Sunday, June 24, 2012

Increased Jewish Risk of Pancreatic Cancer


Medical research experts have discovered that some groups are at greater risk of "familial pancreatic cancer" than the general population. For years it has been known that pancreatic cancer is more common in Jews than in the general population. This increased risk is greater in Ashkenazi Jews (those of European origin) than it is in Sephardic Jews (those of Asian or African descent). While this increased risk could be due to a variety of factors such as diet and cigarette smoking, a growing body of evidence suggests that a significant portion of the increased risk of pancreatic cancer in individuals of Ashkenazi Jewish descent has a genetic basis. By this we mean that these cancers are caused by inherited ("germline") changes ("mutations") in specific cancer associated genes.

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Most causes of this increased risk are unclear; however a portion of this increased risk is due to mutations in the BRCA2 and BRCA1 genes.

BRCA2

Since its discovery in December of 1995, researchers have come to a better understanding of the role of the BRCA2 gene in the development of cancer. Every cell in our body has two copies of BRCA2. One is inherited from our mother and one from our father. It turns out that an ancestor of Eastern European Jews, approximately 29 generations or 3000 years ago, developed a defect in the DNA coding for the BRCA2 gene. This DNA defect, known as the 6174delT mutation, has been passed from generation to generation. As a result, 1% of all Ashkenazi Jews living now inherit a defective copy of one of their BRCA2 genes. Unbeknownst to them, these carriers of the BRCA2 mutation are at increased risk for developing breast, ovarian, prostate and pancreatic cancer.

The risk of cancer to Jews who inherit a defective copy of the BRCA2 gene varies in different families. The reason for this variation in risk is thought to be dependent on "lifestyle factors" such as smoking, dietary influences, the inheritance of other cancer susceptibility genes, and a certain element of chance. In addition, because the risk of cancer in a BRCA2 mutation carrier continues throughout life, we will see more cancers caused by inherited BRCA2 mutations as our population ages.

While most attention in the media has been given to the risk of breast and ovarian cancer, carriers of the BRCA2 gene mutations also have a ten-fold increased risk of developing pancreatic cancer. Current evidence suggests that in Jewish individuals who develop pancreatic cancer approximately 1 in 10 such cancers are caused by inherited BRCA2 gene mutations. In other words, carriers of BRCA2 mutations have a 1 in ten to 1 in 20 chance of developing pancreatic cancer by the age of 80.

One striking feature of carriers of mutations of the BRCA2 gene is that they may not suspect that they are carriers because they may not have a family history of cancer, despite the fact that their ancestors on one side of their family must also have carried the same mutation. There are many reasons for this subtlety. Not every individual with an inherited BRCA2 gene mutation will develop cancer. As mentioned above other genetic and environmental factors influence the risk of developing cancer. A small family size or early death from other causes may also obscure a familial cancer predisposition. In addition, males with BRCA2 mutations may have a lower risk of developing cancer and they may therefore obscure a familial cancer predisposition. Clearly, the absence of a family history of cancer does not mean that one does not carry the BRCA2 gene mutation.

BRCA1

The first breast cancer gene to be discovered is called BRCA1, and inherited (germline) mutations in BRCA1 increase the risk of breast, ovarian, uterus, cervix, pancreatic, and maybe prostate cancer. Approximately one and a half percent of Ashkenazi Jews carry an inherited mutation in the BRCA1 gene. These mutations are usually one of two types, called the 185delAG and the 5382insC mutations. The increased risk of pancreatic cancer associated with inherited BRCA1 mutations is estimated to be about two-fold (about the same increased risk associated with cigarette smoking).

As was true for BRCA2 mutations, the risk of cancer to Jews who inherit a defective copy of the BRCA1 gene varies in different families. The reason for this variation in risk is thought to be dependent on "lifestyle factors" such as smoking, dietary influences, the inheritance of other cancer susceptibility genes, and a certain element of chance.

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Ethnicity Specifics – Ashkenazi Jews

In an ethnic sense, an Ashkenazi Jew is one whose ancestry can be traced to the Jews of Central and Eastern Europe. For roughly a thousand years, the Ashkenazim were a reproductively isolated population in Europe, despite living in many countries, with little inflow or outflow from migration, conversion, or intermarriage with other groups, including other Jews. Human geneticists have identified genetic variations that have high frequencies among Ashkenazi Jews, but not in the general European population. This is true for patrilineal markers (Y-chromosome haplotypes) as well as for matrilineal markers (mitotypes).

Since the middle of the 20th century, many Ashkenazi Jews have intermarried, both with members of other Jewish communities and with people of other nations and faiths, while some Jews have also adopted children from other ethnic groups or parts of the world and raised them as Jews. Conversion to Judaism, rare for nearly 2,000 years, has become more common.

A 2006 study found Ashkenazi Jews to be a clear, relatively homogeneous genetic subgroup. Strikingly, regardless of the place of origin, Ashkenazi Jews can be grouped in the same genetic cohort — that is, regardless of whether an Ashkenazi Jew's ancestors came from Poland, Russia, Hungary, Lithuania, or any other place with a historical Jewish population, they belong to the same ethnic group. The research demonstrates the endogamy of the Jewish population in Europe and lends further credence to the idea of Ashkenazi Jews as an ethnic group. Moreover, though intermarriage among Jews of Ashkenazi descent has become increasingly more common, many Haredi Jews, particularly members of Hasidic or Hareidi sects, continue to marry exclusively fellow Ashkenazi Jews. This trend keeps Ashkenazi genes prevalent and also helps researchers further study the genes of Ashkenazi Jews with relative ease. It is noteworthy that these Haredi Jews often have extremely large families

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Other Genetic Disorders of Ashkenazi Jews

As any other ethnic group substantially isolated by geographic, religious, or other barriers, Ashkenazi Jews can be characterized by increased risk of multiple genetics related disorders, and higher cancer risk is just one of the theoretical implications. This Ashkenazi Jewish Panel detects mutations associated with the following eight disorders that commonly occur in Ashkenazi-Jewish individuals:
  • Bloom syndrome: Children with Bloom syndrome are affected with growth retardation, abnormalities in skin pigmentation, immunodeficiency, a predisposition to cancer, and chromosomal instability. Death usually occurs in the teens or twenties, most often caused by cancer.
  • Canavan disease: Canavan disease (aspartoacylase deficiency) is a progressive neurologic disease characterized by increased head circumference, decreasing muscle tone and motor activity, progressive loss of visual responsiveness, and mental retardation. Death usually occurs by age four.
  • Cystic fibrosis: Characteristic manifestations include recurrent lung infections, malabsorption, malnutrition, and infertility (especially in males). Median survival is 30 years.
  • Familial dysautonomia: Familial dysautonomia is characterized by abnormal functioning of the sensory and autonomic nervous systems. This causes decreased sensitivity to pain, abnormal regulation of body temperature, paroxysmal hypertension, and gastrointestinal abnormalities.
  • Fanconi anemia group C: Fanconi anemia is characterized by deficient bone development and bone marrow function. This can lead to pancytopenia, anemia, leukemia, and malformations of the limbs, kidneys, and heart. The disorder may be mild or severe.
  • Gaucher disease: Gaucher disease is a lysosomal glycolipid storage disorder caused by an enzymatic deficiency (acid beta galactosidase deficiency). Individuals may have an enlarged liver and spleen, thrombocytopenia, anemia, bone pain, bone lesions, and fractures. Life expectancy depends on severity of the symptoms.
  • Niemann-Pick disease types A and B: This lysosomal storage disorder is characterized by diminished acid sphingomyelinase activity. Type A is usually fatal within 2 to 3 years. These children fail to thrive, have an enlarged liver and spleen, and exhibit progressive mental and physical degeneration. Individuals with type B also have hepatosplenomegaly (along with cirrhosis, portal hypertension, ascites, and pancytopenia), but little to no neurologic involvement. They often survive into adolescence and adulthood.
  • Tay-Sachs disease: Tay-Sachs is a progressive, neurodegenerative disorder caused by an enzymatic deficiency (hexosaminidase A). The classic infantile form is characterized by developmental retardation followed by paralysis, dementia, seizures, and blindness. Death usually occurs by age 4.

Treatment Implications

The BRCA1 and BRCA2 genes encode for proteins that function in the "Fanconi's anemia" pathway within normal cells. This cellular pathway functions to repair certain types of damage to DNA (called DNA cross-linking damage). Cells that are defective in BRCA1 or BRCA2 are known to be highly sensitive to certain chemicals. Dr. Scott Kern and colleagues from Johns Hopkins have found that BRCA2-deficient pancreatic cancer cells are especially susceptible to the toxic effects of the anticancer drugs mitomycin and cis-platin. This finding suggests that specific therapies could be targeted to specific patients depending on their BRCA1 and BRCA2 gene status. For example, pancreatic cancers caused by an inherited mutation in BRCA1 or BRCA2 may specifically be sensitive to treatment with one of these drugs. More research in this exciting new area is underway.

Screening of pancreatic cancer for families to detect early pancreatic tumors has proven to be an effective means of reducing the risk of dying from several types of cancer.



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