This page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
_What is Hereditary Nonpolyposis Colorectal Cancer (HNPCC)?
Figure 1 shows the colon and common site of polyp development.
_ Colorectal cancer is the second lading cause of
cancer-related death in the United States, with 143,460 cases
diagnosed and 51,690 deaths projected for 2012 [6]. An estimated 5% of all colorectal cancer
cases can be attributed to Hereditary Nonpolyposis Colorectal Cancer. Hereditary Nonpolyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, is an autosomal dominant
inherited syndrome that is characterized by a predisposition to certain cancers,
particularly colon cancer but also extracolonic cancers including carcinomas of
the endometrium, ovary, stomach, small bowel, ureter, and renal pelvis [1-4]. Table 1 below
shows the likelihood of an individual with HNPCC of developing these
cancers and the mean age of onset. Thee prevalence of HNPCC is predicted between 1-in-500 and 1-in-1,000. This means that there are approximately 600,000 mutation carriers within the U.S., and only 5% of those individuals have been diagnosed to date [7].
Table 1 shows the risk of an individual with HNPCC of developing cancers and the mean age of onset for each cancer. Adapted from [3-4].
_What causes HNPCC?
HNPCC has been linked to germline mutations in deoxyribonucleic
acid (DNA) mismatch repair genes. DNA mismatch repair is a system for
recognizing and repairing insertions, deletions and
mis-incorporations of bases that can arise due to imperfect DNA replication and
recombination. DNA mismatch repair mechanism also repair some forms of DNA
damage.
Figure 2.
_To date, mutations in four DNA mismatch repair genes have
been correlated with susceptibility to HNPCC, including mutS homolog 2
(MSH2), mutL homolog 1 (MLH1), mutS homolog 6 (MSH6), and postmeiotic segregation
increased 2 (PMS2). Figure 2
shows the percentage of HNPCC cases caused by mutations in each of
these genes [1-4]. Figure 3 presents the DNA mismatch repair mechanism for DNA repair involving these proteins. The mutS homolog 2 (MSH2) is the focal point of analysis on subsequent pages of this website.
Figure 3 shows the DNA mismatch repair mechanism for DNA repair involving the proteins MSH2, MSH6, MLH1, and PMS2. Adapted from [2].
_
What is the phenotype of HNPCC, how is it
diagnosed, and what treatments are available?
Unlike other predisposing cancer diseases that may have
hundreds of colonic polyps, HNPCC is characterized by the presence of only a
few polyps in the colon. These polyps are usually benign but if left untreated,
they can develop into cancerous tissue. Symptoms usually associated with
colorectal cancer include bloody stools, a change in bowel habit, abdominal
pain, and unintended weight loss. Diagnosis of HNPCC begins with a detailed
family history, which is directed by the Amsterdam Criteria for HNPCC. The
Amsterdam Criteria for HNPCC are described below [2].
Amsterdam
Criteria: At least three relatives with histologically verified colorectal cancer: ·One is a first-degree relative of the other two; ·At least two successive generations affected; ·At least one of the relatives with colorectal
cancer diagnosed at <50 years of age; (Familial adenomatous polyposis (FAP) is excluded)
Figure 4. Adapted from [2].
_
If the
Amsterdam Criteria are met, it is very suggestive that HNPCC is present; a
family history, however, is insufficient to definitively diagnose HNPCC and
further molecular testing is required. The best measures currently available to
defend against HNPCC are preventative ones. Frequent colonoscopy screenings
have proven to be an effective method for identifying colonic tumors and
at-risk pre-cancerous colonic polyps. In recent decades, widespread increases
in the number of individuals getting screened and the frequency of their
screens has begun to decrease the number of deaths due to colon cancer (Figure 4). When an at-risk pre-cancerous colonic polyp is found during a colonoscopy,
it must be subsequently removed to prevent its progression into cancer. The
video below shows a very large colonic polyp being removed.
From YouTube, 2012. Huge Colon Polyp Removal. Retrieved from http://www.youtube.com/watch?v=7RkH82e9JaE&NR=1&feature=fvwp.
_
Furthermore,
when a cancerous tumor is found during a colonoscopy, a common treatment is to
resect the cancerous tissue of the colon (colectomy) and then subsequently treat with
radiotherapy or chemotherapy to eliminate any cancer cells that may have
remained [5].
HNPCC Timeline
Figure 5 shows a timeline of the discovery of HNPCC. Adapted from [3-4].