Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3-5%) of cases arise from hereditary syndromes ...predisposing to early onset CRC as a result of mutations in over a dozen well defined genes. In contrast, CRC is predominantly a late onset 'sporadic' disease, developing in individuals with no obvious hereditary syndrome. In recent years, genome wide association studies have discovered that over 40 genetic regions are associated with weak effects on sporadic CRC, and it has been estimated that increasingly large genome wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies and development of higher throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarising the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC, and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. Subsequently these new insights will lead to improved treatment and prevention of colorectal cancer.
Objectives: Motor neurotization is essential for functional muscle transfer. The aims of this anatomical study were to map the course of the vastus lateralis muscle motor nerve and determine the ...axonal counts of the main trunk and its branches to assess its suitability as a free functional muscle transfer. Methods: Ten cadaveric thighs were dissected. The length of the nerve and its branches were measured, harvested en bloc, and cross-sectioned at its origin and each branch. Their calibers and axonal counts were analyzed. The vastus lateralis muscle was used for a functional muscle transfer in a clinical case of upper lip reconstruction. Results: The branches of the vastus lateralis muscle motor nerve coursed adjacent to the branches of the lateral circumflex femoral artery. Two nerve branching patterns were identified. Type 1 (70%) consisted of two branches, the transverse and descending. Type 2 (30%) consisted of three branches, the transverse, oblique, and descending. The average lengths and axonal counts of the transverse, oblique, and descending branches were 7.1, 6.7, and 15.2 cm and 1021, 545, and 1158, respectively. The average lengths of the accompanying transverse, oblique, and descending branches of the lateral circumflex femoral artery were 5.7, 9.0, and 10.3 cm, respectively. Our clinical case regained muscle function and oral sphincter competency. Conclusions: Three types of muscle segments of the vastus lateralis muscle may be harvested for functional muscle transfer based on the descending (type A), oblique (type B), and transverse (type C) nerve branches. Types A and C have axonal counts matching the buccal branches of the facial nerve. Clinically, type A functional muscle transfer for lip reconstruction was validated.
In this study we aimed to explore the potential biological effect of ethanol exposure on healthy colon epithelial cells using normal human colon 3D organoid "mini-gut" cultures. In numerous published ...studies ethanol use has been shown to be an environmental risk factor for colorectal cancer (CRC) development; however, the influence of ethanol exposure on normal colon epithelial cell biology remains poorly understood. We investigated the potential molecular effects of ethanol exposure in normal colon 3D organoids in a small pilot study (n = 3) using RNA-seq and ATAC-seq. We identify 1965 differentially expressed genes and 2217 differentially accessible regions of chromatin in response to ethanol treatment. Further, by cross-referencing our results with previously published analysis in colorectal cancer cell lines, we have not only validated a number of reported differentially expressed genes, but also identified several novel candidates for future investigation. In summary, our data highlights the potential importance for the use of normal colon 3D organoid models as a novel tool for the investigation of the relationship between the effects of environmental risk factors associated with colorectal cancer and the molecular mechanisms through which they confer this risk.
Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs ...that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk.
Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing.
Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including
(P
= 1.96 × 10
),
(P
= 2.3 × 10
),
(P
= 9.38 × 10
), and
(P
= 1.44 × 10
). There was a significant interaction between expression level of
and regular use of aspirin only on colorectal cancer risk (P
= 3.23 × 10
). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2.
By incorporating functional information, we discovered several novel genes that interacted with NSAID use.
These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.
Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of ...additional susceptibility loci may capture unexplained familial risk.
We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.
The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval CI = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.
This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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