May 21, 2024

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MIT | Harvard found the new gene mutation associated with colorectal cancer

MIT | Harvard found the new gene mutation associated with colorectal cancer



 

MIT | Harvard found the new gene mutation associated with colorectal cancer

 

On Aug. 01, a research team led by Po-Ru Loh and Ronen E. Mukamel of Harvard Medical School , and Steven A. McCarroll and Robert E. Handsaker of the Broad Institute of MIT-Harvard University published a blockbuster study in the top journal “Cell” [1].

 

They analyzed genome-wide and phenotypic data from 418,136 participants in the UK Biobank (UKB) and 838 participants in the GTEx database and found two important non-coding variable-number tandem repeats (VNTRs), one located in TMCO1 An intron and another downstream of EIF3H were associated with a more than 2-fold increased risk of glaucoma and colorectal cancer, respectively .

 

According to the researchers’ statistics, among all common genetic variations known so far, these two VNTRs contribute the greatest genetic power to the occurrence of glaucoma and colorectal cancer .

More importantly, these results suggest that non-coding VNTRs play a previously unrecognized role in human health. Put simply, this research promises to open new doors in our understanding of diseases like cancer.

 

MIT | Harvard found the new gene mutation associated with colorectal cancer

Screenshot of paper homepage

 

As can be seen from the name, variable number tandem repeats (VNTRs) are composed of nucleotide sequences repeated several to hundreds of times in series.

Since the size of VNTRs varies from person to person, the relationship between VNTRs and human phenotypes has been difficult to study due to the limitation of sequencing technology.

 

In recent years, the advancement of technology and the improvement of research methods have made it possible to study the relationship between VNTRs and phenotypes. Just two years ago, Loh’s team found, based on exome sequencing data, that codable VNTRs were the strongest known genetic basis for different phenotypes such as height, serum urea, and curly hair [2], and related research results were published in Top journal “Science”.

This time, they wanted to explore the role of non-coding and codable VNTRs in shaping human phenotype and gene expression based on whole-genome sequencing data.

 

By analyzing part of the data in the human reference genome and the Human Genome Structural Variation Consortium (HGSVC), Loh’s team identified 9561 VNTRs for subsequent analysis.

They first called the data of 118 neurodevelopmental phenotypes in Simons Simplex Collection (SSC), the largest autism database so far, and 118 neurodevelopmental phenotypes in UKB .

Common neurodevelopmental disorders, including Alzheimer’s disease, have limited impact .

 

Subsequently, they focused their research on non-coding VNTRs, and screened three VNTRs with particularly strong phenotype correlation, which were located in the intron of TMCO1, downstream of EIF3H and intron of CUL4A .

 

MIT | Harvard found the new gene mutation associated with colorectal cancer

Location of VNTRs associated with different traits

 

Let’s first look at the VNTR downstream of EIF3H , which is related to intestinal cancer.

 

Loh’s team believes that from a genetic point of view, colorectal cancer is a complex disease, and more than 100 common risk loci have been found so far, but these have a weak impact on the risk of colorectal cancer (OR<1.2) [3].

 

In contrast, approximately 20 kb downstream of EIF3H , a 27-bp repeat sequence (usually 2-6 repeat units) is strongly associated with the risk of colorectal cancer and colonic polyps .

Compared with any common SNP or insertion/deletion mutation in the genome associated with bowel cancer, the longest VNTR (6 repeat units) was associated with the most increased risk of colorectal cancer (OR = 1.34) .

By comparison, they found that the explanatory power of this locus ranked first among all colorectal cancer-related loci on a genome-wide scale.

 

Of note, bowel cancer and polyp risk increased linearly with VNTR length, with each additional repeat unit associated with a 14% (11%–17%) increase in bowel cancer risk and a 9% (7%–17%) increase in bowel polyp risk. 10%) .

Moreover, the effects of the two alleles are additive , and the VNTR downstream of EIF3H can lead to more than 2-fold increase in the risk of colorectal cancer in different individuals .

 

In addition, Loh’s team also found that in this UK cohort, VNTR downstream of EIF3H contributed 20% of the power to the heritability of UK bowel cancer patients .

If the VNTR downstream of EIF3H is included in the multigene prediction analysis of bowel cancer risk, the accuracy can be increased by 25% .

 

MIT | Harvard found the new gene mutation associated with colorectal cancer

The relationship between EIF3H downstream VNTR and intestinal cancer

 

From the findings of Loh’s team, VNTR in the TMCO1 intron is more strongly associated with glaucoma risk than any other relevant SNP or insertion/deletion mutation .

Specifically, compared with individuals without repeat expansion, individuals homozygous for a long VNTR had a more than 2-fold increased risk of developing glaucoma (OR = 2.27) .

 

As for the molecular mechanism that these two non-coding VNTRs are closely related to the disease, Loh’s team did not find it .

Taking the relationship between VNTR downstream of EIF3H and intestinal cancer as an example, VNTR downstream of EIF3H did not have any effect on the expression of nearby and distant genes.

This requires scientists to explore the specific mechanism of these non-coding VNTRs to promote cancer in follow-up studies.

However, in this study, Loh’s team found that VNTR can affect gene splicing through several different mechanisms .

 

In general, the research results of Loh et al. let us realize that non-coding VNTR has an important impact on human health and is closely related to the occurrence of diseases such as cancer.

This discovery not only gives us a new understanding of the occurrence of cancer and other diseases, but also the mechanism research based on this is expected to discover new targets for the treatment of cancer and other diseases.

 

 

 

 

 

 

 

 

 

references:

[1].Mukamel et al., Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer, Cell, 2023, https://doi.org/10.1016/j.cell.2023.07.002

[2].Mukamel RE, Handsaker RE, Sherman MA, et al. Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science. 2021;373(6562):1499-1505. doi:10.1126/science.abg8289

[3]. Huyghe JR, Bien SA, Harrison TA, et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2019;51(1):76-87. doi:10.1038/s41588-018- 0286-6

MIT | Harvard found the new gene mutation associated with colorectal cancer

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