Chromosomes, Leukemias, Solid Tumors, Hereditary Cancers


Written 2000-06 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated 2008-02 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

  1. I. Haematologic malignancies
  2. II. Solid Tumours
  3. III. Cancer-prone diseases

I. Haematologic malignancies


Malignant blood diseases may be classified:

  • According to the clinical course:
    • Chronic leukemias
    • Acute leukemias
  • According to the lineage:
    • Lymphoid lineage: B or T
    • Myeloid lineage:
      • Myeloproliferative syndromes: quantitative anomalies.
      • Myelodysplastic syndromes: qualitative anomalies.
      • Acute myeloid leukemias (or acute non lymphoblastic leukemia).
  • According to the primary site:
    • Leukemia: originates in the bone marrow; flows into the peripheral blood.
    • Lymphoma: originates in the lymph nodes; invades bone marrow and blood.
Leukaemias are classified according to cytogenetics, cytology and pathology, and immunophenotype of the malignant cells. The WHO (World Health Organization) classification has replaced the FAB classification of leukaemias.

Myeloproliferative syndromes

Myeloproliferations : quantitatives anomalies of the myeloid lineage.

  • Chronic myelogenous leukaemia (CML)
  • Polycytemia vera (PV)
  • Idiopathic myelofibrosis (or agnogenic myeloid metaplasia)
  • Essential thrombocythemia (ET)
+/- Atypical chronic myelogenous leukemia (myelodysplastic/myeloproliferative disease)

Chronic myelogenous leukaemia (CML)

  • Malignant monoclonal process involving a pluripotent hematopoietic progenitor (therefore, most of the lineages are implicated).
  • Splenomegaly, high leukocyte count, basophilia, immature cells in the peripheral blood, low leucocyte alkaline phosphatase, bone marrow expansion with increased neutrophil lineage.
  • Prognosis: chronic phase, followed by blast crises, ending in an acute transformation; median survival was about 4 yrs before the recently introduced antityrosine kinase (imatinib mesylate) therapies.

  • Chromosome anomalies:
    • t(9;22)(q34;q11).
    • Chromosome 22 appears shorter and was called Philadelphia chromosome (noted Ph).
    • Translocates a part of ABL1 (Abelson, 9q34) oncogene, next to a part of a particular DNA sequence of another oncogene, BCR (breakpoint cluster region), in 22q11 --> production of a hybrid gene 5BCR-3ABL.
    • The normal ABL is transcribed, into a m-RNA of 6 to 7 kbases, which produces a protein (tyrosine kinase) of 145 kDalton with a low kinase activity.
    • The hybrid gene 5BCR-3ABL is transcribed into a m-RNA of 8.5 kb, which produces a protein of 210 kDa with:
      1. an increased protein kinase activity
      2. an increased half-life, as compared to normal ABL.
    • In a percentage of cases, there is a variant/complexe translocation (e. g.: t(1;9;22)); the karyotype may even looks normal in some cases ("Ph- CML); however, it has been demonstrated by molecular technics that, whatever the variant translocation was, the hybride gene 5BCR-3ABL was always present (otherwise, it is NOT a CML!).
    • Therefore the translocation t(9;22) is the specific anomaly found in CML; however, this anomaly is not pathognomonic, as it may also be found in ALL or in rare AML cases.
    • Additionnal anomalies : most often, they are found at the time of the blast crisis, they may nonetheless be present at diagnosis; mainly: +Ph, and/or +8, and/or i(17q), and/or +19, and/or -7; Most often; these additional anomalies reflects the clonal evolution in various sub-clones.
Figure 1
Figure 1
Clonal evolution concept
Figure 2
Figure 2

Figure 3
Figure 3

Other myeloproliferative syndromes:

Polycytemia vera (PV)

  • Red cell lineage mainly; median survival: 10 to 15 yrs.
  • JAK2 (9p24) V617F mutation in 2/3 to 100% of cases--> constitutive kinase activity.

Idiopathic myelofibrosis (or agnogenic myeloid metaplasia)

  • Splenic metaplasia with progressive myelofibrosis ; survival is very variable (3 to 15 yrs).
  • JAK2 mutation in 50% of cases.
  • Chromosome anomalies:
    • Rare at diagnosis: del(20q), or+8, or+9, or del (13q), or partial trisomy for 1q.
    • Frequent during acute transformation: anomalies are the one found in usual AML or in secondary leukemias.

Essential thrombocythemia (ET):

  • Megakaryocytic lineage mainly; survival = 10 yrs; chromosome anomalies are rare.
  • JAK2 mutation in ç to ù of cases.

Atypical chronic myelogenous leukemia:

Hybrid genes, with the involvement of :

  1. PDGFRB (5q33), or FGFR1 (8p12), membrane associated tyrosine kinases which dimerize upon PDGF or FGF presence; role in signal transduction; and
  2. A partner.
+/- Non Hodgkin Lymphoma in the case of FGFR1 involvement --> indicating that a stem-cell is likely to be implicated.

Figure 4
Figure 4

Figure 5
Figure 5

Myelodisplastic syndromes


Myelodysplasia: cells look "bizarre", dysplastic.

Classified according to the FAB:

Chromosome anomalies:
Figure 6
Figure 6
  • + 8
  • Various structural rearrangements.

Del(5q) and myeloid malignancies
Figure 7
Figure 7

It is the most common structural rearrangement in myelodysplastic syndromes (MDS) and in acute myeloid leukemias (AML); del (5q) is accompanied with given clinical and haematological features.

We herein summarize these three pictures as:

  1. "the 5q- syndrome", with del(5q) as the sole karyotypic anomaly in MDS,
  2. MDS with del(5q) and additional karyotypic anomalies, and
  3. AML with del(5q) (solely or not).

  1. The 5q- syndrome is a myelodysplastic syndrome (classified as refractory anemia (RA) in 75% of cases, RA with excess blasts (RAEB) in 15%).
    • Possibility of an exposure to a toxic agent in the environment.
    • Treatment: supportive; prognosis: favorable.
  2. MDS with del(5q): de novo MDS and therapy-related MDS (with prior exposure to alkylating agent, with or without radiotherapy); RAEB or RAEBT (RAEB in leukemic transformation); CMML (chronic myelomonocytic leukemia).
    • Prognosis: unfavorable; median survival: 10-12 months.
  3. AML with del(5q) solely (in 20-25% of cases) or not.
    • Phenotype: de novo AML and therapy-related AML; all FAB subgroups, mainly M2 AML.
    • Represents 15% of therapy-related AML with prior exposure to alkylating agents (with or without radiotherapy).
    • Prognosis: extremely poor; median survival: 3 months.

RPS14 (5q33), encoding for a ribosomal protein, was recently discovered (Jan 2008) has having a major role in the 5q- syndrome.


(or Acute Non Lymphocytic Leukaemias (ANLL))


Massive proliferation of myeloid precursors; with a hiatus aspect in the maturation pyramid and entry of immature cells into the bloodstream.
The new WHO/OMS classification replaces and completes the FAB classification (M1 to M7).


  • M0 : Undifferentiated
  • M1 : myeloblastic without maturation
  • M2 : myeloblastic with maturation
  • M3 : promyelocytic
  • M4 : myelomonocytic
  • M5 : monocytic
  • M6 : erythroleukemia
  • M7 : megakaryoblastic

  • First group: - AML with recurrent cytogenetic translocations
  • Second group: - Multilineage AML (mAML)
  • Third group: - Secondary AML
  • Fourth group: - others AML, Morpholocical and Immunophenotyping classification
Prognostic value of the chromosomal anomaly +++.

First group: AML with recurrent cytogenetic translocations

  • M2 mostly
  • The most frequent anomaly in chilhood AML; seen in children and adults: mean age 30 yrs.
  • Prognosis: Complete remission (CR) in most cases (90%); but relapse is frequent; and median survival: 1.5 yrs (adults) to 2 yrs (children).
  • RUNX1 gene (alias: AML1, CBFA2) (21q22), transcription factor implicated in hematopoietic cell maturation; forms heterodimers with CBFB; formation of a hybrid gene; RUNX1 partner: RUNX1T1 (8q22).
Figure 8
Figure 8


  • quasi pathognomonic of M3 AML
  • RARA (17q12) (Retinoic acid receptor, alpha) genes, transcription factor implicated in hematopoietic cell maturation; formation of a hybrid gene; RARA partner: PML (15q22).
  • Good prognosis (compared to others AML).
  • Prognosis improvement due to recent differentiation therapy (all trans retinoic acid): Complete remission is obtained in 80-90% of cases.
Figure 9
Figure 9


  • pathognomonic of M4eo-AML
  • CBFB (16q22) gene, T-cell transcription factor, (forms heterodimers with RUNX1, see above); formation of a hybrid gene; CBFB partner: MYH11 (16p13).
  • good prognosis: median survival = 5 yrs.
Figure 10
Figure 10

11q23 rearrangements

  • M4, M5, biphenotypic acute leukaemia
  • MLL (11q23) is implicated: transcription regulator (yin/yang?), regulates (among others) HOX genes expression. --> hematopoiesis and embryogenesis regulation; formation of a hybrid gene with a partner.
  • Various rearrangements, of which are the t(9;11)(p22;q23), the t(11;19)(q23;p13.1), a partial duplication of MLL, ...
    • -t(9;11)(p22;q23):
      • Phenotype: M5 most often (especially M5a), M4; de novo AML and therapy related AML with antitopoisomerase II drugs (epipodophyllotoxins, anthracyclins, actinomycin D).
      • Prognosis: CR in most de novo AML cases; the prognosis may not be as poor as in other 11q23 leukaemias, with a median survival around 4 yrs in de novo cases; very poor prognosis in secondary AML cases; MLL partner: MLLT3.
      • Figure 11
        Figure 11

        Figure 12
        Figure 12
      • MLL partners
      • Figure 13
        Figure 13


Hundreds of chromosome rearrangements are not listed by the WHO in its "first group"; for example: t(9;22)(q34;q11) (very rare in AML; hybrid gene BCR-ABL1, poor prognosis).

Second group: Multilineage AML

This category is defined by the presence of multilineage dysplasia (in contrast with the t(15;17), for example, which affects only promyelocytes).

Chromosomes abnormalities:

  • del(5q) / -5
  • Figure 14
    Figure 14
  • del(7q) / -7
  • + 8
  • 3q31-3q26 rearrangements:
    • Phenotype: AML, often preceeded by MDS; MDS; may occur as additional anomaly in CML with t(9;22), with thrombocytosis.
    • Prognosis: median survival is only 4 mths.
    • EVI1 (3q26): EVI1 and (antagonist?) MDS1-EVI1 splicing may play an important role in organogenesis, cell migration and differentiation; formation of a hybrid gene; partner: RPN1 (3q21).
    • Figure 15
      Figure 15
      Figure 16
      Figure 16
    • Others ...

Third group: Secondary AML

"Secondary " to exposure to toxins (ex: chemotherapy, radiotherapy, professionnal expositions (benzene), radiations, smoking.

Chromosomes anomalies:

del(5q) / -5,
del(7q) / -7
after alkyliting agent exposure, long-term latency (years).

11q23 (MLL) rearrangements,
21q22 (RUNX1) rearrangements,
after antitopoisomerase II exposure; short-term latency (often some months).

Very poor prognosis.

11q23 rearrangements in therapy related leukaemias:

(Note: 11q23 rearrangements are also -and more often- found in de novo leukaemia)

  • Phenotype: these treatment related myelodysplasias (t-MDS) or treatment related leukaemias (t-AL) exhibit variable phenotypes:
    • CMML or RAEBñT in MDS cases;
    • AML most often (M4 or M5a mainly, M1, M2, M5b at times)
    • ALL (and biphenotypic leukaemias), often CD19+, more rarely; t(4;11) cases are frequently ALL cases.
  • Etiology: 11q23 rearrangements in treatment related leukaemias were thought to be found mainly following a treatment with anti-topoisomerase II (epipodophyllotoxins) or with an intercalating topoisomerase II inhibitor (anthracyclins), as for some 21q22 rearrangements; actually, they may also be found after alkylating agents treatment and/or radiotherapy. The prior cancer is variable: breast cancer, non-Hodgkin lymphoma, Hodgkin disease, leukaemia, lung carcinoma, and other malignancies.
  • Epidemiology: up to 30% of t(11;19)(q23;p13.1), 10% or more of t(9;11), 5% of t(4;11) and 5% of t(10;11) are found in secondary leukaemias: altogether, 5 to 10% of 11q23 leukaemias are treatment related; these 11q23 second leukaemias are found at any age, from infancy to elder age.
  • Clinics: Latency before the outcome of the second leukaemia after the first cancer is often short (mediane 2 yrs), but highly variable, and may not depend on the type of treatment received; it is however most often shorter than in cases of second leukaemias associated with -5/del(5q) or with -7/del(7q).
  • Prognosis is poor, as in other therapy related leukaemias; in a recent excellent study (n=40), only 80% of patients achieved remission, ù relapsed within a year; median remission duration being 5 mths.

Fourth group: others AML, classified by Morphology and Immunophenotyping of the cells

AML M1 to M7, according to the FAB clasification + M0 (undifferentiated) and biphenotypic acute leukaemias (AML + ALL)



  • Heavy proliferation of B or T lymphoid precursors,
  • The immunophenotyping (CD, Ig) allows the recognition of the lineage involved in the malignant process, and the degree of maturation of the malignant cell
  • The cytology differenciates ALL1 and 2 on the one hand, and ALL3 with large Burkitt-type cells on the other hand.
  • --> MIC classification (Morphology, Immunophenotype, Cytogenetics) allows to define entities with given prognoses.
  • ALL often occur in childhood.

Chromosomes anomalies:


  • Immature (CD19+) B-cell.
  • Occurs often in childhood, especially very early (e.g. congenital leukemia, before 1 yr);
  • Very poor prognosis (median survival below 1 yr), the treatment being a bone marrow graft; genes MLL in 11q23 and AF4 in 4q21; formation of a hybrid gene.
  • Figure 17
    Figure 17

    Figure 18
    Figure 18

Other 11q23 rearrangements in leukemias

  • Phenotype:
    de novo and therapy related leukaemias; AML and ALL grossly represent half cases each; MDS in the remaining 5%; biphenotypic leukaemia at times; 11q23 rearrangements in treatment related leukaemias represent 5-10% of 11q23 cases.
    • MDS: most often RA or RAEBñT
    • AML: M5a in half cases, M4 (20%), M1 or M5b (10% each), M2 (5%)
    • ALL: B-cell mostly, L1 or L2, CD19+ in 60% of B-ALL cases, CD10+ 35%;T-ALL in rare cases (less than 1%);
  • Epidemiology:25% are infant (less than 1 yr) cases; children and adults each represent 50% of cases; altogether, 11q23 rearrangements in childhood acute lymphoblastic leukemia is frequent; M/F = 0.9 (NS)
  • Clinics: organomegaly; frequent CNS involvement (5%); high WBC (above 50 x 109/l in 40%).
  • Prognosis very poor in general; variable according to the translocation, the phenotype, the age, and whether the leukaemia is de novo or secondary.

  • Cytogenetics:
    • t(4;11)(q21;q23): represent 1/3 of cases.
    • t(6;11)(q27;q23) : 5% of cases; mostly; children and young adults; male predominance.
    • t(9;11)((p23;q23) : represent of cases; myeloid lineage.
    • t(10;11)(p12;q23) : 5% of cases; M4 or M5 AML; ALL at times; from infants and children to (rare) adult cases.
    • t(11;17)(q23;q21): rare; AML; not to be confused with the t(11;17)(q23;q21) in M3 AML.
    • t(11;19)(q23;p13.1): 5% of cases; M4 or M5 AML most often; de novo and therapy related AL; adult mainly; the gene involved in 19p13.1 is ELL a transcription activator.
    • t(11;19)(q23;p13.3):5% of cases; ALL, biphenotypic AL and AML (M4/M5 mainly); therapy related AL; T-cell ALL at times, these T-cell cases are the only cases of t(11;19) with an excellent prognosis; mostly found in infants (half cases), and other children (altogether: 70%), or young adults; the gene involved in 19p13.3 is MLLT1, a transcription activator.
Figure 19
Figure 19

Figure 20
Figure 20


  • B cell.
  • Very poor prognosis
  • BCR and ABL1; P210 in half cases, P190 in the other half.


  • Paediatric B cell ALL CD10+
  • Epidemiology: 15 to 35% of paediatric B-lineage ALL.
  • Prognosis: CR in all cases; prognosis seems good.
  • Cytogenetic: t(12;21) often remained undetected.
  • Hybrid gene between: ETV6 (12p13), a transcription regulator, and RUNX1/AML1 (21q22), another transcription factor.

t(8;14)(q24;q32) and t(2;8)(p12;q24) and t(8;22)(q24;q11) variants

  • Pathognomonic of L3-ALL and Burkitt lymphoma (mature B malignant cell)
  • The prognosis was poor until recently, where new treatments were accompanied with better outcome.
  • MYC in 8q24; immunoglobulin heavy-chains (IgH), in 14q32, or light-chains K (IgK) in 2p12 and L (IgL) in 22q11; these translocations set the oncogene MYC under the regulation of immunoglobulin transcription-stimulating sequences (actives in the B-lineage), leading to overexpression. Note: there is NO hybrid gene.

14q11 rearrangements

ex: t(11;14)(p13;q11), t(8;14)(q24;q11) and t(10;14)(q24;q11)

  • T cell. T-cell receptor ( TCR D and A) belonging to the immunoglobulin super-familly in 14q11. These translocations set various oncogenes under the regulation of T-cell receptor transcription-stimulating sequences (actives in the T-lineage, inactives in the B-lineage; such a translocation in the B-cell would remain silent, since these T-cell stimulating sequences are asleep in the B-cell), leading to overexpression. Note: there is NO hybrid gene.

B Cell/ T Cell
Figure 21
Figure 21. t(8;14)(q24;q11) MYC/TCR

Figure 22
Figure 22. t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11)

Figure 23
Figure 23.MYC/Ig
B Cell

Figure 24
Figure 24

Figure 25
Figure 25

Domino game
Figure 26
Figure 26


B-cell chronic lymphoproliferative disorders (CLD)

B cell Non Hodgkins lymphomas (NHL)

T Cell:

Figure 27
Figure 27

II. Solid Tumours (short summary)


Sarcomas: it is an heterogeneous group, of many malignant tumours, often the diagnostic is hard to reach; however, a number of these tumours present a specific translocation; which can be of great help for diagnostic ascertainement.

A few examples:

  1. Lipoma:rearrangement of HMGA2 (12q15), high mobility group gene, , non histone protein, architectural factor, preferential binding to AT rich sequences in the minor groove of DNA helix.
  2. Liposarcoma: MDM2 amplification (NO translocation, NOR stimulation by a gene enhancer as for MYC) ; (located in 12q15, MDM2 interacts with TP53 and RB1, inhibits the cell cycle arrest in G1 phase and apoptosis); Often, neighbouring genes too, CDK4 and HMGA2, may be amplified and over-expressed.
  3. Inflammatory myofibroblastic tumor (see above).
  4. Embryonal rhabdomyosarcoma: loss of heterozygoty in 11p15 (function of IGF2, H19, CDKN1C ??); complex karyotype.
  5. Alveolar rhabdomyosarcoma: specific translocation t(2;13)(q35;q14); PAX3 (2q35, transcription factor implicated in proliferation, differentiation, apoptosis) and FKHR (13q14). Variant translocation: t(1;13)(p36;q14): PAX7(1p36) / FKHR.
  6. Figure 28
    Figure 28
  7. Ewings tumors / Primitive neurectodermal tumours (PNET) : small round-cell tumours (difficult to diagnose) deriving from neural crests cells.
    • t(11;22)(q24;q12) FLI1/ EWSR1 and variant translocations all implicating EWSR1.
    • EWSR1 binds to RNA; repressor.



There can be specific translocations, e.g.:

Most often, karyotypes are complex, and still poorly understandable; comparative genomic hybridization (CGH) and CGH array are particularly useful..


  • The diploid form, RER+ (Replication Error +), sporadic, without loss of heterozygoty (LOH), with few TP53 and APC, mutations, in the right-sided colon.
  • The polyploid form, RER-, with LOH 5q, 17p, 18q, p53 mutations, more often in left-sided colon, with a poorer prognosis.

? Colorectal cancers can also be related to given cancer-prone diseases:
  1. Familial adenomatous polyposis (FAP) : characterized by the development of hundreds of polyps at a very early age, due to mutations in APC (5q21); CTNNB1 is phosphorylated by a complex including APC, which leads to CTNNB1 degradation by the ubiquitin-proteasome; CTNNB1 is assumed to transactivate genes which may stimulate cell proliferation or inhibit apoptosis.
  2. Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome : due to germline mutations in genes intervening in the repair of DNA mismatches occurring during replication (MSH2 and MLH1).
Figure 31
Figure 31



  • complex, not yet understood. 
  • losses of heterozygocity (LOH)
  • HSR (homogeneously staining region): --> DNA amplification.

Genes Implicated:

  • ERBB2 (17q21, membrane-associated tyrosine kinase receptor), prognostic indicator. Overexpression of ERBB2 is associated with tumor aggressiveness; if ERBB2 is amplified, a treatment with Erceptin should be given,
  • HRAS, KRAS, NRAS (GTP binding p21 proteins, signal transduction),
  • TP53,
  • CCND1 (cell cycle control related to RB1),
  • FGFR1 (8p11, membrane associated tyrosine kinase),
  • BRCA1, BRCA2,
  • PTEN (10q23, phosphatase, downregulator of the PI3K/AKT pathway, also implicated in Cowden, a cancer prone disease),
  • ATM (see below),
  • MSH2, MLH1, PMS1, PMS2, MSH3 , "Mismatch repair" genes,?etc?.

? 5-10% of breast cancers are due to hereditary predisposition, with germinal mutations in:
  • BRCA1 (17q21; complex role: part of the DNA repair complex, transcriptional regulator, cell cycle regulator, role in apoptosis...)
  • BRCA2 (13q12, phosphorylated by ATM, implicated in the double-strand break response).

? Others hereditary conditions with predisposition to breast cancers:

III. Cancer prone diseases


Some rare genetic diseases:

  • Fanconi Anaemia (FA)
  • Ataxia Telangiectasia (AT)
  • Bloom Syndrome (BS)
  • Xeroderma pigmentosum (XP)
are defined by: These diseases are defined by a high level of breaks or chromosomal rearrangements and/or a high sensibility to mutagen reagents.
If DNA lesions are not properly repaired, mutations and genes rearrangements fast accumulate, leading to oncogene activation or antioncogene inactivation, by chance, at a time or another.

Fanconi Anemia (FA)
Autosomal recessive; q2 = 1/40 000.
  • 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 (MDS) and acute myeloid leukemia (AML): in 10% of cases; i.e. a 15 000 fold increased risk; other cancers (5%).

  • spontaneous chromatid/chromosome breaks.
  • hypersensitivity to the clastogenic effect of DNA cross-linking agents.

Others: slowing of the cell cycle (G2/M transition).

Genes: At least 7 complementation groups; genes FANCA, FANCC, FANCD2?

The FA complex subsequently interacts in the nucleus with FANCD2 during S phase or following DNA damage.
Activated FANCD2, downstream in the FA pathway, will then interact with other proteins involved in DNA repair, possibly BRCA1; after DNA repair, FANCD2 return to the non-ubiquinated form.
Figure 32
Figure 32

Figure 33
Figure 33

Figure 34
Figure 34

Ataxia Telangiectasia (AT)

Autosomal recessive; q2 = 1/40 000.


  • 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.

  • more than 10% of mitoses bear a chromosome rearrangement in 7p14, 7q35, 14q11, (localisations of receptor T genes, immunoglobulin superfamilly) or 14q32.
  • Figure 35
    Figure 35
  • clonal rearrangements further occur --> T-cell malignancy.

  • lenthening of the cell cycle (slower S phase).
  • Radiosensitivity: AT patients present a high sensitivity to radiations and to radiomimetic drugs.

Gene: ATM (11q22), key role in cell cycle control during double-strand DNA breaks; phosphorylate TP53, BRCA1, etc?

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

Bloom Syndrome (BS)

Autosomal recessive; q2 = 2/100 000.


  • 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.

  • spontaneous chromatid breaks.
  • diagnosis on the highly elevated spontaneous sister chromatid exchange rate (90 per cell).

Others: slowing of the cell cycle (lenthening of the G1 and S phases).

Gene: BLM, (15q26) , codes for a DNA helicase.
  • Participates in a supercomplex of BRCA1-associated proteins named BASC (BRCA1-Associated genome Surveillance Complex) and
  • In a complex named BRAFT (BLM, RPA, FA, Topoisomerase IIIalpha) containing five of the Fanconia Anemia (FA) complementation group proteins (FANCA, FANCG, FANCC, FANCE and FANCF).

Figure 36
Figure 36. Micro nuclei. SCE (sister chromatid exchange)

Xeroderma Pigmentosum (XP)

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

  • severe sun photosensitivity --> poikilodermia, premature aging of the skin --> 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.

Others: hypermutability of the cells under UV irradiation.

Genes: 9 complementation groups. Genes ERCC (excision repair cross complement) and XP (e.g.: XPA) : mumerous and dispersed on various chromosomes; role in DNA repair (helicases) and in the complex repair/transcription factor.
All XP genes are implicated in various steps of the NER (nucleotide excision repair) system , except the XP variant that is mutated in a mutagenic DNA polymerase (POL H) able to bypass the UV-induced DNA lesions.



Cancer prone disease at increased risk of the cancer of the retina called retinoblastoma.

  • tumor of the neurectoderma (retina).
  • 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 osteosarcoma .
  • in a (very) few cases, a visible chromosome 13 deletion may be seen on the constitutional karyotype, and, according to the lenght of the deletion, retinoblastoma can either be isolated, or be a part of a malformative syndrome.
These features are unusual, and some appear contradictory...lets tell the story:
  • 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 that of a bilateral retinoblastoma).
    • 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.
Figure 37
Figure 37.

Therefore, the gene is a recessive gene; however it seems to be transmitted with an autosomal dominant pattern in the hereditary forms; How?:
  • The hereditary mutation, first event, has a probability of ½ to be transmitted from the carrier parent.
  • The somatic events probability is close to 1 (the probability of the somatic/second event is the result of the very low rate of mutation for each given cell multiplied by a great number of cells at risk).
    --> so, the final probability to have a retinoblastoma, when one of the two parents is carrier, will be: 1/2 x nearly 1 = "nearly 1/2",
  • ... which usually characterize autosomal dominant transmission (!).

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.
Figure 38
Figure 38.

RB1 (13q14)

  • key regulator of cell division entry; acts as a tumor suppressor.
  • Directly implicated in heterochromatin formation : by maintaining the chromatin structure et, particulary, constitutive heterochromatin; stabilize histone methylation.
  • Also acts as transcription repressor of the E2F target genes.

Li-Fraumeni Syndrome and TP53

  • 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.
  • In the general population, if a given person has a cancer: --> the 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 predisposition:
    • too early in life
    • more than 1 cancer in 1 patient
    • positive family history
  • 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.
  • Mutation of various genes can lead to Li-Fraumeni Syndrome:
    • TP53 in 70% of Li-Fraumeni cases, but also:
    • CHK2 (22q12, role in DNA double-strand break response),
    • PTEN (10q23, downregulator of PI3K/AKT pathway),
    • CDKN2A (9p21, interacts with CDKs (cyclin dependant kinases), activates the cell cycle arrest by preventing RB1 phosphorylation).
...on the other hand, somatic mutations of P53 are found in about 50% of all cancers.


? Example: NF1:

Neurofibromatosis Type 1

  • Heredity: autosomal dominant with almost complete penetrance;
  • frequency: 30/105 newborns (and 1 of 200 mentally handicapped persons): one of the most frequent genetically inheritable disease;
  • Neomutation in 50%, mostly from the paternal allele;
  • highly variable expressivity, from very mild to very severe; expressivity is also age-related.
  • Clinics: NF1 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia; the embryonic origin of dysgenetic tissues involved in NF1 is ectoblastic.
  • Diagnosis is made on the ground of at least 2 of the following:
    • café-au-lait spots
    • 2 neurofibromas or 1 plexiform neurofibromas (mainly cutaneous)
    • 2 Lisch nodules (melanocytic hamartomas of the iris)
    • freckling in the axillary/inguinal region
    • glioma of the optic nerve
    • distintive bone anomalies (scoliosis, pseudoarthroses, bony defects (orbital wall) ...)
    • positive family history
    • Other features: macrocephaly, epilepsy, mental retardation in 10 %; learning diabilities in half patients, sexual precocity and other endocrine anomalies, hypertension (renal artery stenosis).
  • Neoplastic risk:
    • 5% of patients having von Recklinghausen disease will have a cancer.
    • Neurofibromas (especially the plexiform variety) are polyclonal (benign) proliferation; may be present at birth or appear later.They may be a few or thousands, small or enormous, occur in the skin and in various tissus and organs.
    • Neurofibrosarcomatous transformation (malignant) of these in 5-10 %.
    • Schwannomas (optic nerve, see above), meningiomas, astrocytomas, ependymoma.
    • Childhood MDS (myelodysplasia) and AML , often with monosomy 7 ( monosomy 7 syndrome , juvenile myelomonocytic leukaemia): risk, increased by X 200 to 500, most often before the age of 5 yrs; no increased risk of leukaemia in the adult.
    • Pheochromocytomas.
    • Various other neoplasias, of which are rhabdomyosarcomas.
    • Treatement: early diagnosis, lifetime monitoring and surgery are essential.
    • Gene: NF1 (neurofibromin 1) 17q11.2; (GTPase activating protein (GAP)) interacting with p21RAS --> tumour suppressor.
      • Germinal: deletions or insertions in 25% of cases, point mutations and translocations; no "cluster" of mutations, making difficult the diagnosis.
      • Somatic: the second allele stays normal in benign tumours but is often lost in malignant tumours.


Huret JL Huret JL

Atlas of Genetics and Cytogenetics in Oncology and Haematology 2000-06-01

Chromosomes, Leukemias, Solid Tumors, Hereditary Cancers

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