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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.



D

FANCONI ANEMIA (FA)

Autosomal recessive; q2 = 1/40 000.

Clinics :

Neoplastic risk :

Cytogenetics :

Genes :



ATAXIA TELANGIECTASIA (AT)

Autosomal recessive; q2 = 1/40 000.

Clinics :

Neoplastic risk

Cytogenetics :

Radiosensitivity: Genes :

Note : heterozygous for AT may be at increased risk of breast cancer.



BLOOM SYNDROME (BS)

Autosomal recessive; q2 = 2/100 000.

Clinics :

Neoplastic risk Cytogenetics : Gene :



Xeroderma pigmentosum (XP)

Autosomal recessive; q2 = 0,4/100 000.

Clinics :

Neoplastic risk :

Cytogenetics :

Genes :


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.



Retinoblastoma

cancer prone disease at increased risk of the cancer of the retina called (also) retinoblastoma

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.

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:
  • 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 :

    In 1969 FP Li and JF Fraumeni define a syndrome :

    P53 :


    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


    Contributor(s)

    Written2000-07Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon Aug 12 17:30:59 CEST 2019


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