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.
Inherited cancer syndromes
Multiple polyposis syndromes
Familial adenomatous polyposis (FAP) follows autosomal
dominant inheritance and carries a high risk of malignancy
necessitating prophylactic colectomy. The presentation may be
with adenomatous polyposis as the only feature or as the
Gardener phenotype in which there are extracolonic
manifestations including osteomas, epidermoid cysts, upper
gastrointestinal polyps and adenocarcinomas (especially
duodenal), and desmoid tumours that are often
retroperitoneal. Detecting congenital hypertrophy of the
retinal pigment epithelium (CHRPE), that occurs in familial
adenomatous polyposis, has been used as a method of early
identification of gene carriers. The adenomatous polyposis coli
(APC) gene on chromosome 5 responsible for FAP has been
cloned. Mutation detection or linkage analysis in affected
families provides a predictive test to identify gene carriers.
Family members at risk should be screened with regular
colonoscopy from the age of 10 years.
Familial adenomatous polyposis (FAP) follows autosomal
dominant inheritance and carries a high risk of malignancy
necessitating prophylactic colectomy. The presentation may be
with adenomatous polyposis as the only feature or as the
Gardener phenotype in which there are extracolonic
manifestations including osteomas, epidermoid cysts, upper
gastrointestinal polyps and adenocarcinomas (especially
duodenal), and desmoid tumours that are often
retroperitoneal. Detecting congenital hypertrophy of the
retinal pigment epithelium (CHRPE), that occurs in familial
adenomatous polyposis, has been used as a method of early
identification of gene carriers. The adenomatous polyposis coli
(APC) gene on chromosome 5 responsible for FAP has been
cloned. Mutation detection or linkage analysis in affected
families provides a predictive test to identify gene carriers.
Family members at risk should be screened with regular
colonoscopy from the age of 10 years.
In Peutz–Jeghers syndrome
In Peutz–Jeghers syndrome hamartomatous gastrointestinal
polyps, which may bleed or cause intussusception, are
associated with pigmentation of the buccal mucosa and lips.
Malignant degeneration in the polyps occurs in up to 30–40%
of cases. Ovarian, breast and endometrial tumours also occur in
this dominant syndrome.
Mutations causing Peutz–Jehgers syndrome have been
detected in the serine/threonine protein kinase gene (STK11)
on chromosome
polyps, which may bleed or cause intussusception, are
associated with pigmentation of the buccal mucosa and lips.
Malignant degeneration in the polyps occurs in up to 30–40%
of cases. Ovarian, breast and endometrial tumours also occur in
this dominant syndrome.
Mutations causing Peutz–Jehgers syndrome have been
detected in the serine/threonine protein kinase gene (STK11)
on chromosome
Li–Fraumeni syndrome
Li–Fraumeni syndrome is a dominantly inherited cancer
syndrome caused by constitutional mutations in the TP53 or
CHK2 genes. Affected family members develop multiple
primary tumours at an early age that include
rhabdomyosarcomas, soft tissue sarcomas, breast cancer, brain
tumours, osteosarcomas, leukaemia, adrenocortical carcinoma,
lymphomas, lung adenocarcinoma, melanoma, gonadal germ
cell tumours, prostate carcinoma and pancreatic carcinoma.
Mutation analysis may confirm the diagnosis in a family and
enable predictive genetic testing of relatives, but screening for
neoplastic disease in those at risk is difficult.
syndrome caused by constitutional mutations in the TP53 or
CHK2 genes. Affected family members develop multiple
primary tumours at an early age that include
rhabdomyosarcomas, soft tissue sarcomas, breast cancer, brain
tumours, osteosarcomas, leukaemia, adrenocortical carcinoma,
lymphomas, lung adenocarcinoma, melanoma, gonadal germ
cell tumours, prostate carcinoma and pancreatic carcinoma.
Mutation analysis may confirm the diagnosis in a family and
enable predictive genetic testing of relatives, but screening for
neoplastic disease in those at risk is difficult.
Multiple endocrine neoplasia syndromes
Two main types of multiple endocrine neoplasia syndrome exist
and both follow autosomal dominant inheritance with reduced
penetrance. Many affected people have involvement of more
than one gland but the type of tumour and age at which these
develop is very variable within families. The gene for MEN type I
on chromosome 11 acts as a tumour suppressor gene and
encodes a protein called menin. Mutations in the coding region
of the gene are found in 90% of individuals with a diagnosis of
MEN I based on clinical criteria. First-degree relatives in affected
families should be offered predictive genetic testing. Those
carrying the mutation require clinical, biochemical and
radiological screening to detect presymptomatic tumours. MEN
type II is due to mutations in the RET oncogene on chromosome
10 that encodes a tyrosine kinase receptor protein. Mutation
analysis again provides confirmation of the diagnosis in the
index case and presymptomatic tests for relatives. Screening tests
in gene carriers include calcium or pentagastrin provocation
tests that detect abnormal calcitonin secretion and permit
curative thyroidectomy before the tumour cells extend beyond
the thyroid capsule.
and both follow autosomal dominant inheritance with reduced
penetrance. Many affected people have involvement of more
than one gland but the type of tumour and age at which these
develop is very variable within families. The gene for MEN type I
on chromosome 11 acts as a tumour suppressor gene and
encodes a protein called menin. Mutations in the coding region
of the gene are found in 90% of individuals with a diagnosis of
MEN I based on clinical criteria. First-degree relatives in affected
families should be offered predictive genetic testing. Those
carrying the mutation require clinical, biochemical and
radiological screening to detect presymptomatic tumours. MEN
type II is due to mutations in the RET oncogene on chromosome
10 that encodes a tyrosine kinase receptor protein. Mutation
analysis again provides confirmation of the diagnosis in the
index case and presymptomatic tests for relatives. Screening tests
in gene carriers include calcium or pentagastrin provocation
tests that detect abnormal calcitonin secretion and permit
curative thyroidectomy before the tumour cells extend beyond
the thyroid capsule.
von Hippel–Lindau disease
In von Hippel–Lindau disease haemangioblastomas develop
throughout the brain and spinal cord, characteristically
affecting the cerebellum and retina. Renal, hepatic and
pancreatic cysts also occur. The risk of clear cell carcinoma of
the kidney is high and increases with age. Phaeochromocytomas
occur but are less common. The syndrome follows autosomal
dominant inheritance, and clinical, biochemical and
radiological screening is recommended for affected family
members and those at risk, to permit early treatment of
problems as they arise. The VHL gene on chromosome 3 has
been cloned, and identification of mutations allows predictive
testing in the majority of families.
throughout the brain and spinal cord, characteristically
affecting the cerebellum and retina. Renal, hepatic and
pancreatic cysts also occur. The risk of clear cell carcinoma of
the kidney is high and increases with age. Phaeochromocytomas
occur but are less common. The syndrome follows autosomal
dominant inheritance, and clinical, biochemical and
radiological screening is recommended for affected family
members and those at risk, to permit early treatment of
problems as they arise. The VHL gene on chromosome 3 has
been cloned, and identification of mutations allows predictive
testing in the majority of families.
Naevoid basal cell carcinoma
The cardinal features of the naevoid basal cell carcinoma
syndrome, an autosomal dominant disorder delineated by
Gorlin, are basal cell carcinomas, jaw cysts and various skeletal
abnormalities, including bifid ribs. Other features are
macrocephaly, tall stature, palmar pits, calcification of the falx
cerebri, ovarian fibromas, medulloblastomas and other
tumours. The skin tumours may be extremely numerous and
are usually bilateral and symmetrical, appearing over the face,
neck, trunk, and arms during childhood or adolescence.
Malignant change is very common after the second decade,
and removal of the tumours is therefore indicated.
Medulloblastomas occur in about 5% of cases. Abnormal
sensitivity to therapeutic doses of ionising radiation results in
the development of multiple basal cell carcinomas in any
irradiated area. The gene for Gorlin syndrome (PTCH) on
chromosome 9 has been cloned and is homologous to a
drosophila developmental gene called patched.
syndrome, an autosomal dominant disorder delineated by
Gorlin, are basal cell carcinomas, jaw cysts and various skeletal
abnormalities, including bifid ribs. Other features are
macrocephaly, tall stature, palmar pits, calcification of the falx
cerebri, ovarian fibromas, medulloblastomas and other
tumours. The skin tumours may be extremely numerous and
are usually bilateral and symmetrical, appearing over the face,
neck, trunk, and arms during childhood or adolescence.
Malignant change is very common after the second decade,
and removal of the tumours is therefore indicated.
Medulloblastomas occur in about 5% of cases. Abnormal
sensitivity to therapeutic doses of ionising radiation results in
the development of multiple basal cell carcinomas in any
irradiated area. The gene for Gorlin syndrome (PTCH) on
chromosome 9 has been cloned and is homologous to a
drosophila developmental gene called patched.
Neurofibromatosis
The presenting features of neurofibromatosis type 1 (NF1,
peripheral neurofibromatosis, von Recklinghausen disease) and
neurofibromatosis type 2 (NF2, central neurofibromatosis) are
described in chapter 10. Benign optic gliomas and spinal
neurofibromas may occur in NF1 and malignant tumours,
mainly neurofibrosarcomas or embryonal tumours, occur in 5%
of affected people. The gene for NF1 on chromosome 17 has
been cloned, but mutation analysis is not routinely undertaken
because of the large size of the gene (60 exons) and the
diversity of mutations occurring. Deletions of the entire gene
have been found in more severely affected cases.
peripheral neurofibromatosis, von Recklinghausen disease) and
neurofibromatosis type 2 (NF2, central neurofibromatosis) are
described in chapter 10. Benign optic gliomas and spinal
neurofibromas may occur in NF1 and malignant tumours,
mainly neurofibrosarcomas or embryonal tumours, occur in 5%
of affected people. The gene for NF1 on chromosome 17 has
been cloned, but mutation analysis is not routinely undertaken
because of the large size of the gene (60 exons) and the
diversity of mutations occurring. Deletions of the entire gene
have been found in more severely affected cases.
NF2
The main feature of NF2 is bilateral acoustic neuromas
(vestibular schwannomas). Spinal tumours and intracranial
meningiomas occur in over 40% of cases. Surgical removal of
VIIIth nerve tumours is difficult and prognosis for this disorder
is often poor. The NF2 gene on chromosome 22 has been
cloned and various mutations, deletions and translocations
have been identified, allowing presymptomatic screening and
prenatal diagnosis within affected families.
(vestibular schwannomas). Spinal tumours and intracranial
meningiomas occur in over 40% of cases. Surgical removal of
VIIIth nerve tumours is difficult and prognosis for this disorder
is often poor. The NF2 gene on chromosome 22 has been
cloned and various mutations, deletions and translocations
have been identified, allowing presymptomatic screening and
prenatal diagnosis within affected families.
Tuberous sclerosis
Tuberous sclerosis is an autosomal dominant disorder, very
variable in its manifestation, that can cause epilepsy and severe
retardation in affected children. Hamartomas of the brain,
heart, kidney, retina and skin may also occur, and their
presence indicates the carrier state in otherwise healthy family
members. Sarcomatous malignant change is possible but
uncommon. Tuberous sclerosis can be due to mutations in
genes on chromosomes 9 and 16 (TSC1 and TSC2).
variable in its manifestation, that can cause epilepsy and severe
retardation in affected children. Hamartomas of the brain,
heart, kidney, retina and skin may also occur, and their
presence indicates the carrier state in otherwise healthy family
members. Sarcomatous malignant change is possible but
uncommon. Tuberous sclerosis can be due to mutations in
genes on chromosomes 9 and 16 (TSC1 and TSC2).
Retinoblastoma
Sixty percent of retinoblastomas are sporadic and unilateral,
with 40% being hereditary and usually bilateral. Hereditary
retinoblastomas follow an autosomal dominant pattern of
inheritance with incomplete penetrance. About 80–90% of
children inheriting the abnormal gene will develop
retinoblastomas. Molecular studies indicate that two events are
involved in the development of the tumour, consistent with
Knudson’s original “two hit” hypothesis. In bilateral tumours
the first mutation is inherited and the second is a somatic event
with a likelihood of occurrence of almost 100% in retinal cells.
In unilateral tumours both events probably represent new
somatic mutations. The retinoblastoma gene is therefore acting
recessively as a tumour suppressor gene.
with 40% being hereditary and usually bilateral. Hereditary
retinoblastomas follow an autosomal dominant pattern of
inheritance with incomplete penetrance. About 80–90% of
children inheriting the abnormal gene will develop
retinoblastomas. Molecular studies indicate that two events are
involved in the development of the tumour, consistent with
Knudson’s original “two hit” hypothesis. In bilateral tumours
the first mutation is inherited and the second is a somatic event
with a likelihood of occurrence of almost 100% in retinal cells.
In unilateral tumours both events probably represent new
somatic mutations. The retinoblastoma gene is therefore acting
recessively as a tumour suppressor gene.
Tumours may occasionally regress spontaneously
Tumours may occasionally regress spontaneously leaving
retinal scars, and parents of an affected child should be
examined carefully. Second malignancies occur in up to 15%
of survivors in familial cases. In addition to tumours of the
head and neck caused by local irradiation treatment, other
associated malignancies include sarcomas (particularly of the
femur), breast cancers, pinealomas and bladder carcinomas.
retinal scars, and parents of an affected child should be
examined carefully. Second malignancies occur in up to 15%
of survivors in familial cases. In addition to tumours of the
head and neck caused by local irradiation treatment, other
associated malignancies include sarcomas (particularly of the
femur), breast cancers, pinealomas and bladder carcinomas.
A deletion on chromosome
A deletion on chromosome 13 found in a group of affected
children, some of whom had additional congenital
abnormalities, enabled localisation of the retinoblastoma gene
to chromosome 13q14. The esterase D locus is closely linked to
the retinoblastoma locus and was used initially as a marker to
identify gene carriers in affected families. The retinoblastoma
gene has now been cloned and mutation analysis is possible.
children, some of whom had additional congenital
abnormalities, enabled localisation of the retinoblastoma gene
to chromosome 13q14. The esterase D locus is closely linked to
the retinoblastoma locus and was used initially as a marker to
identify gene carriers in affected families. The retinoblastoma
gene has now been cloned and mutation analysis is possible.
Wilms tumour
Wilms tumours are one of the most common solid tumours of
childhood, affecting 1 in 10 000 children. Wilms tumours are
usually unilateral, and the vast majority are sporadic. About
1% of Wilms tumours are hereditary, and of these about 20%
are bilateral. Wilms tumour is associated with aniridia,
genitourinary abnormalities, gonadoblastoma and mental
retardation (WAGR syndrome) in a small proportion of cases.
Identification of an interstitial deletion of chromosome 11 in
such cases localised a susceptibility gene to chromosome 11p13.
The Wilms tumour gene, WT1, at this locus has now been
cloned and acts as a tumour suppressor gene, with loss of
alleles on both chromosomes being detected in tumour tissue.
A second locus at 11p15 has also been implicated in Wilms
tumour. The insulin-like growth factor-2 gene (IGF2), is located
at 11p15 and causes Beckwith–Wiedemann syndrome, an
overgrowth syndrome predisposing to Wilms tumour. Children
with hemihypertrophy are at increased risk of developing
Wilms tumours and a recommendation has been made that
they should be screened using ultrasound scans and abdominal
palpation during childhood. A third gene predisposing to
Wilms tumour has been localised to chromosome 16q. These
genes are not implicated in familial Wilms tumour, which
follows autosomal dominant inheritance with reduced
penetrance, and there is evidence for localisation of a familial
predisposition gene at chromosome 17q.
childhood, affecting 1 in 10 000 children. Wilms tumours are
usually unilateral, and the vast majority are sporadic. About
1% of Wilms tumours are hereditary, and of these about 20%
are bilateral. Wilms tumour is associated with aniridia,
genitourinary abnormalities, gonadoblastoma and mental
retardation (WAGR syndrome) in a small proportion of cases.
Identification of an interstitial deletion of chromosome 11 in
such cases localised a susceptibility gene to chromosome 11p13.
The Wilms tumour gene, WT1, at this locus has now been
cloned and acts as a tumour suppressor gene, with loss of
alleles on both chromosomes being detected in tumour tissue.
A second locus at 11p15 has also been implicated in Wilms
tumour. The insulin-like growth factor-2 gene (IGF2), is located
at 11p15 and causes Beckwith–Wiedemann syndrome, an
overgrowth syndrome predisposing to Wilms tumour. Children
with hemihypertrophy are at increased risk of developing
Wilms tumours and a recommendation has been made that
they should be screened using ultrasound scans and abdominal
palpation during childhood. A third gene predisposing to
Wilms tumour has been localised to chromosome 16q. These
genes are not implicated in familial Wilms tumour, which
follows autosomal dominant inheritance with reduced
penetrance, and there is evidence for localisation of a familial
predisposition gene at chromosome 17q.
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