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Studies of human genetic differences have usually focused on the individual base pair changes in a DNA sequence, but the genetic differences between humans amounts to more than simple "spelling errors." Structural changes such as insertions, duplications, deletions and inversions of DNA are fairly common in the human population. Genes were thought to always occur in two copies per genome, but in some cases have now been found to be present in one, three, or more copies, or missing altogether. This CNV (Copy Number Variation) corresponds to relatively large regions of the genome that have been deleted or amplified on certain chromosomes (Figure:1). CNVs may either be inherited or caused by a de novo mutation.
Figure 1: Structural variation affects ~5% of the human genome and most people have about 400 kb of structurally variant sequence. Some Regions of the genome are prone to structural variation because they are flanked by highly homologous regions called segmental duplications.
Colorectal cancer is the third leading cancer cause and represents the final stage of a progressive, multi-step, carcinogenic process of evolution through an adenoma stage . The average age range of colon cancer diagnosis in untreated individuals is 34-43 years. Colorectal cancers arise from mushroom-shaped growths called adenomatous polpys in the colon. These growths are usually benign, but some develop into cancer over time. Localized colon cancer is usually diagnosed through a colonoscopy and removing colorectal adenomas significantly decreases cancer risk [2, 3]. Colon cancer has four distinct stages that are characterized by different traits including size of a tumor (Figure:2), how deeply it has penetrated, whether it has invaded adjacent organs, and how many lymph nodes it has metachronized.
One-third of colorectal cancers occur in familial cluster and increase risk to family members , however most causative genetic factors are unknown. Here we seek genetic factors associated with metachronous adenoma occurrence, hypothesizing that genetic risk factors have been missed because association studies have sought risk-associated single nucleotide polymorphisms, while ignoring structural variation causing gene copy number changes.
Figure 2: Different stages of colon cancer
Familia Aadenomatous polyposis (FAP) - a colon cancer predisposition syndrome, caused by a mutation in the APC gene in which hundreds to thousands of precancerous colonic polyps begin developing on average at age 16 years. By the age of 35, 95% of individuals with FAP have polyps and without colectomy, colon cancer is inevitable.
Hereditary non-polyposis colon cancer (HNPCC) - caused by a germline mutation of a mismatch repair gene, and is characterized by an increased risk of colon cancer and other cancers. Individuals with HNPCC have an approximately 80% lifetime risk for colon cancer.
Cowden (CS) - have a high risk of forming benign and malignant tumors of the thyroid, breast and endometrium. The lifetime risk of developing breast cancer is 25%-50%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer is around 10% and risk for endometrial cancer is about 5%-10%.