familial chronic lymphoid disorders dr estella matutes murcia, november 2006
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
FAMILIAL CHRONIC FAMILIAL CHRONIC LYMPHOID LYMPHOID
DISORDERSDISORDERS
Dr Estella MatutesDr Estella Matutes
Murcia, November 2006Murcia, November 2006
18871887+1953+1953
18841884+1996+1996
18941894+1968+1968
18951895+1984+1984
18971897+1928+1928
19001900+1980+1980
19031903+1968+1968
19071907 19091909 19121912+1912+1912
19151915 19171917+1980+1980
19251925 19191919+1994+1994
CLLCLL
Epidemiological studies (cohort and case Epidemiological studies (cohort and case control)control)
Vertical transmission and “anticipation”Vertical transmission and “anticipation”
Significantly higher incidence of Significantly higher incidence of asymptomatic MBLasymptomatic MBL
Evidence for a genetic Evidence for a genetic predispositionpredisposition
The main evidence derives from:The main evidence derives from:
Cohort studies – risk 2.4-5.7Cohort studies – risk 2.4-5.7(Gunz, 1975; Giles, 1984; Goldgar, 1994)(Gunz, 1975; Giles, 1984; Goldgar, 1994)
Case control studies – risk 2.3-4.3Case control studies – risk 2.3-4.3(Linet, 1989; Pattern, 1991; Cartwright, 1987)(Linet, 1989; Pattern, 1991; Cartwright, 1987)
Relatives of CLL patients have a six-fold Relatives of CLL patients have a six-fold increase in riskincrease in risk
Familial risks of CLLFamilial risks of CLL
Videbaek’s pedigree 14 revisitedVidebaek’s pedigree 14 revisited (1947-2004)*(1947-2004)*
Original family = 55 membersOriginal family = 55 members
Current pedigree = 221 descendentsCurrent pedigree = 221 descendents
10 diagnosed with CLL; 1 T-cell lymphoma10 diagnosed with CLL; 1 T-cell lymphoma
18 non-haematological cancers (5 breast)18 non-haematological cancers (5 breast)
Relative risk for B-cell LPD = Relative risk for B-cell LPD = 7.9 (p < 0.001)7.9 (p < 0.001)
This family provides further support for an This family provides further support for an inherited predisposition to CLLinherited predisposition to CLL
*J*Jøønsson, Houlston, Catovsky et al (nsson, Houlston, Catovsky et al (LeukemiaLeukemia, , 19,19, 1025, 2005) 1025, 2005)
CaseCase First-degreeFirst-degreerelative withrelative with
Familial RRFamilial RR (95%CI)(95%CI)
CLLCLL CLLCLL 7.57.5 (3.6-15.6)(3.6-15.6)
CLLCLL NHLNHL 1.51.5 (1.0-2.2)(1.0-2.2)
CLLCLL HLHL 2.42.4 (1.1-5.1)(1.1-5.1)
NHLNHL NHLNHL 2.92.9 (1.0-8.5)(1.0-8.5)
HLHL CLLCLL 2.12.1 (1.2-3.8)(1.2-3.8)
Goldin et al., (2004) Blood 104:1850; Goldin et al., (2004) Cancer100; 1902Goldin et al., (2004) Blood 104:1850; Goldin et al., (2004) Cancer100; 1902Goldin et al., (2004) Cancer Epid Bio Prev 13:1415Goldin et al., (2004) Cancer Epid Bio Prev 13:1415
Familial risks of B-cell LPDs Familial risks of B-cell LPDs Evidence of pleiotropismEvidence of pleiotropism
Anticipation in Familial CLLAnticipation in Familial CLL
Yuille (1998) Goldin (1999) Wiernik (2001)Yuille (1998) Goldin (1999) Wiernik (2001)
# families# families 1010 13 13 10 10
Mean ageMean age 74 74 68 68 72 72
Mean age Mean age 52 52 51 51 51 51
A large epidemiological study showed no evidence of A large epidemiological study showed no evidence of anticipation in CLL & NHL:anticipation in CLL & NHL: Daugherty Daugherty et al ,et al ,Cancer Epidemiol Biomarkers Prev.Cancer Epidemiol Biomarkers Prev. (2005) 14:1245(2005) 14:1245
Monoclonal B-cell lymphocytosis (MBL)Monoclonal B-cell lymphocytosis (MBL)
• Diagnostic criteria recently reported Diagnostic criteria recently reported
(Marti (Marti et al, et al, BJH BJH 130130:325, 2005):325, 2005)
• Flow cytometry can detect ‘sub-clinical’ MBL Flow cytometry can detect ‘sub-clinical’ MBL in normal relatives of F-CLL and provides the in normal relatives of F-CLL and provides the possibility of extending the number of possibility of extending the number of affecteds in linkage familiesaffecteds in linkage families
• MBL is found in 3.5% of normal adults by MBL is found in 3.5% of normal adults by flow cytometry flow cytometry
(Rawstron (Rawstron et alet al, Blood , Blood 100100:2289 & :2289 & 100100:635, 2002):635, 2002)
Incidence of MBL in Familial CLL Incidence of MBL in Familial CLL Rawstrom et al (2002)Rawstrom et al (2002)
0%0%
5%5%
10%10%
15%15%
20%20%
25%25%
<50<50 50-5950-59 60-6960-69 70+70+
FamilialFamilialControlControl
yearsyearsCD79b
CD79bCD20CD20
CD
5C
D5
Age Age groupgroup
General General populationpopulation
Normal Normal relatives relatives from CLL from CLL familiesfamilies
Relative Risk Relative Risk (95% C.I.)(95% C.I.)
P-value P-value Fishers Fishers exact exact testtest
All All agesages
33/1242 (2.7%)33/1242 (2.7%) 8/65 (12.3%)8/65 (12.3%) 3.9 (2.0 - 7.6)3.9 (2.0 - 7.6) 0.0010.001
16 - 4016 - 40 1/365 (0.3%)1/365 (0.3%) 2/17 (11.8%)2/17 (11.8%) 16.9 (6.6 – 43.3)16.9 (6.6 – 43.3) 0.0050.005
40 - 6040 - 60 10/457 (2.1%)10/457 (2.1%) 3/30 (10.0%)3/30 (10.0%) 4.1 (1.4 - 11.9)4.1 (1.4 - 11.9) 0.0370.037
60 - 9060 - 90 22/420 (5.2%)22/420 (5.2%) 3/18 (16.7%)3/18 (16.7%) 3.5 (1.1 - 11.2)3.5 (1.1 - 11.2) 0.0670.067
MBL in F-CLL: young adults show the MBL in F-CLL: young adults show the highest relative risk*highest relative risk*
*Tute, Yuille, Rawstron *Tute, Yuille, Rawstron et alet al (2006) Leukemia 20:728 (2006) Leukemia 20:728
Familial CLLFamilial CLL
No differences from sporadic CLL in:No differences from sporadic CLL in:
• Age, M:F ratio, incidence of Zap-70+ Age, M:F ratio, incidence of Zap-70+ **
• IgVH usage and frequency of somatic mutation IgVH usage and frequency of somatic mutation **
• ATM mutationsATM mutations
• Frequency of 6q21, 11q23, 13q14 and p53 Frequency of 6q21, 11q23, 13q14 and p53 deletions or trisomy 12deletions or trisomy 12
** Rassenti et al (2003) Rassenti et al (2003) BloodBlood 102:670a 102:670a
A study from the USA CLL Research ConsortiumA study from the USA CLL Research Consortium
Strategies for identifying CLL Strategies for identifying CLL predisposition genespredisposition genes
1: Linkage analysis of families to identify 1: Linkage analysis of families to identify moderate-high penetrance allelesmoderate-high penetrance alleles
2: Association studies of SNPs to identify low 2: Association studies of SNPs to identify low penetrance allelespenetrance alleles
3: Screening familial cases for mutations in 3: Screening familial cases for mutations in candidate genescandidate genes
UK Familial CLL studyUK Familial CLL study
Families collected to dateFamilies collected to date
• 456 families documented (339 with 2 or more 456 families documented (339 with 2 or more CLL cases)CLL cases)
• 401 of these we have at least 1 sample from 401 of these we have at least 1 sample from the familythe family
• 87 families have at least 1 case of CLL and 1 or 87 families have at least 1 case of CLL and 1 or more cases of LPDmore cases of LPD
• 33 families with 2 or more NHL/HL cases33 families with 2 or more NHL/HL cases
Linkage analysis in Familial CLLLinkage analysis in Familial CLL
A high density single nucleotide A high density single nucleotide polymorphism (SNP) - based polymorphism (SNP) - based genomewide linkage search was genomewide linkage search was undertaken on 115 CLL families by undertaken on 115 CLL families by our group using the Affymetrix our group using the Affymetrix Mapping 10K Array (11,555 markers)Mapping 10K Array (11,555 markers)
• Sample set used for SNP linkage analysis:Sample set used for SNP linkage analysis:
115 CLL/CLL-LPD families115 CLL/CLL-LPD families
80 families with 2 affecteds80 families with 2 affecteds
28 families with 3 affecteds28 families with 3 affecteds
5 families with 4 affecteds5 families with 4 affecteds
2 families with 5+ affecteds2 families with 5+ affecteds
• Median age at diagnosis of CLL 61 years Median age at diagnosis of CLL 61 years
Linkage analysis in Familial CLLLinkage analysis in Familial CLL
Sellick Sellick et al, et al, Am J Hum Genetics (2005) Am J Hum Genetics (2005) 7777:420-9:420-9
Familial CLL – linkage analysisFamilial CLL – linkage analysis
Chromosomal Chromosomal RegionRegion
Non-Non-parametricparametric
Dominant Dominant modelmodel
Recessive Recessive modelmodel
Max Max NPLNPL pp
Max Max HLODHLOD αα
Max Max HLODHLOD αα
5q22-235q22-23 2.012.01 0.0220.022 1.021.02 0.290.29 1.351.35 0.200.20
6p226p22 2.252.25 0.0120.012 1.051.05 0.290.29 1.491.49 0.220.22
10q2510q25 2.122.12 0.0170.017 0.940.94 0.280.28 1.281.28 0.220.22
11p11 3.14 0.0008 1.85 0.41 2.78 0.32
14q3214q32 2.032.03 0.0210.021 1.181.18 0.340.34 0.910.91 0.190.19
Sellick Sellick et alet al, Am J Hum Genet, , Am J Hum Genet, 7777, 420 (2005), 420 (2005)
Linkage analysis: future workLinkage analysis: future work
• Genotyping an additional 40 familiesGenotyping an additional 40 families
• Screening family members for MBL statusScreening family members for MBL status
• Currently undertaking mutation screening of Currently undertaking mutation screening of genes mapping to linked regions genes mapping to linked regions e.g. the 11p11 e.g. the 11p11 locus: locus: SPI1 SPI1 andand MADD MADD
Pathogenesis of Familial CLLPathogenesis of Familial CLL
• High-penetrance mutationsHigh-penetrance mutations
[Genome-wide linkage analysis][Genome-wide linkage analysis]
OROR
• Polygenic model of low penetrance allelesPolygenic model of low penetrance alleles
[Association studies in ethnically matched [Association studies in ethnically matched cases and controls comparing the frequency cases and controls comparing the frequency of polymorphic genotypes] of polymorphic genotypes]
SUMMARYSUMMARY
• Studies are preliminary and “on going” but this Studies are preliminary and “on going” but this requires international collaboration, economical requires international collaboration, economical imput, application of new technologies and imput, application of new technologies and patient’s and relatives “willing”patient’s and relatives “willing”
• At present it is premature to set up a program of At present it is premature to set up a program of counselling as a predisposing gene(s) has not been counselling as a predisposing gene(s) has not been identified although patients and relatives are aware identified although patients and relatives are aware of the inherited susceptibilityof the inherited susceptibility