The aim of the study was to evaluate the association of frequency of polyp diagnosis in relatives with the risk of overall and early-onset colorectal cancer (CRC).

Data from nationwide Swedish family cancer datasets (1964-2018) were leveraged to calculate standardized incidence ratios for individuals with a family history of polyp by frequency of polyp diagnosis in family members.

A total of 11,676,043 individuals were followed for up to 54 years. Compared with the risk in individuals without a family history of colorectal tumor (n = 142,234), the risk of overall CRC was 1.4-fold in those with 1 first-degree relative (FDR) with 1-time polyp diagnosis (95% CI, 1.3-1.4; n = 11,035; early-onset standardized incidence ratio [SIR], 1.4; 95% CI, 1.3-1.5; n = 742). The risk was significantly higher in individuals with 1 FDR with 2 or more (frequent) polyp diagnoses (overall CRC: SIR, 1.8; 95% CI, 1.8-1.9; early-onset CRC: SIR, 2.3; 95% CI, 2.0-2.6). A rather similar risk was observed for individuals with ≥2 FDRs with 1-time polyp diagnosis (overall CRC: SIR, 1.9; 95% CI, 1.7-2.1; early-onset CRC: SIR, 2.2; 95% CI, 1.5-2.9). Individuals with ≥2 FDRs with frequent polyp diagnoses had a 2.4-fold overall risk (95% CI, 2.2-2.7) and a 3.9-fold early-onset risk (95% CI, 2.8-5.3). Younger age at polyp diagnosis in FDRs was associated with an increased risk of CRC. A family history of polyp in second-degree relatives was important only when there were frequent diagnoses of polyp.

A higher frequency of colorectal polyp diagnosis in relatives is associated with a greater risk of CRC, especially early-onset CRC. This risk is independent of number of affected relatives or youngest age at polyp diagnosis. These findings underscore the need for more personalized CRC screening strategies that are tailored to individuals with a family history of polyp.

Colorectal cancer (CRC) is a major global health concern, with genetic factors influencing its development. This study investigated the genomic profile of Amazonian indigenous populations (INDG) by analyzing five genes-APC, MLH1, MSH2, MSH6, and PMS2-associated with CRC. A total of 64 healthy individuals from 12 ethnic groups were analyzed using exome sequencing and bioinformatic tools. We identified 55 genetic variants, including three novel variants exclusive to the INDG, located in the MLH1 and MSH6 genes, which may represent genetic risks for CRC in this population. Additionally, three high-impact variants, already described in the literature, were identified in the APC and MSH2 genes. The study highlights the genetic isolation of Amazonian indigenous groups, with notable differences compared to continental populations. These findings emphasize the need for further genomic research to enhance the understanding of genetic risk factors and improve early detection and targeted therapies in vulnerable populations.

Despite the worrisome rise of early-onset colorectal cancer (EOCRC), risk factors have not been definitively established. We use a large, granular database to evaluate risk factors for EOCRC, investigate differences in associations with EOCRC and later-onset CRC (LOCRC), and compare metrics of accelerated aging, a hypothesized driver of EOCRC.

This was a case-control analysis within the UK Biobank. Risk factors for each cancer were identified and compared, including aging measures (chronological age, telomere length, PhenoAge, and homeostatic dysregulation).

A total of 31,164 persons were matched. We found an increased risk of EOCRC with PRS (OR 1.53; 95% CI 1.19-1.97; p < 0.001). LOCRC was associated with increasing PRS (OR 1.48; 95% CI 1.44 - 1.53; p < 0.001), increasing waist-to-hip ratio (OR 5.81; 95% CI 3.25 - 10.38; p < 0.001), family history of CRC (OR 1.27; 95% CI 1.16 - 1.40; p < 0.001), and history of smoking (OR 1.11; 95% CI 1.03 - 1.19; p = 0.01). Male sex and prior CRC screening were associated with reduced risk of LOCRC. The inclusion of PhenoAge as the measure of aging demonstrated the best model fit for both EOCRC and LOCRC. For each year that PhenoAge exceeded chronological age, the odds of EOCRC increased by 7%, while odds of LOCRC only increased by 1%.

Within this study, we find that genetic risk variants are a significant driver of EOCRC risk. Accelerated aging appears to be associated with increased risk of both EOCRC and LOCRC, and measures such as PhenoAge warrant continued study.

A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.

Colorectal cancer (CRC) is the third most common cancer and is associated with a poor prognosis. The mutation profile and related involved pathways of CRC have been, in broad terms, analyzed. The main current therapeutic approaches have been comprehensively reviewed here, and future possible therapeu-tic options and related technologies have been perspectively presented. The complex scenario represented by the multiple-level resistance mechanism in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, is discussed. Examples of engineered therapeutic approaches from the literature along with a drug combination tested in clinical trials are discussed. The encouraging results observed with the latter combination (the BEACON clinical trial), totally free from chemotherapy, prompted the authors to imagine a future possible nanotechnology-assisted therapeutic approach for bypassing multiple-level resistance mechanisms, hopefully allowing, in principle, a complete biological cancer remission.

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.

The risk of developing a second primary malignancy differs among colorectal cancer patients in different age groups. This study aimed to investigate the differences in prognosis and clinicopathological features of patients with early-onset colorectal cancer and late-onset colorectal cancer who developed second primary malignancies.

The study included 15 489 patients who underwent surgery for colorectal cancer at Fudan University Shanghai Cancer Center between January 2008 and December 2018. Data pertaining to these patients were derived from the database.

A total of 680 (4.5%) patients subsequently developed a second primary malignancy. Considering death as a competing event, the 10-year cumulative risk of second primary malignancy for early-onset colorectal cancer was 5.3%, compared with 7.3% for late-onset colorectal cancer. Cox analysis showed that late-onset colorectal cancer, colon cancer, smaller tumor size, and fewer tumor nodules without residual lymph node structure, chemotherapy, and radiotherapy were independent risk factors for second primary malignancy. In our patient cohort, early-onset colorectal cancer was associated with better prognosis compared to late-onset colorectal cancer, for both overall survival and second primary malignancy-free survival. In addition, there was insufficient evidence that early-onset colorectal cancer also affected prognosis after the occurrence of second primary malignancies.

The risk of early-onset colorectal cancer subsequently developing second primary malignancy was significantly lower than late-onset colorectal cancer, and the second primary malignancies of early-onset colorectal cancer were more likely to be colorectal cancer. Overall survival and second primary malignancy-free survival of early-onset colorectal cancer were consistently better than late-onset colorectal cancer.

Colorectal cancer (CRC) represents a significant health burden worldwide, with a notable increase in early-onset colorectal cancer (EOCRC) cases, defined as those diagnosed before the age of 50 years.

Using data from Taiwan's national cancer registry and a retrospective cohort from Chang Gung Memorial Hospital, this study analyzed CRC cases diagnosed between 2008 and 2019. The analysis compared the EOCRC and late-onset CRC (LOCRC) groups in terms of clinicopathological characteristics, pre-diagnostic symptoms, and survival outcomes.

The analysis revealed a continuous increase in the annual incidence of EOCRC, with colon cancer and rectal cancer rising by 3.2 % and 3.3 %, respectively. Patients with EOCRC presented with more aggressive disease characteristics, such as signet-ring cell adenocarcinoma, mucinous adenocarcinoma, and poorly differentiated grade. Advanced stages at diagnosis, stages III and IV, were more common with EOCRC (62.4 %) than with LOCRC (50.3 %). Patients with EOCRC reported rectal bleeding, changes in bowel habits, and abdominal pain more frequently than those in the LOCRC group. There is a strong association between stool-related symptoms and left-sided CRC. Despite similar surgical outcomes, the 5-year cancer-specific survival rate of patients with stage IV EOCRC was significantly lower than that of patients with LOCRC (32.8 % vs. 51.9 %, p = 0.012).

This study highlights a persistent rise in the incidence of EOCRC, with patients presenting with more aggressive disease and experiencing inferior survival. These findings underscore the importance of heightened awareness and early detection strategies for CRC, especially in younger populations, to improve the prognosis.

(1) Background: Young-onset colorectal adenomas (YOAs) are precursors to early-onset colorectal cancer, a growing concern among individuals under 50 years old. This study investigated the association between surrogate markers of insulin resistance (IR) and YOAs occurrence. (2) Methods: A retrospective cross-sectional analysis was conducted on 4467 individuals aged 20 to 49 years who underwent their first screening colonoscopy at Dong-A University Hospital from 2018 to 2022. IR was assessed using the triglyceride-glucose (TyG) index, triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), and metabolic score for insulin resistance (METS-IR). (3) Results: Individuals with YOAs exhibited significantly higher median TyG index (8.51 ± 0.71 vs. 8.32 ± 0.61, p < 0.001), TG/HDL-C ratio (2.78 ± 3.05 vs. 2.12 ± 1.85, p < 0.001), and METS-IR (35.72 ± 8.37 vs. 33.44 ± 9.11, p < 0.001) values than controls. The adjusted odds ratios for YOAs were 1.064 (95% CI: 1.22-2.23, p = 0.021) for the TyG index, 1.067 (95% CI: 1.031-1.105, p < 0.001) for the TG/HDL-C ratio, and 1.011 (95% CI: 1.002-1.021, p = 0.023) for METS-IR values, indicating a strong association between higher IR marker values and the presence of YOAs. (4) Conclusions: Elevated IR marker values are strongly associated with the occurrence of YOAs in individuals under 50 years old.

The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies.

This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60.

Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative.

Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Early-onset colorectal cancer (EOCRC) incidence has increased in most Western countries over the last decade, with Australia at the forefront. Recent literature has thus focused on characterizing EOCRC from later-onset colorectal cancer (LOCRC). Earlier exposure to modifiable risk factors resulting in gut dysbiosis has been linked with EOCRC development. EOCRCs have more aggressive histopathological features with somatic mutations resulting in pro-inflammatory tumor microenvironments. There is a tendency to treat EOCRCs with multimodal chemotherapeutic regimens and more extensive surgery than LOCRCs with conflicting postoperative outcomes and survival data. Current research is limited by a lack of Australasian studies, retrospective study designs, and heterogeneous definitions of EOCRC. Future research should address these and focus on investigating the role of immunotherapies, establishing minimally invasive diagnostic biomarkers and nomograms, and evaluating the survival and functional outcomes of EOCRC.

Early-onset colorectal cancer (EOCRC), defined as CRC diagnosed before age 50 years, has increased significantly worldwide. The majority of EOCRCs do not appear to be driven by genetic factors and may be influenced by environmental factors. We hypothesized that sociodemographic disparities exist in EOCRC. The purpose was of the study was to examine the geographic disparities in patients with EOCRC.

We retrospectively examined the SEER database from 1976 to 2016 to examine the geographic disparities in EOCRC. A total of 73,378 patients with EOCRC were included in the analysis. We performed univariate and multivariable analyses to evaluate overall survival (OS) and disease-specific survival (DSS). Sociodemographic factors, including the location of residence (metropolitan areas [MA] or rural areas [RA]), sex, race, insurance status, and marital status, were included in the statistical analysis.

The incidence and mortality rates were consistently higher in RA versus MA during the study period. Multivariable analysis showed that patients living in RA had worse OS (hazard ratio [HR], 1.14; P < .01) and DSS (HR, 1.15; P < .001) compared with those living in MA. Similarly, non-Hispanic Black ethnicity and uninsured patients had significantly worse survival when compared with non-Hispanic White and insured patients, respectively. Married status showed better survival outcomes.

Patients with EOCRC living in RA have worse outcomes. Understanding the mechanisms behind such socioeconomic disparities is important so that future studies can reduce these disparities.

The incidence of early-onset (<50 years of age) colorectal cancer (eoCRC) has been steadily increasing in high-income countries including Canada. Despite this increase in incidence, the etiology of eoCRC remains unclear and prospective cohort studies of potential risk factors are limited.

We examined two prospective cohorts of healthy individuals (<50 years of age) who completed baseline questionnaires in the Ontario Health Study and Alberta's Tomorrow Project. We examined the associations between demographic characteristics, chronic health conditions, and lifestyle behaviours with the development of eoCRC using Cox proportional hazard models. Cohorts were analyzed separately and hazard ratios for each risk factor were pooled with random effects meta-analyses.

During an average follow-up of 6.63 years, 98 eoCRC cases occurred among study participants (n=127,852). A family history of CRC alone or with a history of other cancer types was associated with an increased risk of developing eoCRC (HR: 2.76, 95% CI: 1.43-5.32), but a family history of a non-CRC cancer only was not (HR: 1.18, 95% CI: 0.61-2.30). Heavy smokers (≥ 10 pack-years) at baseline had a higher risk of eoCRC compared to non-smokers (HR: 1.87, 95% CI: 1.00-3.52). Sex, socioeconomic factors, diabetes, alcohol consumption, among other factors were not significantly associated with the risk of eoCRC.

Our findings indicate that specific CRC risk factors are also associated with developing eoCRC. The data in the study offers valuable insights that could be integrated in future meta-analyses. Additional prospective cohort studies are required to understand the etiology of eoCRC.

Metastatic colorectal cancer requires a multidisciplinary and individualized approach. Herein, we reported the case of a young woman diagnosed with metastatic rectal cancer who received an individualized multimodal treatment strategy that resulted in a remarkable survival. There were several particular aspects of this case, such as the early onset of the disease, the successful use of conversion therapy, the application of liquid biopsy to guide treatment, and the specific nature of the bone metastasis. To offer more insights for navigating such challenges in patients with metastatic colorectal cancer, we have conducted a literature review to find more data related to the particularities of this case. The incidence of early onset colorectal cancer is on the rise. Data suggests that it differs from older-onset colorectal cancer in terms of its pathological, epidemiological, anatomical, metabolic, and biological characteristics. Conversion therapy and surgical intervention provide an opportunity for cure and improve outcomes in metastatic colorectal cancer. It is important to approach each case individually, as every patient with limited liver disease should be considered as a candidate for secondary resection. Moreover, liquid biopsy has an important role in the individualized management of metastatic colorectal cancer patients, as it offers additional information for treatment decisions.

This position statement, sponsored by the Asociación Española de Gastroenterología, the Sociedad Española de Oncología Médica, the Asociación Española de Genética Humana and the IMPaCT-Genómica Consortium aims to establish recommendations for use of multi-gene panel testing in patients at high risk of hereditary gastrointestinal and pancreatic cancer. To rate the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We reached a consensus among experts using a Delphi method. The document includes recommendations on clinical scenarios where multi-gene panel testing is recommended in colorectal cancer, polyposis syndromes, gastric and pancreatic cancer, as well as the genes to be considered in each clinical scenario. Recommendations on the evaluation of mosaicisms, counseling strategies in the absence of an index subject and, finally, constitutional analysis after identification of pathogenic tumor variants are also made.

Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers.

The unexplained rise of young-onset CRC (yoCRC, age <50 years) is of concern. Evidence suggests that microbial dysbiosis may be a contributing factor, but the tumor microbial profile of yoCRC in comparison to average-onset CRC (aoCRC, age >60) has not been fully investigated.

16S rRNA amplicon sequencing was performed in tumor and paired adjacent non-malignant fresh frozen tissue specimens prospectively collected from 136 yoCRC and 140 aoCRC patients. Phyloseq, microbiomeSeq, metagenomeSeq, and NetComi were utilized for bioinformatics analysis. Statistical tests included Fisher's exact test, ANOVA, PERMANOVA with Bonferroni correction, linear regression, and Wilcoxon test. p-value <0.05 was considered statistically significant.

yoCRC patients were more likely to have left-sided (72.8 vs. 54.3%), rectal (36.7% vs. 25%), and stage IV (28% vs. 15%) tumors. yoCRC tumors had significantly higher microbial alpha diversity (p = 1.5 × 10-5) and varied beta diversity (R2 = 0.31, p = 0.013) than aoCRC tumors. yoCRC tumors were enriched with Akkermansia and Bacteroides, whereas aoCRC tumors showed greater relative abundances of Bacillus, Staphylococcus, Listeria, Enterococcus, Pseudomonas, Fusobacterium, and Escherichia/Shigella. Akkermansia had a predominantly negative correlation with the microbial communities in yoCRC tumors. yoCRC and aoCRC tumors had distinct microbial profiles associated with tumor location, sidedness, stage, and obesity. Fusobacterium (R2 = -0.23, p = 0.001) and Akkermansia (R2 = 0.05, p = 0.001) abundance correlated with overall survival in yoCRC.

Our study provides a comprehensive understanding of the microbial perturbations in yoCRC tumors. We identify microbial candidates that may highlight a distinct pathogenesis of yoCRC and serve as preventive, diagnostic, and therapeutic targets.

Sondra and Stephen Hardis Chair in Oncology Research (A.A.K.).

Adaptive mutagenesis observed in colorectal cancer (CRC) cells upon exposure to EGFR inhibitors contributes to the development of resistance and recurrence. Multiple investigations have indicated a parallel between cancer cells and bacteria in terms of exhibiting adaptive mutagenesis. This phenomenon entails a transient and coordinated escalation of error-prone translesion synthesis polymerases (TLS polymerases), resulting in mutagenesis of a magnitude sufficient to drive the selection of resistant phenotypes.

In this study, we conducted a comprehensive pan-transcriptome analysis of the regulatory framework within CRC cells, with the objective of identifying potential transcriptome modules encompassing certain translesion polymerases and the associated transcription factors (TFs) that govern them. Our sampling strategy involved the collection of transcriptomic data from tumors treated with cetuximab, an EGFR inhibitor, untreated CRC tumors, and colorectal-derived cell lines, resulting in a diverse dataset. Subsequently, we identified co-regulated modules using weighted correlation network analysis with a minKMEtostay threshold set at 0.5 to minimize false-positive module identifications and mapped the modules to STRING annotations. Furthermore, we explored the putative TFs influencing these modules using KBoost, a kernel PCA regression model.

Our analysis did not reveal a distinct transcriptional profile specific to cetuximab treatment. Moreover, we elucidated co-expression modules housing genes, for example, POLK, POLI, POLQ, REV1, POLN, and POLM. Specifically, POLK, POLI, and POLQ were assigned to the "blue" module, which also encompassed critical DNA damage response enzymes, for example. BRCA1, BRCA2, MSH6, and MSH2. To delineate the transcriptional control of this module, we investigated associated TFs, highlighting the roles of prominent cancer-associated TFs, such as CENPA, HNF1A, and E2F7.

We found that translesion polymerases are co-regulated with DNA mismatch repair and cell cycle-associated factors. We did not, however, identified any networks specific to cetuximab treatment indicating that the response to EGFR inhibitors relates to a general stress response mechanism.

The incidence of early-onset colorectal cancer (EOCRC) in adults aged <50 years has increased in several Western nations. National surveys have highlighted significant barriers to accessing timely care for patients with EOCRC, which may be contributing to a late stage of presentation in this population group.

To explore awareness of the increasing incidence of EOCRC, and to understand the potential barriers or facilitators faced by GPs when referring younger adults to secondary care with features indicative of EOCRC.

Qualitative methodology, via virtual semi-structured interviews with 17 GPs in Northern Ireland.

Reflective thematic analysis was conducted with reference to Braun and Clarke's framework.

Three main themes were identified among participating GPs: awareness, diagnostic, and referral challenges. Awareness challenges focused on perceptions of EOCRC being solely associated with hereditary cancer syndromes, and colorectal cancer being a condition of older adults. Key diagnostic challenges centred around the commonality of lower gastrointestinal complaints and overlap in EOCRC symptoms with benign conditions. Restrictions in age-based referral guidance and a GP 'guilt complex' surrounding over-referral to secondary care summarised the referral challenges. Young females were perceived as being particularly disadvantaged with regard to delays in diagnosis.

This novel research outlines potential reasons for the diagnostic delays seen in patients with EOCRC from a GP perspective, and highlights many of the complicating factors that contribute to the diagnostic process.

Early-onset colorectal cancer (age under 50 years) (EOCRC) is an entity of undeniable importance, both because of its growing incidence, and the population it affects. Other current reviews emphasize the essential points regarding the clinical management and knowledge of its molecular bases. However, we intend to go one step further. With the increased significance of patient participation and disease experience in mind, we have integrated the voice of the patient to show the weaknesses and the needs, and next steps in the advancement of knowledge and management of EOCRC. This integrative review of the different perspectives, clinical, research and the patients themselves, can therefore be defined as an integrative needs assessment. Hence, this may be a first step in working towards an essential homogeneity of definitions and action.

Colon cancer remains a leading cause of cancer-related deaths, and there has been a rise in the incidence of early-onset colon cancer or colon cancer diagnosed before the age of 50 years old. Early-onset colon cancer has several differences in clinical presentation, as well as histopathology, genetic alteration, and molecular profiling. Early-onset colon cancer can be differentiated into familial type that includes hereditary familial syndrome and sporadic type. Demographic variance also exists in both developing and developed countries. Due to the rising incidence of colon cancer diagnosed in younger age, it is imperative to examine the available evidence regarding the mortality rate of early-onset colon cancer. Colon cancer is affected by numerous modifiable and non-modifiable risk factors. Increasing obesity and lifestyle disorders in the younger population, such as smoking, may influence this increasing trend. There are existing guidelines for colon cancer screening in both average-risk and high-risk individuals. This narrative review aims to highlight the pathogenesis of early-onset CRC; its clinical presentation, treatment, prognosis; and how it differs from late-onset CRC.

Our objective is to present an exceptional case of a patient diagnosed with Paget's disease of the bone (PDB) while being confirmed with Lynch syndrome (LS). A 44-year-old woman was admitted for progressive pain in the left forearm 2 years ago, and was partially relieved since admission by non-steroidal anti-inflammatory drugs. Suggestive imaging findings and increased blood bone turnover markers helped the diagnosis of PDB. She was offered zoledronate 5 mg. She had two more episodes of relapse, and a decision of new medication was taken within the following years (a second dose of zoledronate, as well as denosumab 60 mg). Her family history showed PDB (mother) and colorectal cancer (father). Whole exome sequencing was performed according to the manufacturer's standard procedure (Ion AmpliSeq™ Exome RDY S5 Kit). A heterozygous pathogenic variant in the SQSTM1 gene (c.1175C>T, p.Pro392Leu) was confirmed, consistent with the diagnosis of PDB. Additionally, a heterozygous pathogenic variant of MSH2 gene (c.2634+1G>T) was associated with LS. The patient's first-degree relatives (her brother, one of her two sisters, and her only daughter) underwent specific genetic screening and found negative results, except for her daughter, who tested positive for both pathogenic variants while being clinically asymptomatic. The phenotype influence of either mutation is still an open issue. To our current knowledge, no similar case has been published before. Both genetic defects that led to the two conditions appeared highly transmissible in the patient's family. The patient might have an increased risk of osteosarcoma and chondrosarcoma, both due to PDB and LS, and a review of the literature was introduced in this particular matter. The phenotypic expression of the daughter remains uncertain and is yet to be a lifelong follow-up as the second patient harbouring this unique combination of gene anomalies.

Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly.

The highest incidence of colorectal cancer (CRC) is in patients diagnosed at 80 years or older highlighting a need for understanding the clinical and molecular features of these tumors. Methods. In this retrospective cohort study, 544 CRCs underwent next generation sequencing and mismatch repair (MMR) evaluation. Molecular and clinical features were compared between 251 patients with traditional-onset CRC (50-69 years at diagnosis) and 60 with late-onset CRC (>80 years at diagnosis).

Late-onset CRC showed a significantly higher rate of right-sided tumors (82% vs 35%), MMR deficiency (35% vs. 8%) and BRAF p.V600E mutations (35% vs. 8%) and a significantly lower rate of stage IV disease (15% vs 28%) and APC mutations (52% vs. 78%). Association of these features with advanced age was supported by stratifying patients into 6 age groups (<40, 40-49, 50-59, 60-69, 70-79 and >80 years). However, the age-related rise in MMR deficient (dMMR) CRC was only seen in the female patients with an incidence of 48% (vs. 10% in the male patient) in the >80y group. In addition, BRAF p.V600E was significantly enriched in MMR deficient CRC of advanced age (67% in late-onset CRC). Categorizing CRC by mutational profiling, late-onset CRC revealed a significantly higher rate of dMMR/BRAF ⁺ APC ^- (18% vs. 2.0%), dMMR/BRAF ^- APC ^- (8.3% vs. 1.2%) and MMR proficient (pMMR)/BRAF ⁺ APC ^- (12% vs. 4.0%) as compared to traditional-onset CRC.

In summary, there was a higher rate of dMMR and BRAF p.V600E in late-onset CRC, independently or in combination. The higher incidence of dMMR in late-onset CRC in females is most likely predominantly driven by BRAF p.V600E induced hypermethylation. Prospective studies with treatment plans designed specifically for these older patients are warranted to improve their outcomes.

Metastatic early-onset colorectal cancer (EO-CRC) is on the rise, yet there is a dearth of predictive models for this disease. Therefore, it is crucial to develop a nomogram to aid in the early detection and management of metastatic colorectal cancer in young patients.

We retrieved data from the SEER database on patients with metastatic colorectal cancer aged 50 or younger between 2010 and 2017. The data were randomly allocated in a 7:3 ratio to training and validation cohorts, and univariate and multivariate Cox regression analyses were used to identify independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS) at 1, 3, and 5 years. The nomograms were developed based on these factors, and their discriminatory and calibration capabilities were validated. Using the nomogram risk scores, patients were stratified into low-risk and high-risk groups.

The study included 2470 patients with metastatic EO-CRC. Univariate and multivariate Cox regression analysis identified 12 independent risk factors that were included in the nomogram. The training cohort had a consistency index (C-index) of 0.71, while the validation cohort had a C-index of 0.70, demonstrating good predictive accuracy. Calibration plots showed a high level of consistency between the observed and predicted values, with overlapping plots along the diagonal. The decision curve analysis (DCA) revealed that the nomogram had a high clinical application value.

The novel nomograms were created to predict the prognosis of patients with metastatic EO-CRC, which can aid clinicians in developing more effective treatment strategies and contribute to more accurate prognostic assessments.

Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC.

After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%.

The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients.

The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

Approximately 5% of colorectal cancers (CRCs) are associated with hereditary cancer syndromes. The natural history of these syndromes differs from sporadic cancers, and due to their increased risk of metachronous carcinomas, surgical approaches also differ. This review focuses on the current recommendations for surgical treatment and what evidence has led to these recommendations in the most clinically relevant hereditary CRC syndromes: Lynch syndrome (LS) and (attenuated) familial adenomatous polyposis (FAP).

LS has no common phenotype and is caused by individual germline variants in one of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). Because each gene is associated with a different risk of metachronous cancer, guidelines now differentiate between genes in their recommendations for oncology interventions. Classical and attenuated FAP are caused by germline mutations in the APC gene and have a characteristic phenotype. Although correlations exist between phenotype and genotype, the indication for surgery is predominantly based on clinical manifestation rather than specific gene mutations.

Currently, the recommendation on the two diseases tends to go in opposite directions: while some forms of FAP may require less extensive surgery, in some LS patients, more sophisticated knowledge of metachronous carcinoma risk leads to more extensive surgery.

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li-Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz-Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.

New methods and demonstrations of feasibility guide future implementation of genomic population health screening programs. This is the first report of genomic population screening in a primary care, non-research setting using existing large carrier and health risk gene sequencing panels combined into one 432-gene test that is offered to adults of any health status. This report summarizes basic demographic data and analyses patterns of pathogenic and likely pathogenic genetic findings for the first 300 individuals tested in this real-world scenario. We devised a classification system for gene results to facilitate clear message development for our Genomic Medicine Action Plan messaging tool used to summarize and activate results for patients and primary care providers. Potential genetic health risks of various magnitudes for a broad range of disorders were identified in 16% to 34% of tested individuals. The frequency depends on criteria used for the type and penetrance of risk. 86% of individuals are carriers for one or more recessive diseases. Detecting, reporting, and guiding response to diverse genetic health risks and recessive carrier states in a single primary care genomic screening test appears feasible and effective. This is an important step toward exploring an exome or genome sequence as a multi-purpose clinical screening tool.

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.

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.

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).

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.

Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 young adults aged 20−49, including 298,117 with diverticular disease. We examined yearly incidence rate of first diagnosis of EOCRC from 2010 through 2021 among patients with and without diverticular disease. The 5-year risk of EOCRC among patients with pre-existing diverticular disease was compared to propensity-matched patients without diverticular disease and EOCRC and odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: The yearly incidence rate of new diagnosis of EOCRC (measured as new cases per 100,000 people per year) in young adults with pre-existing diverticular disease increased from 100 in 2010 to 402 in 2021, 4−6 times higher than in those without diverticular disease (24 in 2010 to 77 in 2021) (p < 0.001). Patients with diverticular disease were at higher risk for EOCRC than those without (OR: 1.76, 95% CI: 1.40−2.32). Conclusion: The incidence of EOCRC continuously increased from 2010 through 2021 in patients with and without diverticular disease and was 4−6 times higher among patients with diverticular disease. Patients with pre-existing diverticular disease were at a significantly increased risk for EOCRC.