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Molecular Research: Proteomics | Molecular Research: Gene Identificaiton

Molecular Research: Gene Identification

It is likely that hereditary factors play a role in 17% or more of pancreatic cancers. Ten percent of patients have a familial history and another 7% of apparently “sporadic” pancreatic cancer patients carry a genetic mutation that causes the disease. Kindreds, with 2 or more family members who have been diagnosed with pancreatic cancer and who are first degree relatives, are considered to have familial pancreatic cancer (FPC). Not all patients who carry a mutation in a gene that predisposes to pancreatic cancer will get the disease. The lifetime cancer risk for a gene-carrying individual from a FPC kindred can range from 5% to100%, depending upon the gene inherited and environmental-gene interactions. Smoking is the chief environmental risk factor that influences penetrance of pancreatic cancer in these kindreds. Not only does smoking increase the risk of cancer by >3 fold, but it also decreases the age of onset by approximately 10 years.

Indications for Genetic Testing:
General indications for genetic testing have been proposed by the American Society of Clinical Oncology. The first indication for genetic testing is identification of an individual who has a personal or family history of cancer with features that suggest a genetic predisposition. The second indication is the existence of genetic tests whose results can be adequately interpreted. The third indication is that the test results will influence the management of the patient or at-risk family members.

Findings that Might Suggest a
Genetic Predisposition for Pancreatic Cancer:

• Multiple, closely related family members who have been diagnosed
  with pancreatic cancer (adenocarcinoma).
• Pancreatic cancer in more than one generation of the
  individual's family.
• Clustering of pancreatic and non-pancreatic cancers in family members (especially colon, breast, melanoma, ovarian and uterine).
• Pancreatic cancer diagnosed under the age of 45.

Inherited Syndromes Associated with Pancreatic Cancer:
Inherited pancreatic cancer is may be caused by any one of multiple hereditary syndromes. Therefore, it is important to try and define the syndrome that the family has inherited (Table 1), as this information can affect the clinical management of the patient. Gather information about any cancer in the family (especially melanoma, GI cancers, breast, or genito-urinary cancers). By assessing this information, one can determine whether the pancreatic cancer develops in the context of specific hereditary cancer syndromes such as Hereditary Non-polyposis Colon Cancer (GI cancers and genito-urinary cancers) or due to mutations in specific tumor suppressor genes, such as BRCA2 (breast and ovarian cancers) or p16 (melanoma). Some hereditary causes of pancreatic cancers are not associated with any cancers other than pancreas—in this case the term Familial Pancreatic Cancer (FPC) is applied. FPC is usually autosomal dominant and likely has more than one genetic cause.

Table 1. Cancer Sydromes Associated with Increased Risk of Pancreatic Cancer (PC).
Syndrome	Gene(s)	Lifetime Risk of PC	Locus
Hereditary Breast/Ovarian Cancer	BRCA2	5%	13q
Familial Pancreatic Cancer (FPC)	Palladin and Other Unidentified Genes	Unknown	4q
Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)	CDKN2A	19%	9p
Peutz-Jeghers Syndrome (PJS)	STK11	36%	19p
Familial Adenomatous Polyposis	APC	Unknown	5q
Hereditary Non-Polyposis Colon Cancer	DNA Mismatch Repair Genes	Unknown	2p; 3p

Principles of Genetic Testing:
FWith regard to the inherited pancreatic cancer syndromes, genetic testing could be considered when an individual meets the clinical criteria for FPC, FAMMM, BRCA2, or PJS, or is a relative of someone with a specific genetic defect. Currently, assays are available that detect mutations in the genes responsible for most cases of high-risk, inherited colon cancer syndromes, including FAP, MAP, HNPCC, JPS, and PJS. A list of the commercial and academic sites that currently offer these tests can be found on the GeneTests website.

The likelihood of finding a disease-causing mutation in an index case that meets the clinical criteria for one of the high-risk colon cancer syndromes depends on the disease. Finding a specific genetic mutation in a patient who satisfies the clinical criterion for an inherited cancer syndrome allows other family members to be tested for that same mutation with virtually 100% accuracy. Failure to discover a disease-causing mutation in an index case (or finding a mutation of unknown significance) does not, however, rule out the syndrome in question. Relatives of the proband should not be tested in these cases, as the results are uninformative.

Mutation Analysis:
Genetic testing is performed on DNA isolated froma blood sample. There are several methods that can be used to detect genetic mutations. DNA sequencing is generally the most accurate method, but is also the most expensive. Therefore, it is often combined with other methods that identify mutations and refine the location of DNA to be sequenced.

The test results are generally reported as 1) positive for a disease-causing mutation, or 2) a harmless polymorphism (a change that doesn’t cause disease), or 3) a sequence variation of unknown significance. In the latter case, the result is considered uninformative (a genetic diagnosis can not be made), and management guidelines depend on the patient's clinical findings. It is crucial to bear in mind that the inability to find a disease-causing mutation in the first tested individual of a family does not necessarily signify that the particular syndrome is not present; sometimes a person can carry a genetic mutation that can not be detected by standard methods. In contrast, a negative test result in a member of a family that carries a known mutation indicates that the tested individual does not have the heritable syndrome in question.

Genetic Counseling and Informed Consent:
Patients who are contemplating genetic testing should first meet with a professional genetic counselor. At the meeting, the genetic counselor should take a careful family history, particular attention should be paid to uncovering all cancers in family members, including the age at which the cancers were diagnosed. educate the individual about the syndrome in question, discuss the psychosocial aspects that relate to the disorder, and obtain written informed consent for the test. The informed consent document should contain information that is specific to each genetic test, including the benefits, risks, and limitations of testing, and the meaning of positive, negative, and uninformative results. Patient education about the syndrome should include any screening and surveillance recommendations that are pertinent to the disorder, should the result be positive.

The psychosocial ramifications of a positive (or negative) test result have been well described. A positive result affects many family members, and individuals diagnosed with a hereditary cancer syndrome typically experience some degree of guilt. In addition, patients frequently have concerns in relation to health-insurance discrimination and the confidentiality of medical records and test results.

Clinicians and their patients must also bear in mind that a negative genetic test does not necessarily imply that the inherited colon cancer syndrome is not present. False-negative test results can occur, and the sensitivity of genetic testing varies with the syndrome.

Palladin Gene Testing:
Palladin gene testing might be appropriate for families with 2 or more members with pancreatic cancer. PLEASE NOTE: The test is not yet available for clinical use. Stay tuned for future information regarding this test.