Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Cancer Prone Diseases
I. CHROMOSOME INSTABILITY SYNDROMES
II. RETINOBLASTOMA / LI-FRAUMENI SYNDROME
III. HAMARTO-NEOPLASTIC SYNDROMES
I. CHROMOSOME INSTABILITY SYNDROMES
A handfull of rare genetic diseases associate chromosome instability, DNA
replication and/or repair anomalies , some shared clinical features, and an
increased risk of cancer. These diseases are characterized by a high level of
spontaneous chromatid breaks and chromosome rearrangements, and/or a
hypersensitivity to clastogens
(see an introduction to chromosomal aberrations). The genes implicated in these diseases are partly known and
seem to have a role in DNA repair and/or in the cell cycle regulation. If
lesions into DNA are not correctly repared, mutations and rearrangements will
accumulate, until, by chance, one of these mutations results in the activation
of an oncogene or in the inactivation of the allele(s) of a tumor suppressor
gene. Whence, chromosome instability syndromes are paradigmatic.
Autosomal recessive; q2 = 1/40 000.
Clinics :
- growth retardation.
- skin abnormalities: hyperpigmentation and/or café au lait spots.
- squeletal malformations, particularly radius axis defects.
- progressive bone marrow failure --> bone marrow aplasia.
Neoplastic risk :
- myelodysplasia and acute non lymphocytic leukemia: in 10% of cases; i.e. a
15000 fold increased risk; other cancers (5%).
Cytogenetics :
- spontaneous chromatid/chromosome breaks.
- hypersensitivity to the clastogenic effect of DNA cross-linking agents.
- slowing of the cell cycle (G2/M transition).
Genes :
- 4 complementation groups; genes
FACC,
FA1
Autosomal recessive; q2 = 1/40 000.
Clinics :
- telangiectasia: facial region exposed to sunlight.
- progressive cerebellar ataxia.
- combined immunodeficiency --> infections --> 80% of deaths.
Neoplastic risk
- T-cell malignancies (a 70 fold and 250 fold increased risks of leukaemia and
lymphoma respectively) --> 20% of deaths.
Cytogenetics :
- more than 10% ofs mitoses bear a chromosome rearrangement in 7p14, 7q35,
14q11, or 14q32 (illegitimate recombinations between immunoglobulin
superfamilly genes Ig and TCR).
- clonal rearrangements further occur --> T-cell malignancy.
- lenthening of the cell cycle (slower S phase).
Radiosensitivity:
- high sensitivity to radiations and to radiomimetic drugs.
Genes :
- gene in 11q23: ATM
probable role in DNA repair,
recombinaison, and in the cell cycle control.
Note : heterozygous for AT may be at increased risk of breast cancer.
Autosomal recessive; q2 = 2/100 000.
Clinics :
- sun sensitive telangiectatic erythema.
- dwarfismn.
- normal intelligence.
- combined immunodeficiency --> infections.
Neoplastic risk
- carcinomas (30%), lymphomas (25%), acute lymphocytic and non lymphocytic
leukemias (15 % each), .....
- mean age at first cancer onset: 21 yrs; more than one cancer in a given
patient.
Cytogenetics :
- spontaneous chromatid breaks.
- diagnosis on the highly elevated spontaneous sister chromatid exchange rate
(90 per cell).
- slowing of the cell cycle (lenthening of the G1 and S phases).
Gene :
- gene BLM , codes for a DNA helicase.
Xeroderma pigmentosum (XP)
Autosomal recessive; q2 = 0,4/100 000.
Clinics :
- sun sensitiviromic lesions --> skin cancers.
- photophobia.
- neurologic features.
Neoplastic risk :
- multiple cutaneous and ocular tumors as early as from the age of 8 yrs (in
sun exposed zones).
Cytogenetics :
- normal level of breaks and chromatid exchanges.
- hypermutability of the cells under UV irradiation.
Genes :
- 9 complementation groups. Genes ERCC (excision repair cross complement) and
XP (ex: XPAC ) : mumerous and dispersed on various chromosomes;
role in DNA repair (helicases) and in the complex repair/transcription
factor.
II RETINOBLASTOMA and LI-FRAUMENI SYNDROME
These two diseases are examples of the involvement of tumor suppressor genes;
they are also of interest for various reasons; retinoblastoma mixes
constitutional and acquired chromosome features, the gene Rb is autosomal
recessive but the disease appears to be autosomal dominantly inherited, due to
rare events multiplied by numerous cells and conditional probabilities;
Li-Fraumeni syndrome is a rare disease discovered from epidemiological studies,
and P53 is, otherwise, THE gene involved in 50% of the cancers. Both genes are
involved in the cell cycle regulation and arrest. If the cell cycle is not
stopped until the background lesions into DNA are correctly repared, mutations
and rearrangements will accumulate along the cycles, until, by chance, one of
these mutations results in the activation of an oncogene or in the inactivation
of the allele(s) of a tumor suppressor gene.
cancer prone disease at increased risk of the cancer of the retina called
(also) retinoblastoma
- embryonnic tumor of the neurectoderma.
- appears most often in childhood.
- there are sporadic forms (with a negative familly history) and hereditary
forms.
- there are unilateral forms (mostly in the sporadic cases) and bilateral
forms (mainly in the hereditary cases).
- hereditary forms seem to be transmitted as an autosomal dominant
disease with a 90 % penetrance.
- patients having a retinoblastoma have an increased frequency of other
cancers, in particular of osteosarcoma and pinealoma.
- in a (very) few cases, a visible chromosome 13 deletion may be seen on the
constitutionnal karyotype, and, according to the lenght of the deletion, the
patients present with dysmorphic features and mental impairment (as usual for
unbalanced constitutional anomalies), in addition to the cancer(s) of the
retina they have.
These features are unusual, and some appear contradictory...
They will be explained by the two-step inactivation mechanism, according to AG
Knudson (1971): both alleles of a tumor suppressor gene must be inactivated to
let the cancer develop.
- 1st event : deletion
- in a germ cell : hereditary form (therefore each of the cells of the
patient, in particular each of the cells of each of the 2 eyes bear the
deletion : that will considerably increase the risk of multiple retinoblastomas
in 1 eye, or of bilateral retinoblastoma: conditional probability P(1st allele)
X P(2nd allele) with the first proba already = 1).
- or in a retinoblast : sporadic form.
- 2nd event : 2nd deletion : in a retinoblast (somatic deletion).
- finally : when homozygosity for inactivation is reached --> the tumor
develops.
The gene is recessive; it however seems to be transmitted as an autosomal
dominant disease in hereditary forms: the hereditary mutation, first event, has
a probability 1/2 to be transmitted to the "patient". If, by some means or
other, the (second) somatic hit has a probability close to 1, then, the
resulting probability to have a retinoblastoma will be 1/2 x 1 = 1/2, what is
characteristic of autosomal dominant transmission.
The somatic event's probability is close to 1 (the "some means or other"
above noted is the result of the low rate of mutations multiplied by the great
number of cells at risk).
This somatic hit is produced either by:
- loss of the normal chromosome 13 --> monosomy with only the deleted 13
(hemizygosity).
- loss of the normal chromosome 13 and duplication of the deleted 13
(homozygosity).
- deletion within the normal 13 where `the important gene' sits.
- mutation (or any other kind of inactivation) of `the important gene'
present on the normal 13 .
This gene has been called Rb , and belongs to the class of
tumor suppressor genes (earlier "antioncogenes"), as, when they are normal and
active, they prevent from cancer.
Rb: gene sitting in 13q14; 180 kb, 27 exons, mRNA of 4,7 kb --;> P105 Rb
protein : can form complexes with nuclear oncogenes; phosphorylated in S and
G2/M phases of the cell cycle; unphosphorylated in G0 and G1 and associated
with E2F; anti proliferative activity.
LI-Fraumeni syndrome and
P53
1/3 of the population will have a cancer;
Besides, exist familial cancers; more than a hundred genetic diseases are
accompanied with an increased risk of cancers (either specific or
pleiotropic).
In the general population, if a given person has a cancer: --> risk is
increased by 2 or 3 in the family.
In certain types of familial cancers : --> risk X 103 !
How to suspect an hereditary cancer :
- too early in life;
- more than 1 cancer in 1 patient;
- positive family history (other cancers, more than usual, in the family).
In 1969 FP Li and JF Fraumeni define a syndrome :
- autosomal dominant,
- with : breast cancers, sarcomas, brain tumors, leukemias, ...
- inclusion criteria: 1 individual having a sarcoma and at least 2 related
persons with a sarcoma or a carcinoma.
P53 :
- gene sitting in 17p13; 20 kb, 11 exons (1st exon is non coding), mRNA
of 3,0 kb.
- the protein presents a transactivation domain, a DNA-binding domain,
nuclear localization signals and a tetramerization domain<
- transcriptional regulator: in response to DNA damage, P53 activates the
transcription of genes implicated in the cell-cycle arrest and genes implicated
in apoptosis; these activations allow either the cells to repair DNA damage
before entering further in the cell cycle, or to be eliminated.
- P53 is the most frequently (50%) mutated gene in cancers (with loss of
fonction of the second allele) (SOMATIC MUTATION = ACQUIRED ANOMALY).
- P53 is found mutated as an inborn condition in most (but not all!) patients
with the congenital genetic disease named Li-Fraumeni syndrome
(GERMINAL
MUTATION = CONSTITUTIONNAL ANOMALY ).
III HAMARTO-NEOPLASTIC SYNDROMES
Hamartomas are localized tissue proliferations with faulty differenciation and
mixture of component tissues; these diseases are heritable; hamartomas are
benign proliferations that have a potential towards neoplasia; patients may
also be at increased risk of benign and malignant tumors of other tissues and
organs. The genes known so far are tumor suppressor genes, but no common
fonction has yet been established.
... This chapter is in progress ...
NEUROFIBROMATOSIS TYPE 1 (NF1)
NEUROFIBROMATOSIS TYPE 2 (NF2)
VON HIPPEL-LINDAU SYNDROME
| Written | 07-2000 | Jean-Loup Huret |
| | |
| This paper should be referenced as such : |
Huret JL . Cancer Prone Diseases. Atlas Genet Cytogenet Oncol Haematol. July 2000 .
URL : http://AtlasGeneticsOncology.org/Educ/Cancers_e.html |
|
© Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Sat Dec 6 17:43:49 2008
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