Colorectal cancer, depression and genes

Bowel cancer or colorectal cancer patients experience depression before and for next 2 years after surgery.

The Colorectal Wellbeing (CREW) study follows more than 1,000 people with colorectal cancer from before their surgery until five years afterwards. Results showed that people with colorectal cancer saw a reduction in affection, social interaction and practical and emotional support after surgery – and for up to two years afterwards.

 Even more worryingly, those that lacked social support, such as having someone to talk to or help with practical tasks like household chores, were at a greater risk of a poor quality of life. For example, at diagnosis, 5% patients said they had little or no affection. Two years after diagnosis, this had almost trebled to 13%.

Inflammatory bowel disease

People with inflammatory bowel disease (ulcerative colitis and Crohn’s disease) are at increased risk of colon cancer.[20] The risk increases the longer a person has the disease,[21] and the worse the severity of inflammation.[22] In these high risk groups, both prevention with aspirin and regular colonoscopies are recommended.[21]People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly.[22] In those with Crohn’s disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years.[22] In those with ulcerative colitis approximately 16% develop either a cancer precursor or cancer of the colon over 30 years.[22]

Genetics

Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer.[15] Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome,[23] and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases.[24] A total proctocolectomy may be recommended for people with FAP as a preventative measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventative measure because of the high risk of rectal cancer if the rectum remains.[25]

Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic disease, metastasis associated in colon cancer 1 (MACC1), has been isolated.[26] It is a transcriptional factor that influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion and scattering of colon cancer cells in cell culture, and tumor growth and metastasis in mice. MACC1 may be a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies.[27]

Epigenetic factors, such as abnormal DNA methylation of tumor suppressor promoters play a role in the development of colorectal cancer.[28]

Pathogenesis

Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that increase signaling activity. The mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell.[29][30][31]The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein prevents the accumulation of β-cateninprotein. Without APC, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of proto-oncogenes. These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in other genes with function similar to APC such as AXIN1, AXIN2, TCF7L2, or NKD1.[32]

Beyond the defects in the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is mutated instead.[32]

Genes

According to The Cancer Genome Atlas Network, 16% of all CRC have been identified as hypermutated and among these, APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, TCF7L2 and NRAS were found to be the most frequently mutated genes. Moreover, CTNNB1 (β-catenin), SMAD2, FAM123B and SOX9 genes have also been found often mutated in CRC. Recent large scale sequencing analyses also have highlighted the predominance of large number of CRC patients carrying sequence variants in proteins involved in Wnt signaling pathway.

Identification of sequence variants in genes has advanced our understanding of how cancer develops, progresses and how these sequence variants can be targeted for a cure.

http://colonatlas.org/


TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours1, 2. A tremendous effort has been made to restore p53 activity in cancer therapies3, 4, 5, 6, 7. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin8, 9. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity10. However, we found that α-amanitin-based antibody–drug conjugates are highly effective therapeutic agents with reduced toxicity11. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.

http://www.nature.com/nature/journal/v520/n7549/full/nature14418.html


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https://clubalthea.com/2016/10/14/your-complete-dna-sequence-will-help-shape-the-future-of-medicine/

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connie dello buono

Health educator, author and enterpreneur motherhealth@gmail.com or conniedbuono@gmail.com ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at www.clubalthea.com Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at quora.com and posts in this site.

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