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Open research questions in Genetic factors in colorectal cancer

127 unresolved questions extracted from the limitations and future-work sections of 260 Genetic factors in colorectal cancer papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The paper does not explicitly state the research gap. The study aims to understand the characteristics of mucinous adenocarcinoma. The paper highlights the need for molecular and survival data to understand prognosis.

    Clinical and pathological characteristics of mucinous adenocarcinoma in colon cancer: comparison with classic adenocarcinoma · 2026 · DOI

  • One challenge is the limited activity of immune checkpoint inhibitors in testicular germ cell tumors due to low tumor mutational burden and immunologically cold tumor microenvironments. Another challenge is the discordance between germline Lynch syndrome and tumor-level biomarkers in non-Lynch spectrum malignancies.

    When Lynch syndrome is not MSI-H: embryonal testicular carcinoma treated with combined BEP chemotherapy and immunotherapy despite MSS/low TMB: a case report · 2026 · DOI

  • Limited guidance for incorporating precision oncology approaches in patients with hereditary cancer syndromes, - Germline Lynch syndrome does not uniformly predict tumor MSI-H/dMMR status, - Small sample size (single case report)

    When Lynch syndrome is not MSI-H: embryonal testicular carcinoma treated with combined BEP chemotherapy and immunotherapy despite MSS/low TMB: a case report · 2026 · DOI

  • However, whether antigen-independent mechanisms contribute to immune evasion in MSS colorectal cancer remains unclear.

    Mismatch Repair–Proficient Colorectal Cancer Can Evade Immune Surveillance through an Intrinsic Suppressive Program · 2026 · DOI

  • Although elevated PAXX expression has been reported in colon cancer, its functional role and downstream mechanisms in colorectal cancer (CRC) remain incompletely defined.

    Integrated multi-omics analyses reveal the role of PAXX in colorectal cancer progression and the tumor immune microenvironment · 2026 · DOI

  • The incidence and spectrum of somatic and pathogenic germline variants (PGV) in this population are not well understood.

    Genomic Landscapes of Early-Onset Versus Average-Onset Colorectal Cancer Populations · 2025 · DOI

  • Abstract Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive.

    Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses · 2024 · DOI

  • BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers.

    Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques · 2024 · DOI

  • Importance: Among patients with metastatic colorectal cancer (mCRC), data are limited on disparate biomarker testing and its association with clinical outcomes on a national scale.

    Biomarker Testing Disparities in Metastatic Colorectal Cancer · 2024 · DOI

  • Delayed diagnosis due to nonspecific symptoms and low clinical suspicion. Limited access to molecular testing and timely diagnostic pathways. Lack of data on colorectal cancer in children, particularly in low-resource settings.

    Signet-ring cell colon carcinoma in a Northern Ghanaian child: a case report · 2026 · DOI

  • There is a lack of data on colorectal cancer in children, particularly in low-resource settings. The available evidence does not yet support a confirmed epidemiologic trend, highlighting the need to strengthen regional cancer registries and systematic reporting.

    Signet-ring cell colon carcinoma in a Northern Ghanaian child: a case report · 2026 · DOI

  • The co-occurrence of MSI-H/dMMR and BRAF V600E creates a complex biological landscape that is not well understood. There is a need for effective treatment strategies for patients with MSI-H and BRAF V600E co-mutated mCRC.

    Durable complete response to pembrolizumab after BRAF/MEK inhibition in recurrent MSI-H/dMMR, BRAF V600E–mutant colon cancer: a case report · 2026 · DOI

  • Current gene expression profiles for identifying LNM are generic and do not account for tumour location and mismatch repair status. There is a need for more accurate and personalized gene expression profiles for clinical translation.

    Tumour location and mismatch repair status impact gene expression profiles associated with lymph node metastases in T1 colon cancers · 2026 · DOI

  • Further studies are needed to evaluate the effectiveness of surveillance strategies for gastric, small bowel, and pancreatic cancers in Lynch syndrome carriers. Research is needed to quantify the natural history of gastric precursor lesions in PV carriers. The development of AI-assisted endoscopy and other emerging technologies may enhance surveillance strategies in the future.

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

  • There is a lack of robust data demonstrating an impact of EGD surveillance on clinically meaningful outcomes. The natural history of gastric precursor lesions has not been well quantified in PV carriers. Comprehensive cost-effectiveness analyses remain scarce, particularly outside selected high-risk subgroups.

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

  • Balancing maternal tumor control, fetal safety, and genetic considerations. Managing LS-associated rectal cancer during pregnancy with limited evidence on comprehensive multidisciplinary management. Achieving significant tumor regression while minimizing fetal and genetic risks.

    Management of locally advanced lynch syndrome rectal cancer during pregnancy with neoadjuvant immunochemotherapy: a case report · 2026 · DOI

  • There is a lack of evidence on the management of LS-associated rectal cancer during pregnancy. Current literature mainly focuses on diagnostic delay and surgical timing, with limited evidence on comprehensive multidisciplinary management.

    Management of locally advanced lynch syndrome rectal cancer during pregnancy with neoadjuvant immunochemotherapy: a case report · 2026 · DOI

  • The drivers or biomarkers of LS benign colon tissue approaching malignant CRC are not completely understood. The molecular and cellular changes during malignant transition in LS are not well understood.

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

  • The prevalence of POT1-TPD is unknown. The clinical spectrum of POT1-associated tumors is not fully understood.

    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

  • Due to limited sample size, regression analyses were not performed for some treatment combination, - Patients who died within 90 days of diagnosis were excluded to minimize immortal-time bias, - The study was exempt from Institutional Review Board approval because the data were deidentified

    Prognostic and Treatment-Associated Survival Effects of Microsatellite Instability Across Disease Stages in Colon Cancer: An NCDB Analysis · 2026 · DOI

  • The stage-specific prognostic value of MSI in colon cancer is not well understood. The treatment-modifying role of MSI in colon cancer is not fully defined. There is a need for large-scale studies to evaluate the association between MSI status and overall survival in colon cancer patients.

    Prognostic and Treatment-Associated Survival Effects of Microsatellite Instability Across Disease Stages in Colon Cancer: An NCDB Analysis · 2026 · DOI

  • Further studies are needed to confirm the findings and explore the underlying mechanisms. Research should focus on identifying biomarkers to predict response to adjuvant chemotherapy. Studies should investigate the optimal treatment strategies for patients with high-risk stage II colon cancer harboring dMMR or MSI-H status.

    The Role of Adjuvant Chemotherapy in High-Risk Stage II Colon Cancer with Microsatellite Instability-High or DNA Mismatch Repair Deficiencies: A Multicenter Pooled Analysis (KCSG-CO24-03) · 2026 · DOI

  • Future studies can investigate the use of other LLMs or machine learning models for MSI prediction. Future studies can evaluate the performance of LLMs in predicting MSI status from different types of cancer. Future studies can investigate the use of LLMs in combination with other diagnostic tools for MSI prediction.

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

  • The ability of LLMs to infer molecular genotype from text-based morphologic descriptions remains underexplored. The study addresses the gap by evaluating the performance of two LLMs in predicting MSI status from colorectal carcinoma reports.

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

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127 open questions have been extracted from the limitations and future-work passages of 260 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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