Germline (likely-)pathogenic variants (PV) in CDH1 predispose carriers to hereditary diffuse gastric cancer and lobular breast cancer. Previous studies from the United States suggest CDH1 variant carriers have an increased risk for adenomas or sessile serrated lesions (SSL), yet data linking CDH1 PVs and colorectal neoplasia are scarce. We aimed to investigate colonoscopy findings in CDH1 PVs. Adults carrying a PV/LPV in CDH1 with ≥ 1 colonoscopy between 01/01/2004-12/31/2023 were included. Patients were sourced from the David G. Jagelman Inherited Colorectal Cancer Registries at Cleveland Clinic and the German Consortium for Familial Intestinal Cancer. 103 CDH1 PV carriers were included. Most were female (66%) and white (93.1%). The median age at first colonoscopy was 47 years. The adenoma detection rate (ADR) was 29.4% (95% CI:19.9-41.1%) in the German cohort and 48.6% (95% CI: 33.0-64.4%) in the Cleveland cohort (p = 0.055) and significantly correlated with age (< 45 years, 13.6% (95% CI: 6.40-26.7%); 45-49 years, 52.4% (95% CI: 32.4-71.7%); ≥50 years, 52.6% (95% CI: 37.3-67.5%); p < 0.001). The ADR in Cleveland was higher than the U.S. average ADR but the difference was not statistically significant (48.6% vs. 35.6%, p = 0.08), and the ADR in the German cohort (29.4%) was similar to the national German average risk screening cohort (31.3% in men, p = 0.84; 20.1% in women, p = 0.08). In our screening cohort with CDH1 PV carriers, we demonstrated an ADR of 13.5% in individuals under 45 years, similar to the ADR in patients aged 25-40 years with a family history of CRC. Overall, SSL detection rate was 9.7%. Colorectal cancer was diagnosed in 3 patients (3.2%), 2/3 with an early age of onset before the age of 50 years. This first international study provides preliminary evidence of a higher ADR in U.S. CDH1 PV carriers compared to the general population, with a high number of adenomas detected before the age of 50. This may indicate an increased CRC risk that should be explored in larger studies.

Approximately 10% of colorectal cancer (CRC) cases occur in the context of hereditary cancer-predisposing conditions caused by germline pathogenic variants (PVs) in cancer predisposition genes, with Lynch syndrome and familial adenomatous polyposis at the top of the list. Although the identification of hereditary CRC has traditionally relied on clinical characteristics, including familial accumulation, multiple and early onset of CRC and other related cancers, and the presence of gastrointestinal polyposis, more comprehensive approaches, such as universal tumor screening and universal germline testing, have recently been employed. From a technical standpoint, next-generation sequencing has enabled genome-wide analysis of genetic alterations in germline and somatic settings. Taking advantage of this technology, germline multigene panel testing has been utilized in genetic testing, which leads to the identification of PVs, not only in well-known hereditary CRC genes but also in rare causal genes, moderate-risk genes, and high-risk genes previously not linked to CRC predisposition. In addition, comprehensive genomic profiling and companion diagnostics for solid tumors occasionally yield unexpected hereditary CRC diagnoses. Thus, more hereditary CRCs have been identified not based on clinical phenotypes but rather by comprehensive approaches or as secondary findings of treatment drug testing. In this review, we discuss the impact of recent advances in genomic medicine on the clinical aspects of hereditary CRC, which has promoted an understanding of the entire landscape of genetic predisposition to CRC.

DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk.

We hypothesized that a subset of women with POI and family members would have increased risk for cancer.

Case-control population-based study using records from 1995 to 2022.

Two major Utah academic health care systems serving 85% of the state.

Women with POI (n = 613) were identified using International Classification of Diseases codes and reviewed for accuracy. Relatives were linked using the Utah Population Database.

Cancer diagnoses were identified using the Utah Cancer Registry.

The relative risk of cancer in women with POI and relatives was estimated by comparison to population rates. Whole genome sequencing was performed on a subset of women.

Breast cancer was increased in women with POI (OR, 2.20; 95% CI, 1.30-3.47; P = .0023) and there was a nominally significant increase in ovarian cancer. Probands with POI were 36.5 ± 4.3 years and 59.5 ± 12.7 years when diagnosed with POI and cancer, respectively. Causal and candidate gene variants for cancer and POI were identified. Among second-degree relatives of these women, there was an increased risk of breast (OR, 1.28; 95% CI, 1.08-1.52; P = .0078) and colon cancer (OR, 1.50; 95% CI, 1.14-1.94; P = .0036). Prostate cancer was increased in first- (OR, 1.64; 95% CI, 1.18-2.23; P = .0026), second- (OR, 1.54; 95% CI, 1.32-1.79; P < .001), and third-degree relatives (OR, 1.33; 95% CI, 1.20-1.48; P < .001).

Data suggest common genetic risk for POI and reproductive cancers. Tools are needed to predict cancer risk in women with POI and potentially to counsel about risks of hormone replacement therapy.

Although the overall colorectal cancer (CRC) incidence has been steadily declining in the United States, a dramatic increase in the number of CRC cases among individuals younger than 50 years of age (early-onset CRC) has been observed. CRC is the second and first leading cause of cancer death in the United States and among Hispanic men and women living in Puerto Rico (PRH), respectively. We report CRC incidence rates from 2000 to 2021 among PRH and compare them to data in the Surveillance, Epidemiology, and End Results Program (SEER).

Data on colorectal adenocarcinomas diagnosed between January 1, 2000, and December 31, 2021, were obtained from the Puerto Rico Central Cancer Registry and SEER17, including race and ethnicity. Age-standardized incidence rates were calculated using the direct method. The Joinpoint Regression Program calculated temporal trends on CRC incidence rates based on age-adjusted Average Annual Percent Change (AAPC) estimates.

A total of 729,479 incident cases of CRC were analyzed. US Hispanics had the highest percentage of early-onset CRC (EOCRC) cases (17.0%) among the racial and ethnic groups studied. PRH had the highest age-standardized EOCRC incidence rate (12.18 per 100,000 persons) and the highest increase in EOCRC incidence temporal trends (AAPC = 2.68; 95% CI: 1.83 to 3.51).

A significantly higher increase in EOCRC incidence was observed among Hispanic populations. Future studies should disaggregate Hispanic subpopulations by considering the country of ancestral origin, which will help identify specific risk factors and exposures and aid in developing tailored prevention and risk stratification strategies to reduce EOCRC incidence.

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 one of the most prevalent forms of cancer globally. The human gut microbiome plays an important role in the development of CRC and serves as a biomarker for early detection and treatment. This research effort focuses on the identification of potential taxonomic biomarkers of CRC using a grouping-based feature selection method. Additionally, this study investigates the effect of incorporating biological domain knowledge into the feature selection process while identifying CRC-associated microorganisms. Conventional feature selection techniques often fail to leverage existing biological knowledge during metagenomic data analysis. To address this gap, we propose taxonomy-based Grouping Scoring Modeling (G-S-M) method that integrates biological domain knowledge into feature grouping and selection. In this study, using metagenomic data related to CRC, classification is performed at three taxonomic levels (genus, family and order). The MetaPhlAn tool is employed to determine the relative abundance values of species in each sample. Comparative performance analyses involve six feature selection methods and four classification algorithms. When experimented on two CRC associated metagenomics datasets, the highest performance metric, yielding an AUC of 0.90, is observed at the genus taxonomic level. At this level, 7 out of top 10 groups (Parvimonas, Peptostreptococcus, Fusobacterium, Gemella, Streptococcus, Porphyromonas and Solobacterium) were commonly identified for both datasets. Moreover, the identified microorganisms at genus, family, and order levels are thoroughly discussed via refering to CRC-related metagenomic literature. This study not only contributes to our understanding of CRC development, but also highlights the applicability of taxonomy-based G-S-M method in tackling various diseases.

Epigenetics is currently considered the investigation of inheritable changes in gene expression that do not rely on DNA sequence alteration. Significant epigenetic procedures are involved, such as DNA methylations, histone modifications, and non-coding RNA actions. It is confirmed through several investigations that epigenetic changes are associated with the formation, development, and metastasis of various cancers, such as colorectal cancer (CRC). The difference between epigenetic changes and genetic mutations is that the former could be reversed or prevented; therefore, cancer treatment and prevention could be achieved by restoring abnormal epigenetic events within the neoplastic cells. These treatments, consequently, cause the anti-tumour effects augmentation, drug resistance reduction, and host immune response stimulation. In this article, we begin our survey by exploring basic epigenetic mechanisms to understand epigenetic tools and strategies for treating colorectal cancer in monotherapy and combination with chemotherapy or immunotherapy.

National guidelines recommend germline genetic testing (GT) for all patients with early-onset colorectal cancer. With recent advances in targeted therapies and GT, these guidelines are expected to expand to include broader groups of patients with colorectal cancer. However, there is a shortage of genetic professionals to provide the necessary education and support for informed consent. As such, there is a pressing need to identify alternative approaches to facilitate and expedite access to GT.

This study describes the development of a pretest education intervention, Nest-CRC, to facilitate the uptake of germline GT among patients with early-onset colorectal cancer. Patients with early-onset colorectal cancer and health care providers reviewed Nest-CRC, and their reactions and recommendations were captured using a nested mixed methods approach.

Using the learner verification approach, we conducted 2 sequential phases of surveys and interviews with English- and Spanish-speaking patients with early-onset colorectal cancer and health care providers. The surveys assessed participants' experiences with genetic services and provided immediate feedback on the Nest-CRC genetic education modules. Semistructured interviews evaluated participants' perceptions of self-efficacy, attraction, comprehension, cultural acceptability, and usability of Nest-CRC. Survey data were analyzed using descriptive statistics (mean, median, and proportions), while interview data were analyzed through line-by-line coding of the transcribed interviews. After each phase, Nest-CRC was refined based on participants' recommendations.

A total of 52 participants, including 39 patients with early-onset colorectal cancer and 13 providers, participated in the study. Of these, 19 patients and 6 providers participated in phase 1 (N=25), and 20 patients and 7 providers participated in phase 2 (N=27). Most participants (phase 1: 23/25, 92%, to 25/25, 100%; phase 2: 24/27, 89%, to 27/27, 100%) agreed that each of the 5 education modules was easy to understand and helpful; 13 patients reported no history of GT, with 11 (85%) expressing interest in GT and 2 (15%) remaining unsure after completing Nest-CRC. Participants reported that Nest-CRC provided sufficient information to help them decide about GT. The tool was deemed acceptable by individuals from diverse backgrounds, and participants found it visually attractive, easy to comprehend, and user-friendly.

The findings revealed that Nest-CRC is a promising strategy for facilitating pretest education and promoting GT. Nest-CRC has been refined based on participant recommendations and will be re-evaluated.

Hereditary polyposis syndromes are significant contributors to colorectal cancer (CRC). These syndromes are characterized by the development of various types and numbers of polyps, distinct inheritance patterns, and extracolonic manifestations. This review explores these syndromes with a focus on their genetic characteristics. Advances in diagnostics, particularly the identification of pathogenic germline variants through massive sequencing technologies, have enhanced our understanding of the genetic alterations associated with polyp formation and CRC risk. Identifying pathogenic variants beyond traditional diagnostic criteria improves the management and surveillance of these syndromes. Genetic diagnosis not only refines patient treatment and surveillance, but also informs relatives of potential risks, enabling appropriate management. However, challenges persist in determining the pathogenicity of newly discovered mutations due to their low prevalence. This review covers hereditary polyposis syndromes, from well-established to newly recognized types, providing insights into their genetic landscapes and highlighting the need for tailored surveillance based on genotype.

Lynch syndrome (LS) is an autosomal-dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch-repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1-associated LS. The objective of this study was to assess anticipation in families with MLH1-associated LS by using statistical models while controlling for potential confounders.

Data from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed-rank tests on parent-child-pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed-effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth-cohort effects.

A trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity.

The current results demonstrated evidence in support of anticipation in families with MLH1-associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1-LS families is recommended.

APC and MUTYH genes are key in hereditary attenuated adenomatous polyposis syndromes. Guidelines recommend genetic testing based on polyp count, often overlooking age despite its impact on polyp prevalence.

To enhance genetic testing strategies for suspected attenuated adenomatous polyposis by combining polyp count and age in a probability calculator.

Retrospective study of adult patients referred to NGS genetic testing for suspected attenuated adenomatous polyposis (accumulated history of < 100 adenomas) (discovery cohort, N = 138). Data included age, adenoma count, and test results. A multivariable logistic regression model was developed to associate positive genetic test results with age and adenoma count. The model was externally validated with 259 patients from two tertiary hospitals in our region (validation cohort, N = 259).

In the discovery cohort, 13 (9.4%) patients had pathogenic mutations, being younger (OR:0.91, 95%CI 0.86-0.96) and having more adenomas (OR:1.08, 95%CI 1.04-1.13) compared to negative cases. The logistic regression model combining age and polyp count demonstrated an AUC of 0.92. Using a cutoff probability of 3.5%, the model achieved 100% sensitivity and 58% specificity in identifying positive cases. In the external validation, the model accurately predicted 14 out of 16 positive cases (88%). The remaining two positive cases were a patient with an AXIN2 mutation in heterozygosis, and a patient with a NTHL1 mutation in homozygosis. Performance evaluation of both hospitals yielded AUC values of 0.77 and 0.90.

Older individuals with fewer polyps are less likely have hereditary syndromes. Including age in genetic testing criteria can enhance patient selection and cost-effectiveness.

Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions.

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], p = 0.034 and Adj HR: 1.53 [1.09-2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), present significant clinical challenges due to the heightened cancer risks associated with these genetic conditions. This review explores genetic profiling impact on surgical decisions for hereditary colorectal cancer (HCRC), assessing options, timing, and outcomes. Genotypes of different HCRCs are discussed, revealing a connection between genetic profiles, disease severity, and outcomes. For Lynch syndrome, mutations in the MLH1, MSH2, MSH6, and PMS2 genes guide the choice of surgery. Subtotal colectomy is recommended for patients with mutations in MLH1 and MSH2, while segmental colectomy is preferred for those with MSH6 and PMS2 mutations. In cases of metachronous colon cancer after segmental colectomy, subtotal colectomy with ileorectal anastomosis is advised for all mutations. Surgical strategies for primary rectal cancer include anterior resection or abdominoperineal resection (APR), irrespective of the specific mutation. For rectal cancer occurring after a previous segmental colectomy, proctocolectomy with ileal pouch-anal anastomosis (IPAA) or APR with a permanent ileostomy is recommended. In FAP, surgical decisions are based on genotype-phenotype correlations. The risk of desmoid tumors post-surgery supports a single-stage approach, particularly for certain APC gene variants. Juvenile Polyposis Syndrome (JPS) surgical decisions involve genetic testing, polyp characteristics with attention to vascular lesions in SMAD4 mutation carriers. However, genetic profiling does not directly dictate the specific surgical approach for JPS. In conclusion this review highlights the critical role of personalized surgical plans based on genetic profiles to optimize patient outcomes and reduce cancer risk. Further research is needed to refine these strategies and enhance clinical guidelines.

Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related death. Over the past two decades, numerous researchers have provided important evidence regarding the role of tight junction (TJ) proteins in the occurrence and progression of CRC. The causal relationship between the presence of specific TJ proteins and the development of CRC has also been confirmed. Despite the large number of publications in this field, a bibliometric study to review the current state of research and highlight the research trends and hotspots in this field has not yet been performed.

To analyze research on TJs and CRC, summarize the field's history and current status, and predict future research directions.

We searched the Science Citation Index Expanded database for all literature on CRC and TJs from 2001-2023. We used bibliometrics to analyze the data of these papers, such as the authors, countries, institutions, and references. Co-authorship, co-citation, and co-occurrence analyses were the main methods of analysis. CiteSpace and VOSviewer were used to visualize the results.

A total of 205 studies were ultimately identified. The number of publications on this topic has steadily increased since 2007. China and the United States have made the largest contributions to this field. Anticancer Research was the most prolific journal, publishing 8 articles, while the journal Oncogene had the highest average citation rate (68.33). Professor Dhawan P was the most prolific and cited author in this field. Co-occurrence analysis of keywords revealed that "tight junction protein expression", "colorectal cancer", "intestinal microbiota", and "inflammatory bowel disease" had the highest frequency of occurrence, revealing the research hotspots and trends in this field.

This bibliometric analysis evaluated the scope and trends of TJ proteins in CRC, providing valuable research perspectives and future directions for studying the connection between the two. It is recommended to focus on emerging research hotspots, such as the correlations among intestinal microbiota, inflammatory bowel disease, TJ protein expression, and CRC.

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes.

A man in his 70s with metastatic colorectal cancer presented with worsening clinical symptoms and imaging studies concerning for disease progression. He had received two cycles of pembrolizumab, but due to his symptomatic presentation and significant decline in performance status, there was concern for worsening disease. Transitioning to hospice was briefly considered, given his clinical decline and the notable increase in tumour size. Despite the presence of clinical symptoms and radiographic findings, pseudoprogression-defined as an increase in the size(s) of and/or visual appearance of new lesion(s), followed by a response-was also considered as part of the diagnostic possibilities. Consequently, the decision was made to proceed with a third cycle of pembrolizumab. During his subsequent outpatient follow-up, the patient showed significant symptomatic improvement and reported a decrease in his palpable right flank mass. With further immunotherapy, the patient continued to demonstrate symptomatic and radiological improvement.

Germline variant interpretation often depends on population-matched control cohorts. This is not feasible for population groups that are underrepresented in current population reference databases.

We classify germline variants with population-matched controls for 2 ancestrally diverse cohorts of patients: 132 early-onset or familial colorectal carcinoma patients from Singapore and 100 early-onset colorectal carcinoma patients from the United States. The effects of using a population-mismatched control cohort are simulated by swapping the control cohorts used for each patient cohort, with or without the popmax computational strategy.

Population-matched classifications revealed a combined 62 pathogenic or likely pathogenic (P/LP) variants in 34 genes across both cohorts. Using a population-mismatched control cohort resulted in misclassification of non-P/LP variants as P/LP, driven by the absence of ancestry-specific rare variants in the control cohort. Popmax was more effective in alleviating misclassifications for the Singapore cohort than the US cohort.

Underrepresented population groups can suffer from higher rates of false-positive P/LP results. Popmax can partially alleviate these misclassifications, but its efficacy still depends on the degree with which the population groups are represented in the control cohort.

Immunotherapy shows efficacy for multiple cancer types and potential for expanded use. However, current immune checkpoint inhibitors (ICIs) are ineffective against microsatellite-stable colorectal cancer (CRC), which is more commonly diagnosed. Immunotherapy strategies for non-responsive CRC, including new targets and new combination therapies, are being tested to address this need. Importantly, a subset of inherited germline genetic variants associated with CRC risk are predicted to regulate genes with immune functions, including genes related to existing ICIs, as well as new potential targets in the major histocompatibility complex (MHC) region and immunoregulatory cytokines. We review discoveries in the inherited genetics of CRC related to the immune system and draw connections with ongoing developments and emerging immunotherapy targets.

Colorectal neoplasia is one of the most common tumors affecting Western populations.

In this study we used a custom amplicon sequencing platform and an in-house bioinformatic pipeline to study constitutional DNA from two different case series of Ashkenazi Jews undergoing colonoscopy (n = 765). The first series all had pathologically confirmed colorectal adenomas and/or carcinoma. The second series consisted of persons who had undergone a colonoscopy within the five years prior to ascertainment, regardless of findings. Ninety-one percent of all patients were asymptomatic at the time of colonoscopy.

In the first group (n = 438), we identified 65 founder variants (56 in APC, 2 in GREM1, 3 in MSH2 and 4 in BLM). In the second group (n = 327), the findings were 30, nothing, 1 and 1, respectively, as well as 2 MSH6 variants.

Overall, we found that 10 to 15% of Ashkenazi Jewish persons undergoing colonoscopy harbor variants of interest in colorectal and/or polyposis predisposition. This includes pathogenic variants in MSH6, which is associated with colorectal cancer but not with polyposis. We identified no pathogenic variants in more recently discovered polyposis predisposition genes (POLE, POLD1 or NTHL1), rendering the presence of such founder variants rare.

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.

MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility.

We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants.

Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2-2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5-3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2-22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7-2.3).

In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.

High-fat (HF) diets (HFDs) and inflammation are risk factors for colon cancer; however, the underlying mechanisms remain to be fully elucidated. The transcriptional corepressor HDAC3 has recently emerged as a key regulator of intestinal epithelial responses to diet and inflammation with intestinal-specific Hdac3 deletion (Hdac3IKO) in mice increasing fatty acid oxidation genes and the rate of fatty acid oxidation in enterocytes. Hdac3IKO mice are also predisposed to experimentally induced colitis; however, whether this is driven by the intestinal metabolic reprogramming and whether this predisposes these mice to intestinal tumorigenesis is unknown. Herein, we examined the effects of intestinal-specific Hdac3 deletion on colitis-associated intestinal tumorigenesis in mice fed a standard (STD) or HFD. Hdac3IKO mice were highly prone to experimentally induced colitis, which was further enhanced by an HFD. Hdac3 deletion also accelerated intestinal tumor development, specifically when fed an HFD and most notably in the small intestine where lipid absorption is maximal. Expression of proteins involved in fatty acid metabolism and oxidation (SCD1, EHHADH) were elevated in the small intestine of Hdac3IKO mice fed an HFD, and these mice displayed increased levels of lipid peroxidation, DNA damage, and apoptosis in their villi, as well as extensive expansion of the stem cell and progenitor cell compartment. These findings reveal a novel role for Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover.NEW & NOTEWORTHY We reveal a novel role for the transcriptional corepressor Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We also identify a unique mouse model for investigating the complex interplay between diet, metabolic reprogramming, and tumor predisposition in the intestinal epithelium.

Multiple studies have identified pathogenic germline variants in cancer susceptibility genes (CSGs) in Chinese lung cancer patients; however, accurate assessment of these variants' contributions to cancer predisposition is always hampered by the absence of data on the prevalence of these variants in the general population. It is necessary to conduct a large-scale case-control study to identify CSGs that significantly increase the risk of lung cancer.

We performed targeted sequencing of a CSGs panel in 1117 lung cancer patients and 16,327 controls from the general Chinese population.

In comparison to controls, lung cancer patients had a considerably higher prevalence of pathogenic and likely pathogenic (P/LP) variations. Among lung cancer patients, 72% of P/LP variants carriers did not have a family cancer history, who would be ignored if germline testing was only provided for patients meeting family history-based criteria. Furthermore, compared to individuals with late-onset lung cancer, patients with early-onset lung cancer had a considerably higher prevalence of P/LP variations. With odds ratios (ORs) ranging from 4-fold (BRCA1: OR, 4.193; 95%CI, 1.382-10.768) to 29-fold (TP53: OR, 29.281; 95%CI, 1.523-1705.506), P/LP variants in the BRCA1 and TP53 genes were discovered to be strongly related to increased lung cancer risk. Additionally, with ORs ranging from 7.322-fold to infinity, we discovered 23 variations previously categorized as non-P/LP variants were highly enriched in lung cancer patients.

Our findings indicated that P/LP variants in BRCA1 and TP53 conferred increased risk of lung cancer in Chinese.

Lynch syndrome (LS) is characterised by an increased risk of developing colorectal cancer (CRC) and other extracolonic epithelial cancers. It is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes or the EPCAM gene, leading to a less functional DNA MMR system. Individuals diagnosed with LS (LS individuals) have a 10-80% lifetime risk of developing cancer. However, there is considerable variability in the age of cancer onset, which cannot be attributed to the specific MMR gene or variant alone. It is speculated that multiple genetic and environmental factors contribute to this variability, including two single nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene: C677T (rs1801133) and A1298C (rs1801131). By decreasing MTHFR activity, these SNPs theoretically reduce the silencing of DNA repair genes and increase the availability of nucleotides for DNA synthesis and repair, thereby protecting against early-onset cancer in LS. We investigated the effect of these SNPs on LS disease expression in 2,723 LS individuals from Australia, Poland, Germany, Norway and Spain. The association between age at cancer onset and SNP genotype (risk of cancer) was estimated using Cox regression adjusted for gender, country and affected MMR gene. For A1298C (rs1801131), both the AC and CC genotypes were significantly associated with a reduced risk of developing CRC compared to the AA genotype, but no association was seen for C677T (rs1801133). However, an aggregated effect of protective alleles was seen when combining the alleles from the two SNPs, especially for LS individuals carrying 1 and 2 alleles. For individuals with germline pathogenic variants in MLH1, the CC genotype of A1298C was estimated to reduce the risk of CRC significantly by 39% (HR = 0.61, 95% CI 0.42, 0.89, p = 0.011), while for individuals with pathogenic germline MSH2 variants, the AC genotype (compared to AA) was estimated to reduce the risk of CRC by 26% (HR = 0.66, 95% CI 0.53, 0.83, p = 0.01). In comparison, no association was observed for C677T (rs1801133). In conclusion, our study suggests that combining the MMR gene information with the MTHFR genotype, including the aggregated effect of protective alleles, could be useful in developing an algorithm that estimates the risk of CRC in LS individuals.

The pathogenesis, clinical phenotype, treatment strategy, and family management of hereditary tumor syndromes are different from those of sporadic tumors. Nearly a quarter of patients with colorectal cancer show significant familial aggregation and genetic predisposition, and 5 to 10% are associated with definite genetic factors. According to the clinical phenotype, it can be divided into nonpolyposis syndrome and polyposis syndrome. Among the polyposis syndrome patients with definite clinical symptoms, there are still some patients with unknown etiology (especially attenuated familial adenomatous polyposis), which is a difficult problem in clinical diagnosis and treatment. Therefore, for this rare disease, it is urgent to carry out multicenter studies, complete the gene variation spectrum, explore new pathogenic factors, and accumulate clinical experience. This article mainly introduces the research progress and related work of colorectal polyposis syndrome in China.

Early-onset colorectal cancer (CRC), which refers to CRC diagnosed in individuals below the age of 50 years, is a growing health concern that presents unique challenges in diagnosis, treatment, and long-term outcomes. Although approximately 70% of early-onset CRC cases are sporadic, with no apparent family history, approximately 25% have a familial component, and up to 20% may be associated with germline mutations, indicating a higher prevalence compared with the general population. Despite the progress in identifying the environmental, molecular, and genetic risk factors of early-onset CRC, the underlying causes for the global increase in its incidence remain unclear. This comprehensive review aims to provide a thorough analysis of early-onset CRC by examining the trends associated with its incidence, clinical and pathological characteristics, risk factors, molecular and genetic profiles, prognosis and screening strategies. By deepening our understanding of early-onset CRC, significant advances related to improving the outcomes and alleviating the burden of this disease on individuals, families, and healthcare systems can be achieved.

Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue- and liquid-based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount. A second major driver is the development of smart clinical trials and trial concepts which, complemented by real-world evidence, rapidly broaden the spectrum of therapeutic options. Tight coordination with regulatory agencies and health technology assessment bodies is crucial in this context. Multicentric networks operating nationally and internationally are key in implementing precision oncology in clinical practice and support developing and improving the ecosystem and framework needed to turn invocation into benefits for patients. The review provides an overview of the diagnostic tools, innovative clinical studies, and collaborative efforts needed to realize precision cancer medicine.

Hereditary colorectal cancer is an increasingly complex field in which the commoner syndromes are being augmented by rarer genetic presentations contributing to familial polyposis and colorectal cancer. Coming to grips with the complexity is difficult because of the phenotypic and genotypic overlap between syndromes.

This study aimed to describe a new way of thinking about syndromes of hereditary colorectal cancer based on their embryonic tissue of origin.

Articles were searched through PubMed and MEDLINE.

The terms "hereditary colorectal cancer," "syndromes of hereditary colorectal cancer," and "hereditary polyposis" were used to direct the search.

Primarily endoderm-derived syndromes were different from mesoderm-derived syndromes in their genetics, molecular biology, histology, and clinical course.

There is considerable phenotypic and genotypic overlap between syndromes, even when considering embryonic tissue of origin.

Thinking about hereditary syndromes of colorectal cancer from the perspective of embryonic tissue of origin provides a fresh look at phenotype and genotype that opens new areas of exploration.

ANTECEDENTES:El cáncer colorrectal hereditario es un campo cada vez más complejo donde los síndromes más comunes se ven aumentados por presentaciones genéticas más raras que contribuyen a la poliposis familiar y al cáncer colorrectal. Hacer frente a esta complejidad resulta difícil debido a la superposición fenotípica y genotípica entre los síndromes.OBJETIVO:En este artículo, describimos una nueva forma de pensar sobre los síndromes de cáncer colorrectal hereditario en función del origen de su tejido embrionario.FUENTES DE DATOS:Se realizaron búsquedas de artículos en Pubmed y Medline.SELECCIÓN DE ESTUDIOS:Se utilizaron los términos "cáncer colorrectal hereditario", "síndromes de cáncer colorrectal hereditario", "poliposis hereditaria" para dirigir la búsqueda.RESULTADOS:Principalmente los síndromes derivados del endodermo fueron diferentes a los síndromes derivados del mesodermo en su genética, biología molecular, histología y curso clínico.LIMITACIONES:Existe una superposición fenotípica y genotípica considerable entre los síndromes, incluso cuando se considera el tejido de origen embrionario.CONCLUSIÓN:Pensar en los síndromes hereditarios del cáncer colorrectal desde la perspectiva del tejido embrionario de origen proporciona una nueva mirada al fenotipo y al genotipo que abre nuevas áreas de exploración. (Traducción-Dr Osvaldo Gauto ).

The incidence of early-onset colorectal cancer (CRC), which affects people under 50, is increasing for unknown reasons. Additionally, no underlying genetic cause is found in 20%-30% of patients suspected of having familial CRC syndrome. Whole exome sequencing (WES) has generated evidence for new genes associated with CRC susceptibility, but many patients remain undiagnosed. This study applied WES in five early-onset CRC patients from three unrelated families to identify novel genetic variants that could be linked to rapid disease development. Furthermore, the candidate variants were validated using Sanger sequencing. Two heterozygote variations, c.1077-2A>G and c.199G>A, were found in the MSH2 and the MLH1 genes, respectively. Sanger sequencing analysis confirmed that these (likely) pathogenic mutations segregated in all the affected families' members. In addition, we identified a rare heterozygote variant (c.175C>T) with suspected pathogenic potential in the MAP3K1 gene; formally the variant is of uncertain significance (VUS). Our findings support the hypothesis that CRC onset may be oligogenic and molecularly heterogeneous. Larger and more robust studies are needed to understand the genetic basis of early-onset CRC development, combined with novel functional analyses and omics approaches.

In this installment of the "Paradigm Shifts in Perspective" series, the authors, all scientists who have been involved in colorectal cancer (CRC) research for most or all of their careers, have watched the field develop from early pathological descriptions of tumor formation to the current understanding of tumor pathogenesis that informs personalized therapies. We outline how our understanding of the pathogenetic basis of CRC began with seemingly isolated discoveries-initially with the mutations in RAS and the APC gene, the latter of which was initially found in the context of intestinal polyposis, to the more complex process of multistep carcinogenesis, to the chase for tumor suppressor genes, which led to the unexpected discovery of microsatellite instability (MSI). These discoveries enabled the authors to better understand how the DNA mismatch repair (MMR) system not only recognizes DNA damage but also responds to damage by DNA repair or by triggering apoptosis in the injured cell. This work served, in part, to link the earlier findings on the pathogenesis of CRC to the development of immune checkpoint inhibitors, which has been transformative-and curative-for certain types of CRCs and other cancers as well. These discoveries also highlight the circuitous routes that scientific progress takes, which can include thoughtful hypothesis testing and at other times recognizing the importance of seemingly serendipitous observations that substantially change the flow and direction of the discovery process. What has happened over the past 37 years was not predictable when this journey began, but it does speak to the power of careful scientific experimentation, following the facts, perseverance in the face of opposition, and the willingness to think outside of established paradigms.

Metabolomics refers to the technology for the comprehensive analysis of metabolites and low-molecular-weight compounds in a biological system, such as cells or tissues. Metabolites play an important role in biological phenomena through their direct involvement in the regulation of physiological mechanisms, such as maintaining cell homeostasis or signal transmission through protein-protein interactions. The current review aims provide a framework for how the integrated analysis of metabolites, their functional actions and inherent biological information can be used to understand biological phenomena related to the regulation of metabolites and how this information can be applied to safety assessments of crops created using biotechnology. Advancement in technology and analytical instrumentation have led new ways to examine the convergence between biology and chemistry, which has yielded a deeper understanding of complex biological phenomena. Metabolomics can be utilized and applied to safety assessments of biotechnology products through a systematic approach using metabolite-level data processing algorithms, statistical techniques, and database development. The integration of metabolomics data with sequencing data is a key step towards improving additional phenotypical evidence to elucidate the degree of environmental affects for variants found in genome associated with metabolic processes. Moreover, information analysis technology such as big data, machine learning, and IT investment must be introduced to establish a system for data extraction, selection, and metabolomic data analysis for the interpretation of biological implications of biotechnology innovations. This review outlines the integrity of metabolomics assessments in determining the consequences of genetic engineering and biotechnology in plants.

Familial pancreatic cancer (FPC) is a rare hereditary tumor entity with broad phenotypic heterogeneity, including colorectal carcinoma (CRC) in some families. The underlying factors for this co-occurrence are still not well evaluated. FPC families in the National Case Collection of Familial Pancreatic Cancer with an additional occurrence of CRC were analyzed regarding the phenotype, genotype and recommendation for a clinical screening program. The total cohort of 272 FPC families included 30 (11%) families with at least one CRC case. The proportion of affected family members with PDAC was 16.1% (73/451) compared to 9.3% of family members with CRC (42/451, p < 0.01). Females were affected with PDAC in 49% (36/73) and CRC in 38% (16/42). The median age of PDAC was 63 compared to 66 years in CRC, whereas 8 (26.6%) of families had an early onset of PDAC and 2 (6.7%) of CRC. Seventeen families had 2 or more affected generations with PDAC and 6 families with CRC. Eleven (9.6%) of affected patients had both PDAC and CRC. Potentially causative germline mutations (2 ATM, 1 CDKN2a, 1 MLH1, 1 PALB2) were detected in 5 of 18 (27.7%) analyzed cases. These findings provide a step forward to include the phenotypic and genotypic characteristics of FPC-CRC families for the genetic counseling and management of these families. Nevertheless, results need to be verified in a larger patient cohort beforehand.

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.

Hereditary genetic mutations causing predisposition to colorectal cancer are accountable for approximately 30% of all colorectal cancer cases. However, only a small fraction of these are high penetrant mutations occurring in DNA mismatch repair genes, causing one of several types of familial colorectal cancer (CRC) syndromes. Most of the mutations are low-penetrant variants, contributing to an increased risk of familial colorectal cancer, and they are often found in additional genes and pathways not previously associated with CRC. The aim of this study was to identify such variants, both high-penetrant and low-penetrant ones.

We performed whole exome sequencing on constitutional DNA extracted from blood of 48 patients suspected of familial colorectal cancer and used multiple in silico prediction tools and available literature-based evidence to detect and investigate genetic variants.

We identified several causative and some potentially causative germline variants in genes known for their association with colorectal cancer. In addition, we identified several variants in genes not typically included in relevant gene panels for colorectal cancer, including CFTR, PABPC1 and TYRO3, which may be associated with an increased risk for cancer.

Identification of variants in additional genes that potentially can be associated with familial colorectal cancer indicates a larger genetic spectrum of this disease, not limited only to mismatch repair genes. Usage of multiple in silico tools based on different methods and combined through a consensus approach increases the sensitivity of predictions and narrows down a large list of variants to the ones that are most likely to be significant.

Background: Colorectal cancer (CRC) is a significant global health challenge with increasing incidence and mortality rates in developing countries. Genome-wide association studies have identified new low-penetrance genetic variants linked to CRC. This study aimed to explore the relationship between HLA-G polymorphism and serum expression with CRC. Methodology: In a case-control configuration, standard PCR was used for genotyping HLA-G 3' indel polymorphism and ELISA for quantifying soluble HLA-G in plasma. Results: The study revealed a significant association between the rs371194629 deletion allele and CRC, as well as higher soluble HLA-G levels in CRC patients. Conclusion: These findings suggest that HLA-G could be a promising biomarker for CRC, and further research could lead to improved screening and treatment for more personalized care.