High and Lower penetrance conditions
Genetic tests are now available to detect the presence of a
number of high and lower penetrance inherited cancer
Familial Adenomatous Polyposis (FAP)
? highly penetrant
FAP is a condition which causes hundreds of polyps to
develop in the colon, and they begin to appear at an average
age of 16 years. The risk of colorectal cancer developing
from a polyp is virtually 100 per cent unless prophylactic
(before symptoms) removal of the colon is carried out.
Polyps also develop in the upper gastrointestinal tract and
cancer may occur in other sites including the brain and the
thyroid (although not as frequently). The penetrance of FAP
is 95-100 per cent meaning that most people who carry a
faulty gene for this condition will develop the cancer
unless they have prophylactic surgery.
Multiple Endocrine Neoplasia 2 (MEN
2) ? highly penetrant
MEN2 is a complex inherited condition that causes a
predisposition to various cancers, often with different
risks. For example, medullary thyroid cancer, parathyroid
adenomas and an adrenal tumour called a phaeochromocytoma.
Because of the difficulty of screening for the thyroid
cancer it is recommended that children diagnosed with MEN2
have the thyroid gland removed in early childhood to prevent
them from developing this cancer. If they do not, the risk
of medullary thyroid cancer is very high. If the thyroid
gland is removed, it is still necessary to screen for
adrenal tumours, which may develop in adulthood. The
penetrance for the thyroid cancer is 95 per cent in most
families (although the other cancers develop less
frequently), with an age at diagnosis between 20-40 years
for thyroid cancer, and later for the adrenal tumours.
Affected people often develop parathyroid tumours but these
are not usually malignant. The risk of specific tumours
varies with different faults in the same gene.
Retinoblastoma ? highly penetrant
Retinoblastoma is a cancer which develops in the cells of
the retina, the light sensitive lining of the eye. In cases
of inherited retinoblastoma, the penetrance is about 90 per
cent. The tumour usually develops before the age of 5 years
and some children are born with retinoblastoma. Children
with bilateral (both eyes) disease tend to present during
the first year of life whilst the peak age of diagnosis for
children with unilateral disease (one eye) is between 24 and
Breast cancer and ovarian cancer ?
Inherited forms of breast and ovarian cancer can both be
caused by faults in the BRCA1 and BRCA2 genes (BReast CAncer).
Around 5-10 per cent of all breast and ovarian cancer are
caused by an inherited fault in one of these predisposition
genes. The age at diagnosis for breast cancer in women with
such an inherited fault is about 10 to 20 years earlier than
for sporadic breast cancer. Women who carry a fault in the
BRCA1 gene have a lifetime risk of breast cancer of about 80
per cent, and 40 per cent of ovarian cancer ? women carrying
a fault in the BRCA2 gene have a similar risk of breast
cancer but a smaller risk of ovarian cancer. Men carrying
these mutations have some increase of prostate cancer risk,
and men who carry an alteration in the BRCA2 gene have a 5-7
per cent risk of developing breast cancer in their lifetime.
Screening measures are not sufficiently sensitive and
specific at present and so prophylactic options to reduce
the risks of breast and ovarian cancer (mastectomy and
oophorectomy) are often considered, although management of
these risks is likely to improve with time.
Bowel cancer (Hereditary non-polyposis
colorectal cancer (HNPCC)) ? lower penetrance
Individuals with HNPCC have up to an 80 per cent lifetime
risk of colorectal cancer and increased risks of uterine
cancer (up to 60 per cent) and other mostly gastrointestinal
cancers. Screening is available by colonoscopies annually
from 25 years, and ultrasound scans may be offered to women
with HNPCC. The age at diagnosis of colorectal cancer in the
condition is usually in the forties but can be earlier.
two most prevalent syndromes are breast and hereditary non-polyposis
colon cancers that are associated with mutations in the
BRCA1/2 genes and MSH2 /MLH1 genes respectively. Other
syndromes include multiple endocrine neoplasia (MEN1, MEN2
genes), retinoblastoma (RB1 gene), Neurofibromatoses (NF1,
NF2 genes), Li Fraumeni syndrome (p53 gene) and Familial
Polyposis (FAP gene).
All these cancers are autosomal dominant traits that usually
manifest in adulthood, but can occur occasionally in
children. Malfunction of tumour suppressor genes, impairment
of DNA repair genes or the transformation of a normal gene
into an oncogene are well known events that lead to the
development of these genetic cancers. The lifetime risk for
an individual carrying a cancer-predisposing gene mutation
to develop disease is <100%. People who inherit specific p53
suppressor gene mutations have a high chance of developing
Li-Fraumeni syndrome that frequently manifests as breast
tumours or bone and soft tissue sarcomas.
Their chance of developing a tumour by age 30 years is 50%
(compared with 1% in the general population) and by age 70,
the chance escalates to 90%. The lifetime risk for women who
inherit either a BRCA1 or BRCA2 cancer gene is equally high.
For example, by the age of 70, the lifetime risk of breast
cancer is in the order of 60?80%, with an additional
lifetime risk of 20?40% for ovarian cancer. For women in the
general population without the mutation, there is only an 8%
lifetime risk of developing breast cancer.
Options for affected families