FAMILIAL CHRONIC LYMPHOID DISORDERS Dr Estella Matutes Murcia

FAMILIAL CHRONIC LYMPHOID DISORDERS Dr Estella Matutes Murcia, November 2006

1887 +1953 1884 1895 1897 1900 +1996 +1968 +1984 +1928 +1980 1903 +1968 CLL 1907 1909 1912 +1912 1915 1917 1925 1919 +1980 +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 Case Familial RR (95%CI) CLL First-degree relative with CLL 7. 5 (3. 6 -15. 6) CLL NHL HL NHL CLL 1. 5 2. 4 2. 9 2. 1 (1. 0 -2. 2) (1. 1 -5. 1) (1. 0 -8. 5) (1. 2 -3. 8) Goldin et al. , (2004) Blood 104: 1850; Goldin et al. , (2004) Cancer 100; 1902 Goldin et al. , (2004) Cancer Epid Bio Prev 13: 1415

Family 005 Family 094 Family 037 Family 039

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) 25% CD 5 20% Familial Control 15% 10% CD 20 b 9 7 D C 5% 0% <50 50 -59 60 -69 70+ years

MBL in F-CLL: young adults show the highest relative risk* Age group General population Normal relatives from CLL families Relative Risk (95% C. I. ) 33/1242 (2. 7%) 8/65 (12. 3%) 3. 9 (2. 0 - 7. 6) All ages 2/17 (11. 8%) 16. 9 (6. 6 – 43. 3) 16 - 40 1/365 (0. 3%) P-value Fishers exact test 0. 001 0. 005 40 - 60 10/457 (2. 1%) 3/30 (10. 0%) 4. 1 (1. 4 - 11. 9) 0. 037 60 - 90 22/420 (5. 2%) 3/18 (16. 7%) 3. 5 (1. 1 - 11. 2) 0. 067 *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+ * • Ig. VH usage and frequency of somatic mutation * • ATM mutations • Frequency of 6 q 21, 11 q 23, 13 q 14 and p 53 deletions or trisomy 12 * Rassenti et al (2003) Blood 102: 670 a 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 10 K 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 Chromosomal Region Nonparametric Max p NPL Dominant model Max α HLOD Recessive model Max α HLOD 5 q 22 -23 2. 01 0. 022 1. 02 0. 29 1. 35 0. 20 6 p 22 2. 25 0. 012 1. 05 0. 29 1. 49 0. 22 10 q 25 2. 12 0. 017 0. 94 0. 28 1. 28 0. 22 11 p 11 3. 14 0. 0008 1. 85 0. 41 2. 78 0. 32 14 q 32 2. 03 0. 021 1. 18 0. 34 0. 91 0. 19 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 11 p 11 locus: SPI 1 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