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Open research questions in Genetic factors in colorectal cancer

25 unresolved questions extracted from the limitations and future-work sections of 171 Genetic factors in colorectal cancer papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • While TP53 inactivation is well established as a late event in the adenoma-to-carcinoma sequence, its functional role during the early stage of colorectal polyp development remains unclear.

    TP53 loss attenuates C1q-associated macrophage remodeling in early adenomatous polyps in a porcine FAP model · 2026 · DOI

  • Although the loss of APC is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of APC and TP53 facilitates the onset of colorectal tumorigenesis remain poorly characterized.

    Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids · 2026 · DOI

  • It should also be noted that the majority of our patients carried MSH6 and PMS2 variants and thus may not be representative of all Lynch syndrome cohorts.

    Polyposis in Lynch syndrome: A retrospective study · 2026 · DOI

  • These findings indicate that variability in the language of morphologic reporting remains a significant limitation to downstream morphology-based molecular inference. Joint evaluation of these tasks revealed that the accuracy of downstream MSI prediction was directly limited by the extraction of MSI-associated morphologic features.

    Large Language Model Morphology-to-Genotype Inference for Microsatellite Instability From Colorectal Carcinoma Histopathology Reports · 2026 · DOI

  • Limitations of acquired clinical samples An obvious limitation of the present study is that only four LS patients were enrolled for a single-cell omics study plus two additional LS donors for experimental verification, and no longitu- dinal biopsy samples were included. Considering that clinical studies rely on biopsy sample availability in practice, the six donors represent a small LS population. Nonetheless, this study is certainly instructive to the field since we are using single-cell sequencing technologies to monitor the transition (or the difference) between latent LS colon tissue and diseased (malignant) LS colon tissue. Importantly, two members of a family with LS were enrolled in the study (a mother and a son), and the mother was a relapsed LS patient, while the other three LS patients were treatment-naive. This diversified representation of the enrolled LS cohort with the scRNA- seq dataset represents an invaluable resource for future LS studies. Another obvious limitation of the present study is that no whole-exome-sequencing (WES) analysis was conducted to validate the findings, as we only used the availability of the scRNA-seq dataset to compare the mutation burden of LS-CA and LS-paraCA (27). Reutilization of the scRNA-seq dataset by the SComatic algorithm enabled us to compute the SBS mutation burden without additional sequencing costs. The addition of WES sequencing to paired samples of colon tissue or single-cell DNA sequencing offers an opportunity to observe the mutation burden at the whole- genome and single-cell levels. Limitations of our bio-computation analysis and the future direction of the study The present study largely relies on the computational analysis of scRNA-seq or snRNA-seq datasets with transcriptomic features and a large number of cells. Annotation of the single cells with a regular analysis protocol on the Seurat platform enabled us to identify the changes in the proportion of cell types and cell-cell communica- tions. Using SCEVAN and SComatic algorithms, we were also able to profile CNV alterations and SBS mutations. These two algo- rithms are particularly important because LS is a heritable CRC with mutations in MMR genes. Furthermore, we validated our findings using immunohistochemistry and flow cytometry experi- ments. In addition, considering that the current scRNA-seq dataset is only about 150 bp of 3’ regions of expressed genes, full-length sequencing of the cDNA will be more informative for the SComatic analysis. If the mutation burden of LS-paraCA and LS-CA is indeed comparable, epi-mutation analysis should be considered in the future. By the way, combination of scRNA-seq and scATAC-seq will assist the cell atlas study of LS as well. We envision that an improved bio-computational analysis working-flow will be instruc- tive for future LS studies when more donors are enrolled.

    Tracing the stemness and malignant transition in a heritable colorectal cancer Lynch Syndrome by single-cell RNA-seq analysis · 2026 · DOI

  • Previous studies have identified germline truncating variants of the RNF43; however, patients harboring these variants comprise a small part of those with SPS, in most of whom the causative gene remains unknown.

    Genetic testing of Japanese patients with serrated polyposis syndrome: A multicentric study. · 2024 · DOI

  • While the paper recommends early MMR gene mutation status testing to determine appropriate treatment regimens, it does not provide comprehensive guidance on optimal timing or clinical protocols for implementing such testing in practice.

    Survival of colorectal cancer patients based on mismatch repair gene mutation status · 2024 · DOI

  • The paper identifies significant variation in MSI proportion depending on tumor location (26% right colon, 3% left colon, 1% other locations) but does not fully explain the biological mechanisms underlying these geographic differences within the colorectum.

    Survival of colorectal cancer patients based on mismatch repair gene mutation status · 2024 · DOI

  • The mechanism behind why no prognostic advantage is observed in stage IV colorectal cancer with dMMR/MSI remains speculative, with researchers attributing it to overexpression of immune checkpoint proteins such as PD-1 and CTLA-4, but this lacks definitive explanation.

    Survival of colorectal cancer patients based on mismatch repair gene mutation status · 2024 · DOI

  • Public datasets such as TCGA and cBioPortal include very limited information on germline POT1 vari- ants, precluding robust comparative analyzes.

    Case Report: The revelation of a new pathogenic variant in the POT1 gene in a patient with a pediatric high-grade glioma and a renal cell carcinoma · 2026 · DOI

  • In recent years, increasing research efforts have focused on surveillance for less frequent Lynch syndrome-associated malignancies, however, prospective data from large, well-characterized cohorts remain scarce.

    Optimal upper gastrointestinal surveillance strategies for gastric, small bowel and pancreatic cancer detection in Lynch syndrome · 2026 · DOI

  • Abstract Colorectal carcinoma (CRC) is a common cause of mortality 1 , but a comprehensive description of its genomic landscape is lacking 2–9 .

    The genomic landscape of 2,023 colorectal cancers · 2024 · DOI

  • The document is a review article citing existing studies; it lacks original data collection or prospective cohort studies to validate the claimed survival differences between pMMR and dMMR patient populations across different disease stages.

    Survival of colorectal cancer patients based on mismatch repair gene mutation status · 2024 · DOI

  • The paper discusses side effects of pembrolizumab including pneumonitis, adrenal insufficiency, kidney failure, thyrotoxicosis, colitis, and hepatitis but notes these are rare without providing detailed incidence rates or risk stratification data.

    Survival of colorectal cancer patients based on mismatch repair gene mutation status · 2024 · DOI

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25 open questions have been extracted from the limitations and future-work passages of 171 Genetic factors in colorectal cancer papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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