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FAMILIAL CHRONIC LYMPHOID DISORDERS Dr Estella Matutes Murcia, November 2006

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

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  1. FAMILIAL CHRONIC LYMPHOID DISORDERS Dr Estella Matutes Murcia, November 2006

  2. 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

  3. Evidence for a genetic predisposition Epidemiological studies (cohort and case control) Vertical transmission and “anticipation” Significantly higher incidence of asymptomatic MBL

  4. 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

  5. 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)

  6. 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

  7. Family 005 Family 094 Family 037 Family 039

  8. 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

  9. 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)

  10. 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+

  11. MBL in F-CLL: young adults show the highest relative risk* *Tute, Yuille, Rawstron et al (2006) Leukemia 20:728

  12. 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

  13. 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

  14. 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

  15. 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)

  16. 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

  17. Familial CLL – linkage analysis Sellick et al, Am J Hum Genet, 77, 420 (2005)

  18. 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

  19. 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]

  20. 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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