MEDICAL POLICY POLICY TITLE
GENETIC TESTING FOR INHERITED SUSCEPTIBILITY TO COLON CANCER
POLICY NUMBER
MP-2.213
Original Issue Date (Created):
July 1, 2002
Most Recent Review Date (Revised):
December 18, 2007
Effective Date:
July 31, 2008- RETIRED
I.
DESCRIPTION/BACKGROUND There are currently two well-defined types of hereditary colorectal cancer: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome). FAP is typically apparent by age ten (10). If left untreated, all affected individuals will go on to develop colorectal cancer. FAP accounts for one percent (1%) of colorectal cancer and may be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina, referred to as Gardner's syndrome. FAP is identified by the appearance of characteristic polyps. HNPCC is estimated to account for three percent (3%) to five percent (5%) of colorectal cancers and is also associated with an increased risk of other cancers such as endometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell cancer of renal pelvis or ureters. The lifetime risk of developing colorectal cancer in patients with certain HNPCC gene mutations is approximately eighty percent (80%). The identification of HNPCC is based primarily on a very strong family history of colon cancer. Several organizations have established criteria that must be met in order to suspect a diagnosis of HNPCC based on family history. Two of the most common genetic tests for inherited susceptibility to colon cancer include testing to determine the carrier status of the adenosis polyposis coli gene (APC) and testing to determine the carrier status of the HNPCC gene. HNPCC is associated with mutations in one (1) of five (5) different genes, located on chromosomes two (2), three (3), or seven (7). These genes are known as MLH1, MSH2, PMS1, PMS2, and MSH6; all of the genes are involved in DNA mismatch repair (MMR) mechanisms. The majority of HNPCC patients have mutations in either hMLH1 or hMSH2. As a result, sequencing for MMR gene mutations in suspected HNPCC families is usually limited to MLH1 and MSH2. HNPCC genetic mutations may also be detected by examination of tumor tissue. Two tests called Microsatellite Instability testing (MSI) and immunochemistry (IHC) staining assist in identifying tissue changes which increase the likelihood that an HNPCC gene mutation is involved. If these tissue tests are negative or inconclusive, the likelihood that the cancer Page 1 [Note: Final page is signature page and is kept on file, but not issued with Policy.]
MEDICAL POLICY POLICY TITLE
GENETIC TESTING FOR INHERITED SUSCEPTIBILITY TO COLON CANCER
POLICY NUMBER
MP-2.213
is related to a HNPCC gene mutation is extremely small. Therefore, continued genetic testing of the affected individual or family members is not indicated. If the MSI or IHC test is positive, then the affected individual should be further tested for hMLH1 and hMSH2 mutations. If one or more of these are found, testing should progress to selected family members. If the MSI or IHC test is positive, but no HNPCC genetic mutations are found, additional genetic testing of family members is not warranted. Genetic testing involves a blood test, which is sent to a lab where DNA is extracted from the white blood cells. DNA sequencing is then carried out where gene mutations can be identified. Genetic testing is most reliable when there is a known gene mutation in the family that can be used for comparison. In the absence of such a comparison, a positive finding of an isolated gene mutation is inconclusive. II.
DEFINITIONS ADENOMA is a benign tumor made of epithelial cells, usually arranged like a gland. FAMILIAL ADENOMATOUS POLYPOSIS is an inherited disorder characterized by the development of myriad polyps in the colon beginning in late adolescence or early adulthood. Untreated, the condition leads to colon cancer. FIRST-DEGREE RELATIVE refers to a parent, sibling or child. LYNCH SYNDROME is a hereditary predisposition to nonpolyposis colorectal cancer and other solid tumors. METACHRONOUS means not synchronous; multiple separate occurrences, such as multiple primary cancers developing at intervals. OSTEOMA refers to a benign bony tumor. PHENOTYPE is the expression of genes present in an individual. This may be directly observable (e.g. eye color) or apparent only with specific tests (e.g. blood type). SECOND-DEGREE RELATIVE refers to an aunt, uncle, niece, nephew, or grandparent. SYNCHRONOUS refers to occurring at the same time. THIRD-DEGREE RELATIVE refers to a great aunt/uncle, first cousin or great grandmother/grandfather.
Page 2 [Note: Final page is signature page and is kept on file, but not issued with Policy.]
MEDICAL POLICY POLICY TITLE
GENETIC TESTING FOR INHERITED SUSCEPTIBILITY TO COLON CANCER
POLICY NUMBER
MP-2.213
III.
POLICY Genetic testing to determine carrier status of the adenomatous polyposis coli gene (APC) may be considered medically necessary in the following subjects: Patients with greater than 20 colonic polyps; OR In first-degree relatives (i.e., siblings, parents, offspring) of patients diagnosed with familial adenomatous polyposis (FAP). Genetic testing to determine the carrier status of the HNPCC gene may be considered medically necessary in patients with a history of colorectal cancer who meet either the Amsterdam II or revised Bethesda criteria, as described below: Amsterdam II criteria (patients must meet all of the following): Three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND HNPCC-associated cancer involving at least 2 generations; AND Cancer in 1 or more affected relatives diagnosed before 50 years of age; AND Familial adenomatous polyposis excluded in any cases of colorectal cancer. Modifications allow for small HNPCC families: these families must have 2 colorectal cancers in first-degree relatives involving at least 2 generations, with at least 1 individual diagnosed by age 55. Revised Bethesda criteria (patients may meet any of the following):
Individuals diagnosed with colorectal cancer before age 50; OR
Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age. (Hereditary nonpolyposis colorectal cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors (usually glioblastoma as seen in Turcot syndrome), sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel); OR
Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR
Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age
