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Genetic factors in colorectal cancer
Research Guide
What is Genetic factors in colorectal cancer?
Genetic factors in colorectal cancer refer to the specific molecular alterations, including mutations in oncogenes, tumor suppressor genes, microsatellite instability, and DNA mismatch repair deficiencies, that drive the development and progression of colorectal tumors.
Research on genetic factors in colorectal cancer encompasses 78,496 works focused on molecular characterization, genetic testing, and hereditary syndromes such as Lynch syndrome and polyposis syndromes. Key studies identify sequential genetic changes like ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18 during tumor progression from adenomas to carcinomas. Vogelstein et al. (1988) demonstrated these alterations in colorectal neoplasia stages.
Topic Hierarchy
Research Sub-Topics
Microsatellite Instability
This sub-topic covers MSI detection methods, its association with colorectal tumors, and prognostic implications. Researchers study MSI-high phenotypes, immune responses, and therapeutic targeting.
DNA Mismatch Repair Deficiency
This sub-topic focuses on MMR gene mutations, deficiency mechanisms, and their role in Lynch syndrome. Researchers investigate repair pathway disruptions, somatic vs. germline alterations, and diagnostic assays.
Lynch Syndrome
This sub-topic examines genetic screening, penetrance estimates, and surveillance strategies for Lynch syndrome carriers. Researchers analyze MLH1/MSH2 mutations, extracolonic risks, and cascade testing.
Familial Adenomatous Polyposis
This sub-topic addresses APC gene variants, polyposis phenotypes, and chemoprevention trials in FAP. Researchers study genotype-phenotype correlations, desmoid tumors, and surgical outcomes.
Molecular Subtyping of Colorectal Cancer
This sub-topic explores CMS classification, consensus molecular subtypes, and their prognostic value. Researchers integrate genomics, transcriptomics, and clinical correlations for personalized therapy.
Why It Matters
Genetic factors enable precise risk assessment and personalized treatment in colorectal cancer management. Mismatch repair deficiency, a key genetic feature, predicts response to PD-1 blockade immunotherapy; Le et al. (2015) showed clinical benefit in tumors with this deficiency using pembrolizumab in a trial (NCT01876511), with mismatch-repair status guiding therapy. Le et al. (2017) extended this to solid tumors beyond colon cancer, where MMR loss-of-function mutations correlated with favorable immunotherapy outcomes in a phase 2 trial. The Cancer Genome Atlas Network (2012) provided comprehensive molecular profiling of colon and rectal cancers, informing targeted adjuvant chemotherapy strategies.
Reading Guide
Where to Start
"A genetic model for colorectal tumorigenesis" by Fearon and Vogelstein (1990) is the starting point, as it provides a foundational framework for understanding sequential genetic changes in colorectal cancer progression, cited 12,006 times.
Key Papers Explained
Fearon and Vogelstein (1990) established the multistep genetic model building on Vogelstein et al. (1988), who detailed specific alterations like ras mutations and chromosomal deletions in tumor stages. The Cancer Genome Atlas Network (2012) extended this with comprehensive molecular subtypes, while Le et al. (2015) and Le et al. (2017) linked mismatch repair deficiency—a feature from these models—to immunotherapy responses. Alexandrov et al. (2013) added mutational signatures contextualizing colorectal changes pan-cancer.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Current research emphasizes integrating mismatch repair testing into routine genetic screening for adjuvant chemotherapy decisions, as informed by Le et al. (2017). Frontiers involve applying pan-cancer insights from Weinstein et al. (2013) to refine Lynch syndrome risk models, though no recent preprints detail new breakthroughs.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 | 2010 | International Journal ... | 21.3K | ✕ |
| 2 | A genetic model for colorectal tumorigenesis | 1990 | Cell | 12.0K | ✕ |
| 3 | Signatures of mutational processes in human cancer | 2013 | Nature | 9.9K | ✓ |
| 4 | PD-1 Blockade in Tumors with Mismatch-Repair Deficiency | 2015 | New England Journal of... | 9.2K | ✓ |
| 5 | The Cancer Genome Atlas Pan-Cancer analysis project | 2013 | Nature Genetics | 9.0K | ✓ |
| 6 | Comprehensive molecular characterization of human colon and re... | 2012 | Nature | 8.5K | ✓ |
| 7 | Design and analysis of randomized clinical trials requiring pr... | 1977 | British Journal of Cancer | 8.4K | ✕ |
| 8 | TGF-β SIGNAL TRANSDUCTION | 1998 | Annual Review of Bioch... | 7.6K | ✕ |
| 9 | Genetic Alterations during Colorectal-Tumor Development | 1988 | New England Journal of... | 6.7K | ✕ |
| 10 | Mismatch repair deficiency predicts response of solid tumors t... | 2017 | Science | 6.4K | ✕ |
Frequently Asked Questions
What genetic alterations occur during colorectal tumor development?
Vogelstein et al. (1988) identified four key genetic changes: ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18 in colorectal adenomas and carcinomas. These alterations accumulate progressively from early to late-stage neoplasia. Fearon and Vogelstein (1990) proposed a genetic model outlining this multistep tumorigenesis process.
How does mismatch repair deficiency affect colorectal cancer treatment?
Mismatch repair deficiency predicts response to PD-1 blockade; Le et al. (2015) found it conferred clinical benefit from pembrolizumab in mismatch-repair-deficient tumors. Le et al. (2017) confirmed this in solid tumors, with MMR mutations enabling immunotherapy success. This guides patient selection for immune checkpoint inhibitors.
What is the role of microsatellite instability in colorectal cancer?
Microsatellite instability arises from DNA mismatch repair deficiencies, a hallmark in hereditary syndromes like Lynch syndrome. The Cancer Genome Atlas Network (2012) characterized this in human colon and rectal cancer molecular profiles. It influences tumor behavior and immunotherapy responsiveness as shown by Le et al. (2015).
What does the genetic model for colorectal tumorigenesis describe?
Fearon and Vogelstein (1990) outlined a model of sequential genetic events leading to colorectal cancer. It builds on earlier findings of specific mutations and deletions by Vogelstein et al. (1988). The model explains progression from benign adenomas to malignant carcinomas.
How has pan-cancer analysis contributed to understanding colorectal cancer genetics?
Weinstein et al. (2013) conducted The Cancer Genome Atlas Pan-Cancer analysis, integrating colorectal cancer data with other tumors. This revealed mutational signatures relevant to colorectal pathogenesis, as in Alexandrov et al. (2013). It supports cross-cancer genetic insights for risk assessment.
What molecular subtypes were identified in colorectal cancer?
The Cancer Genome Atlas Network (2012) performed comprehensive molecular characterization of human colon and rectal cancer, defining subtypes based on genetic profiles. This includes microsatellite instability-high tumors linked to mismatch repair defects. Findings inform hereditary syndrome diagnosis and management.
Open Research Questions
- ? How do specific mutational signatures from Alexandrov et al. (2013) differentiate colorectal cancer subtypes for targeted therapies?
- ? What sequential genetic events beyond those in Fearon and Vogelstein (1990) drive metastasis in mismatch repair-proficient colorectal tumors?
- ? Can mismatch repair status alone predict immunotherapy response across all colorectal cancer stages, as expanded from Le et al. (2015)?
- ? How do pan-cancer patterns from Weinstein et al. (2013) reveal novel hereditary factors in polyposis syndromes?
- ? What role do TGF-β pathway alterations, as in Massagué (1998), play in colorectal tumor progression alongside APC and ras mutations?
Recent Trends
The field maintains steady focus on established genetic markers like microsatellite instability and mismatch repair, with 78,496 works accumulated; growth rate unavailable.
Le et al. reinforced immunotherapy predictions from 2015 findings, sustaining interest in MMR-deficient tumors.
2017No new preprints or news in the last 12 months indicate consolidation of molecular characterization from The Cancer Genome Atlas Network .
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