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.
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.
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
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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