FAMILIAL CHRONIC LYMPHOID DISORDERS
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FAMILIAL CHRONIC LYMPHOID DISORDERS Dr Estella Matutes Murcia, November 2006. 1887 +1953. 1884 +1996. 1894 +1968. 1895 +1984. 1897 +1928. 1900 +1980. 1903 +1968. CLL. 1907. 1909. 1912 +1912. 1915. 1917 +1980. 1925. 1919 +1994. Evidence for a genetic predisposition.

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FAMILIAL CHRONIC LYMPHOID DISORDERS

Dr Estella Matutes

Murcia, November 2006


1887

+1953

1884

+1996

1894

+1968

1895

+1984

1897

+1928

1900

+1980

1903

+1968

CLL

1907

1909

1912

+1912

1915

1917

+1980

1925

1919

+1994


Evidence for a genetic predisposition

Epidemiological studies (cohort and case control)

Vertical transmission and “anticipation”

Significantly higher incidence of asymptomatic MBL


Familial risks of CLL

The main evidence derives from:

Cohort studies – risk 2.4-5.7(Gunz, 1975; Giles, 1984; Goldgar, 1994)

Case control studies – risk 2.3-4.3(Linet, 1989; Pattern, 1991; Cartwright, 1987)

Relatives of CLL patients have a six-fold increase in risk


Videbaek’s pedigree 14 revisited

(1947-2004)*

Original family = 55 members

Current pedigree = 221 descendents

10 diagnosed with CLL; 1 T-cell lymphoma

18 non-haematological cancers (5 breast)

Relative risk for B-cell LPD = 7.9 (p < 0.001)

This family provides further support for an inherited predisposition to CLL

*Jønsson, Houlston, Catovsky et al (Leukemia, 19, 1025, 2005)


Familial risks of B-cell LPDs Evidence of pleiotropism

Goldin et al., (2004) Blood 104:1850; Goldin et al., (2004) Cancer100; 1902

Goldin et al., (2004) Cancer Epid Bio Prev 13:1415


Family 005

Family 094

Family 037

Family 039


Anticipation in familial cll
Anticipation in Familial CLL

Yuille (1998) Goldin (1999) Wiernik (2001)

# families 10 13 10

Mean age 74 68 72

Mean age 52 51 51

A large epidemiological study showed no evidence of anticipation in CLL & NHL:

Daugherty et al ,Cancer Epidemiol Biomarkers Prev.(2005) 14:1245


Monoclonal B-cell lymphocytosis (MBL)

  • Diagnostic criteria recently reported

  • (Marti et al, BJH 130:325, 2005)

  • Flow cytometry can detect ‘sub-clinical’ MBL in normal relatives of F-CLL and provides the possibility of extending the number of affecteds in linkage families

  • MBL is found in 3.5% of normal adults by flow cytometry

  • (Rawstron et al, Blood 100:2289 & 100:635, 2002)


Incidence of mbl in familial cll rawstrom et al 2002

CD5

Familial

Control

CD79b

CD20

Incidence of MBL in Familial CLL Rawstrom et al (2002)

25%

20%

15%

10%

5%

0%

years

<50

50-59

60-69

70+


MBL in F-CLL: young adults show the highest relative risk*

*Tute, Yuille, Rawstron et al (2006) Leukemia 20:728


Familial CLL

No differences from sporadic CLL in:

  • Age, M:F ratio, incidence of Zap-70+ *

  • IgVH usage and frequency of somatic mutation *

  • ATM mutations

  • Frequency of 6q21, 11q23, 13q14 and p53 deletions or trisomy 12

* Rassenti et al (2003) Blood 102:670a

A study from the USA CLL Research Consortium


  • Strategies for identifying CLL predisposition genes

  • 1: Linkage analysis of families to identify moderate-high penetrance alleles

  • 2: Association studies of SNPs to identify low penetrance alleles

  • 3: Screening familial cases for mutations in candidate genes


  • UK Familial CLL study

  • Families collected to date

  • 456 families documented (339 with 2 or more CLL cases)

  • 401 of these we have at least 1 sample from the family

  • 87 families have at least 1 case of CLL and 1 or more cases of LPD

  • 33 families with 2 or more NHL/HL cases


Linkage analysis in Familial CLL

A high density single nucleotide polymorphism (SNP) - based genomewide linkage search was undertaken on 115 CLL families by our group using the Affymetrix Mapping 10K Array (11,555 markers)


Linkage analysis in Familial CLL

  • Sample set used for SNP linkage analysis:

  • 115 CLL/CLL-LPD families

  • 80 families with 2 affecteds

  • 28 families with 3 affecteds

  • 5 families with 4 affecteds

  • 2 families with 5+ affecteds

  • Median age at diagnosis of CLL 61 years

Sellick et al, Am J Hum Genetics (2005) 77:420-9


Familial CLL – linkage analysis

Sellick et al, Am J Hum Genet, 77, 420 (2005)


  • Linkage analysis: future work

  • Genotyping an additional 40 families

  • Screening family members for MBL status

  • Currently undertaking mutation screening of genes mapping to linked regions e.g. the 11p11 locus: SPI1 and MADD


  • Pathogenesis of Familial CLL

  • High-penetrance mutations

  • [Genome-wide linkage analysis]

  • OR

  • Polygenic model of low penetrance alleles

  • [Association studies in ethnically matched cases and controls comparing the frequency of polymorphic genotypes]


  • SUMMARY

  • Studies are preliminary and “on going” but this requires international collaboration, economical imput, application of new technologies and patient’s and relatives “willing”

  • At present it is premature to set up a program of counselling as a predisposing gene(s) has not been identified although patients and relatives are aware of the inherited susceptibility


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