Clinicopathologic and Genetic Studies of the Lynch Syndromes and Familial Nonpolyposis Colorectal Cancer: An Update with Screening Recommendations1

Colorectal cancer (CRC) lymph node metastases are common but their genetics and the mechanism whereby these metastases occur are not well understood. Here we present recent data regarding genetic heterogeneity in primary CRCs and their metastasis. In addition, we explain the different potential models describing the mechanisms of metastasis and the data supporting them. Multiple studies have also revealed a variety of prognostic molecular markers that are associated with lymph node metastasis in CRC. A better understanding of genetic heterogeneity and the mechanisms of metastasis is critical to predicting clinical response and resistance to targeted therapy.

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A New Polygenic Model for Nonfamilial Colorectal Cancer Inheritance Based on the Genetic Architecture of the Azoxymethane-Induced Mouse Model

Genetics ◽

10.1534/genetics.119.302833 ◽

2019 ◽

Vol 214 (3) ◽

pp. 691-702

Author(s):

Anika C. Bissahoyo ◽

Yuying Xie ◽

Lynda Yang ◽

R. Scott Pearsall ◽

Daekee Lee ◽

...

Keyword(s):

Colorectal Cancer ◽

Mouse Model ◽

Genetic Architecture ◽

Inbred Strains ◽

Genome Wide Association ◽

Polygenic Resistance ◽

Genetic Studies ◽

Polygenic Model ◽

Genome Wide ◽

Dominant Characteristic

The azoxymethane model of colorectal cancer (CRC) was used to gain insights into the genetic heterogeneity of nonfamilial CRC. We observed significant differences in susceptibility parameters across 40 mouse inbred strains, with 6 new and 18 of 24 previously identified mouse CRC modifier alleles detected using genome-wide association analysis. Tumor incidence varied in F1 as well as intercrosses and backcrosses between resistant and susceptible strains. Analysis of inheritance patterns indicates that resistance to CRC development is inherited as a dominant characteristic genome-wide, and that susceptibility appears to occur in individuals lacking a large-effect, or sufficient numbers of small-effect, polygenic resistance alleles. Our results suggest a new polygenic model for inheritance of nonfamilial CRC, and that genetic studies in humans aimed at identifying individuals with elevated susceptibility should be pursued through the lens of absence of dominant resistance alleles rather than for the presence of susceptibility alleles.

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Clinical Applications of Genetic Studies in Hereditary Colorectal Cancer

Hereditary Cancer ◽

10.1159/000425574 ◽

2015 ◽

pp. 173-190

Author(s):

Shozo Baba

Keyword(s):

Colorectal Cancer ◽

Clinical Applications ◽

Hereditary Colorectal Cancer ◽

Genetic Studies

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Genetic Studies of Colorectal Cancer

Critical Reviews™ in Oncogenesis ◽

10.1615/critrevoncog.v13.i2.40 ◽

2007 ◽

Vol 13 (2) ◽

pp. 185-187

Author(s):

Johanna Skoglund

Keyword(s):

Colorectal Cancer ◽

Genetic Studies

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Precancerous Lesions in Colorectal Cancer

Gastroenterology Research and Practice ◽

10.1155/2013/457901 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Fayez Sandouk ◽

Feras Al Jerf ◽

M. H. D. Bassel Al-Halabi

Keyword(s):

Colorectal Cancer ◽

Precancerous Lesions ◽

Middle Eastern ◽

Age Distribution ◽

The West ◽

Genetic Studies ◽

Common Cause ◽

The Third ◽

The World ◽

Surveillance Programs

Colorectal cancer (CRC) is the third most common cause of cancer death in the world. The incidence rate (ASR) and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE) and North America and Europe for many reasons. However, in all areas, “CRC” is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families.

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A third Notch in colorectal cancer progression and metastasis

Journal of Experimental Medicine ◽

10.1084/jem.20201017 ◽

2020 ◽

Vol 217 (10) ◽

Author(s):

Ute Koch ◽

Freddy Radtke

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Lymph Node ◽

Cancer Progression ◽

Molecular Subtype ◽

Tumor Staging ◽

Bioinformatic Analysis ◽

Genetic Studies ◽

Colorectal Cancer Progression ◽

Consensus Molecular Subtype

In this issue of JEM, Varga et al. (https://doi.org/10.1084/jem.20191515) describe a mouse model of invasive and metastatic colorectal cancer (CRC) closely resembling the human consensus molecular subtype (CMS) 4 associated with the poorest overall survival of the four CMSs. Transcriptomic and bioinformatic analysis combined with pharmacological and genetic studies identified Notch3 as a promoter of tumor progression and metastasis. NOTCH3 expression was up-regulated in CMS4 CRC patients and associated with tumor staging, lymph node and distant metastasis. These findings feature NOTCH3 as putative therapeutic target for advanced CMS4 CRC patients.

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