Monday, June 20, 2011

Genetic Risk Factors for Pancreatic Cancer

Cancer of the pancreas is a genetic disease which means that it is caused by changes (mutations) in DNA. These changes can be inherited (we are born with them) or they can be acquired (they develop after we are born). The inherited changes explain why cancer of the pancreas runs in some families, and the acquired changes can be the result of either bad luck during cell replication or by exposure to carcinogens (cancer causing chemicals) such as those found in cigarette smoke, or unexpected exposure to cancerous substances at job.

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What are the chances a mutated gene is inherited?

Every cell usually has two copies of each gene: one inherited from a person’s mother and one inherited from a person’s father. Most types of hereditary pancreatic cancer follow an autosomal dominant inheritance pattern, in which a mutation needs to happen in only one copy of the gene for the person to have an increased risk of getting the disease. This means that a parent with a gene mutation may pass on a copy of the normal gene or a copy of the gene with a mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A brother, sister, or parent of a person who has a gene mutation also has a 50% chance of having the same mutation.

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A person with an average risk of pancreatic cancer has less than a 1% chance of developing pancreatic cancer sometime during his or her life.

Up to 5% to 10% of pancreatic cancer cases are considered by researchers to be due to a primary genetic factor; in certain families, this is associated with an autosomal dominant pattern of inheritance. So, if you have the confirmed genetic risk for the pancreatic cancer development, your chances are about 10 times higher than for an average person.

The genetic risk factors associated with pancreatic cancer can be divided into three groups: (1) defined genetic syndrome associated with pancreatic cancer, (2) familial clusters of pancreatic cancer with no obvious genetic syndrome, and (3) pancreatic cancer in primary relatives of patients with a non-pancreatic cancer.

Reviewing Family History

While reviewing your family genetic history, it is important to take in consideration both your father’s and your mother’s sides of the family since the affected gene can be inherited from either parent. You may also need to gather data on all types of cancerous diseases in the family, as other cancers may also be associated with hereditary pancreatic cancer.

The European Registry of Hereditary Pancreatic Diseases (EUROPAC) uses the following criteria to identify patients at increased risk:
  • Two or more first-degree relatives (brothers and sisters, parents and children) with pancreatic cancer,
  • At least three relatives of any degree with pancreatic cancer,
  • Any two relatives with pancreatic cancer if the sum of their ages at diagnosis was less than 110 years.

Secondary risk criteria might be considered as follow:
·         One first-degree relative who developed pancreatic cancer before age 50.
·         Two or more second-degree relatives (aunts, uncles, grandparents) on the same side of the family with pancreatic cancer, one of whom developed the cancer at an early age.
·         Family members with confirmed cancer gene mutations or cancer syndromes.

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Gene Mutations, Responsible for Pancreatic Cancer

Familial Pancreatic cancer

Familial pancreatic cancer (FPC) was first described in 1987. The causative mutation remains unknown, although recent work has identified a subset of patients with BRCA2 germline mutation. One of the recent studies of a single large kindred suggested that there is a linked gene on 4q32-q34, and they are currently pursuing candidate genes in this large region.

The National Familial Pancreas Cancer Registry (NFPTR) now contains over 250 families in which two or more family members have had pancreas cancer.

BRCA2 Mutations

The BRCA2 protein product plays a diverse role through its interaction with proteins involved in cell cycle regulation, transcriptional regulation, and DNA repair. Loss of function is thought to lead to chromosomal instability, and carriers of the defective gene have a 26% to 86% increased risk of developing breast cancer. The risk for pancreatic cancer appears to besignificantly lower; in recent studies, germline BRCA2 mutations (mostly 6174delT) were found in approximately 5% of patients with pancreatic cancer who had no family history of pancreatic cancer and in up to 17% in FPC families. In all but two cases, however, the affected individuals were Ashkenazi Jews. Thus there was uncertainty as to the general relevance of these results since the carrier frequency of the 6174delT mutation in the general Ashkenazi population is approximately 1%.

Hereditary breast and ovarian cancer (HBOC) syndrome

HBOC is associated with mutations in the BRCA1 and/or BRCA2 (BRCA stands for BReast CAncer). Women with HBOC have an increased risk of breast cancer and ovarian cancer. Men with HBOC have an increased risk of breast cancer and prostate cancer. People with HBOC also have an increased risk of pancreatic cancer, specifically people who have a mutation on the BRCA2 gene but a BRCA1 mutation may also cause a small increased risk.

Familial Atypical Multiple Mole-Melanoma Syndrome

The familial atypical multiple mole-melanoma (FAMMM) syndrome is a rare hereditary syndrome in which affected family members develop skin moles and melanomas (an aggressive form of skin cancer). These patients also have an increased risk of developing pancreas cancer. Its pathogenesis has been linked to inactivation of the p16INK4A tumor suppresser gene, and carriers have a 2-fold increased risk of pancreatic cancer.

Hereditary Pancreatitis

Hereditary pancreatitis is an autosomal dominant condition characterized by recurrent childhood attacks of acute pancreatitis resulting in the development of chronic pancreatitis in teenage years. Any form of pancreatitis is thought to pose a risk for pancreatic cancer development, ranging from a 15- to 25-fold risk in sporadic chronic pancreatitis to a 70- to 100-fold risk in hereditary pancreatitis.  It is believed that an imbalance in proteases and their inhibitors resulting from genetic mutations leads to autodigestion and inflammation of the pancreas. Two of the key mutations in hereditary pancreatitis are in the PRSS1 gene, resulting in intracellular accumulation of trypsin and autodigestion, and the gene coding for the synthesis of a serine protease inhibitor, Kazal type 1 (SPINK1).

Peutz-Jeghers Syndrome

This is a very rare hereditary syndrome in which affected family members develop polyps in their small intestines and pigmented spots on their lips. These polyps are masses of tissue that protrude from the normal surface of the intestine. It is associated with the development of cancer at multiple sites and has an autosomal dominant pattern of inheritance with a relative risk of pancreatic cancer estimated at 132. The responsible genetic abnormality is mutation of the LKB1/STK11 gene that encodes for serine/threonine kinase with an as yet undefined role.

Hereditary Nonpolyposis Colorectal Carcinoma

Affected individuals of this autosomal dominant condition have an increased risk of colonic and extra-colonic cancers. Caused by mutations in the DNA repair genes HMSH2, HMLH1 and HPMS2 the proportion of familial cancers associated with these mutations appears to be less than p16INK4A and BRCA2, but the exact risk of pancreatic cancer is unknown.

Hereditary colon cancer

The Hereditary Non-polyposis Colorectal Cancer (HNPCC) syndrome strikes as many as 1 in 200 individuals and it is characterized by the inherited predisposition to develop colon cancer, endometrial (uterine) cancer, stomach cancer and ovarian cancer. Patients with HNPCC may also have an increased risk of developing pancreas cancer. Indeed, the DNA finding typical of HNPCC, called microsatellite instability has recently been reported in a small (about 4%) fraction of pancreas cancers.

Ataxia Telangiectasia

Ataxia telangiectasia is an autosomal recessive condition that is associated with the loss of the ATM (ataxia telangiectasia mutated) gene. The protein product has an important role in the cellular response to genetic stress. Although the mechanisms are unclear, ATM induces cell cycle arrest and DNA repair or apoptosis via p53 and p53-independent pathways. Carriers of the mutated gene have an approximately 3-fold relative risk of pancreatic cancer.

Li-Fraumeni Syndrome

Germline mutations in p53 have been described as Li-Fraumeni syndrome an autosomal dominantly inherited condition, which predisposes to several neoplasms. Pancreatic neoplasms however are rare, and the exact risk is unknown due to limited data availability.

Familial Adenomatous Polyposis

Characterized by the appearance of hundreds to thousands of colonic polyps that invariably undergo malignant transformation, familial adenomatous polyposis is an autosomal dominant condition with near complete penetrance. There is an increased risk of extra-colonic malignancy and approximately a 4.5-fold increased risk of pancreatic cancer.



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