Structural chromosomal abnormalities are well documented in
leukaemias and lymphomas and are used as prognostic
indicators. They are also evident in solid tumours, for example,
an interstitial deletion of chromosome 3 occurs in small cell
carcinoma of the lung. More than 100 chromosomal
translocations are associated with carcinogenesis, which in
many cases is caused by ectopic expression of chimaeric fusion
proteins in inappropriate cell types. In addition, chromosome
instability is seen in some autosomal recessive disorders that
predispose to malignancy, such as ataxia telangiectasia, Fanconi
anaemia, xeroderma pigmentosum, and Bloom syndrome.
Saturday, April 11, 2009
Burkitt lymphoma
Burkitt lymphoma is common in children in parts of tropical
Africa. Infection with Epstein–Barr (EB) virus and chronic
antigenic stimulation with malaria both play a part in the
pathogenesis of the tumour. Most lymphoma cells carry an 8;14
translocation or occasionally a 2;8 or 8;22 translocation. The
break points involve the MYC oncogene on chromosome 8 at
8q24, the immunoglobulin heavy chain gene on chromosome
14, and the K and A light chain genes on chromosomes 2 and
22 respectively. Altered activity of the oncogene when
translocated into regions of immunoglobulin genes that are
normally undergoing considerable recombination and
mutation plays an important part in the development of the
tumour.
Africa. Infection with Epstein–Barr (EB) virus and chronic
antigenic stimulation with malaria both play a part in the
pathogenesis of the tumour. Most lymphoma cells carry an 8;14
translocation or occasionally a 2;8 or 8;22 translocation. The
break points involve the MYC oncogene on chromosome 8 at
8q24, the immunoglobulin heavy chain gene on chromosome
14, and the K and A light chain genes on chromosomes 2 and
22 respectively. Altered activity of the oncogene when
translocated into regions of immunoglobulin genes that are
normally undergoing considerable recombination and
mutation plays an important part in the development of the
tumour.
Inherited forms of common cancers
Inherited forms of the common cancers, notably breast, ovary
and bowel, constitute a small proportion of all cases, but their
identification is important because of the high risk of
malignancy associated with inherited mutations in cancer
predisposing genes. Identification of such families can be
difficult, as tumours often vary in the site of origin, and the risk
and type of malignancy may vary with sex. For example, in
HNPCC, females have a higher risk of uterine cancer than
bowel cancer. In breast or breast–ovary cancer families, most
males carrying the predisposing mutations will manifest no
signs of doing so, but their daughters will be at 50% risk of
inheriting a mutation, associated with an 80% risk of
developing breast cancer. With the exception of familial
adenomatosis polyposis (FAP, see below), where the sheer
number of polyps or systemic manifestations may lead to the
correct diagnosis, pathological examination of most common
tumours does not usually help in determining whether or not a
particular malignancy is due to an inherited gene mutation,
since morphological changes are seldom specific or invariable.
Determining the probability that any particular malignancy is
inherited requires an accurate analysis of a three-generation
family tree. Factors of importance are the number of people
with a malignancy on both maternal and paternal sides of the
family, the types of cancer that have occurred, the relationship
of affected people to each other, the age at which the cancer
occurred, and whether or not a family member has developed
two or more cancers. A positive family history becomes more
significant in ethnic groups where a particular cancer is rare. In
other ethnic groups there may be a particularly high
population incidence of particular mutations, such as the
BRCA1 and BRCA2 mutations occurring in people of Jewish
Ashkenazi origin.
and bowel, constitute a small proportion of all cases, but their
identification is important because of the high risk of
malignancy associated with inherited mutations in cancer
predisposing genes. Identification of such families can be
difficult, as tumours often vary in the site of origin, and the risk
and type of malignancy may vary with sex. For example, in
HNPCC, females have a higher risk of uterine cancer than
bowel cancer. In breast or breast–ovary cancer families, most
males carrying the predisposing mutations will manifest no
signs of doing so, but their daughters will be at 50% risk of
inheriting a mutation, associated with an 80% risk of
developing breast cancer. With the exception of familial
adenomatosis polyposis (FAP, see below), where the sheer
number of polyps or systemic manifestations may lead to the
correct diagnosis, pathological examination of most common
tumours does not usually help in determining whether or not a
particular malignancy is due to an inherited gene mutation,
since morphological changes are seldom specific or invariable.
Determining the probability that any particular malignancy is
inherited requires an accurate analysis of a three-generation
family tree. Factors of importance are the number of people
with a malignancy on both maternal and paternal sides of the
family, the types of cancer that have occurred, the relationship
of affected people to each other, the age at which the cancer
occurred, and whether or not a family member has developed
two or more cancers. A positive family history becomes more
significant in ethnic groups where a particular cancer is rare. In
other ethnic groups there may be a particularly high
population incidence of particular mutations, such as the
BRCA1 and BRCA2 mutations occurring in people of Jewish
Ashkenazi origin.
Epidemiological
Epidemiological studies suggest that mutations in BRCA1
account for 2% of all breast cancers and, at most, 5% of
ovarian cancer. Mutations in BRCA2 account for less than
2% of breast cancer in women, 10% of breast cancer in men
and 1% of ovarian cancer. Most clustering of breast cancer
in families is therefore probably due to the influence of
other, as yet unidentified, genes of lower penetrance,
with or without an effect from modifying environmental
factors.
account for 2% of all breast cancers and, at most, 5% of
ovarian cancer. Mutations in BRCA2 account for less than
2% of breast cancer in women, 10% of breast cancer in men
and 1% of ovarian cancer. Most clustering of breast cancer
in families is therefore probably due to the influence of
other, as yet unidentified, genes of lower penetrance,
with or without an effect from modifying environmental
factors.
Hereditary non-polyposis colon cancer
Hereditary non-polyposis colon cancer (HNPCC) has been
called Lynch syndrome type I in families where only bowel
cancer is present, and Lynch syndrome type II in families with
bowel cancer and other malignancies. HNPCC is due to
inheritance of autosomal genes that act in a dominant fashion
and accounts for 1–2% of all bowel cancer. In most cases of
bowel cancer, a contribution from other genes of moderate
penetrance, with or without genetic modifiers and
environmental triggers seems the likely cause.
called Lynch syndrome type I in families where only bowel
cancer is present, and Lynch syndrome type II in families with
bowel cancer and other malignancies. HNPCC is due to
inheritance of autosomal genes that act in a dominant fashion
and accounts for 1–2% of all bowel cancer. In most cases of
bowel cancer, a contribution from other genes of moderate
penetrance, with or without genetic modifiers and
environmental triggers seems the likely cause.
Gene testing
Gene testing to confirm a high genetic risk of malignancy
has received a lot of publicity, but is useful in the minority of
people with a family history, and requires identification of the
mutation in an affected person as a prerequisite. When the
family history clearly indicates an autosomal dominant pattern
of inheritance, risk determination is based on a person’s
position in the pedigree and the risk and type of malignancy
associated with the mutation. In families where an autosomal
dominant mode of transmission appears unlikely, risk is
determined from empiric data. Studies of large numbers of
families with cancer have provided information as to how likely
a cancer predisposing mutation is for a given family pedigree.
These probabilities are reflected in guidelines for referral to
regional genetic services.
has received a lot of publicity, but is useful in the minority of
people with a family history, and requires identification of the
mutation in an affected person as a prerequisite. When the
family history clearly indicates an autosomal dominant pattern
of inheritance, risk determination is based on a person’s
position in the pedigree and the risk and type of malignancy
associated with the mutation. In families where an autosomal
dominant mode of transmission appears unlikely, risk is
determined from empiric data. Studies of large numbers of
families with cancer have provided information as to how likely
a cancer predisposing mutation is for a given family pedigree.
These probabilities are reflected in guidelines for referral to
regional genetic services.
Management of those at increased risk of malignancy
Management of those at increased risk of malignancy
because of a family history is based on screening. Annual
mammography between ages 35 and 50 is suggested for women
at 1 in 6 or greater risk of breast cancer, and annual
transvaginal ultrasound for those at 1 in 10 or greater risk of
ovarian cancer. In HNPCC (as in the general population), all
bowel malignancy arises in adenomatous polyps, and regular
colonoscopy with removal of polyps is offered to people whose
risk of bowel cancer is 1 in 10 or greater. The screening interval
and any other screening tests needed are influenced by both
the pedigree and tumour characteristics.
because of a family history is based on screening. Annual
mammography between ages 35 and 50 is suggested for women
at 1 in 6 or greater risk of breast cancer, and annual
transvaginal ultrasound for those at 1 in 10 or greater risk of
ovarian cancer. In HNPCC (as in the general population), all
bowel malignancy arises in adenomatous polyps, and regular
colonoscopy with removal of polyps is offered to people whose
risk of bowel cancer is 1 in 10 or greater. The screening interval
and any other screening tests needed are influenced by both
the pedigree and tumour characteristics.
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