatellite instability (MSI). In 15 MSI cases, a germline mutation in 1 of the MMR genes was identified, 7 of which were not identified before. The positive predictive value (PPV) of right colon CRC for a positive genetic MMR test is 30.6%, whereas "signet ring" cells and fulfillment Amsterdam II criteria have PPVs of 42.9% and 47.8%, respectively. Combining right-sided CRC with mucin production, with fulfilling Amsterdam II criteria, or with "signet ring" cells, PPVs are 54.5, 64.3, and 100%. The probability of the absence of a mutation when CRC is located in the left colon is 94.7%, whereas absence of aggregation for Lynch-related neoplasm has a 100% probability. CONCLUSIONS: Early age of onset is an effective method to identify retrospectively Lynch syndrome. Taking into account the location and histology features of the tumor, and the familial history of the cases, we notably increase the a priori probability of detecting a germline MMR mutation.

Influencia de la edad en el tratamiento quirúrgico del síndrome de Lynch / Influence of age on the surgical treatment of lynch syndrome

No disponible

No disponible

Approach to early-onset colorectal cancer: clinicopathological, familial, molecular and immunohistochemical characteristics.

AIM: To characterize clinicopathological and familial features of early-onset colorectal cancer (CRC) and compare features of tumors with and without microsatellite instability (MSI). METHODS: Forty-five patients with CRC aged 45 or younger were included in the study. Clinical information, a three-generation family history, and tumor samples were obtained. MSI status was analyzed and mismatch repair genes were examined in the MSI families. Tumors were included in a tissue microarray and an immunohistochemical study was carried out with a panel of selected antibodies. RESULTS: Early onset CRC is characterized by advanced stage at diagnosis, right colon location, low-grade of differentiation, mucin production, and presence of polyps. Hereditary forms represent at least 21% of cases. Eighty-one percent of patients who died during follow-up showed a lack of expression of cyclin E, which could be a marker of poor prognosis. beta-catenin expression was normal in a high percentage of tumors. CONCLUSION: Early-onset CRC has an important familial component, with a high proportion of tumors showing microsatellite stable. Cyclin E might be a poor prognosis factor.