Epilymph and beyond—haematological cancer aetiology, genetics and serendipity
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Transcript of Epilymph and beyond—haematological cancer aetiology, genetics and serendipity
Epilymph and beyond—haematological cancer aetiology,
genetics and serendipity
Anthony Staines,School of Nursing,
DCU.
Topics
Haematological cancers Causes known and unknown Process The case of myeloma Where do we go next?
Lymphomas
Complex group of malignant diseases of varied prognosis arising in lymphocyte precursors
May be hard to distinguish one from another, but most can be reliably classified
Basic grouping now known to be into those of T-cell origin and those of B-cell origin
We will focus on multiple myeloma
Multiple myeloma
A haematological malignancy A non-Hodgkins lymphoma The malignant cells look and behave a bit like
mature B-cells Most of the other lymphomas the cells look like
immature lymphocytes Probably a long latency period
Normal haematopoiesis
Normal haematopoiesis (2)
Rare diseases?
Cancer incidence, mortality, treatment and survival in the North and South of Ireland: 1994-2004 (Summary report)
Rare diseases?
Cancer incidence, mortality, treatment and survival in the North and South of Ireland: 1994-2004 (Summary report)
Rare diseases?
Cancer incidence, mortality, treatment and survival in the North and South of Ireland: 1994-2004 (Summary report)
Rare diseases?
Cancer incidence, mortality, treatment and survival in the North and South of Ireland: 1994-2004 (Summary report)
Rare diseases?
Cancer incidence, mortality, treatment and survival in the North and South of Ireland: 1994-2004 (Summary report)
Rare diseases?
No F 814 cases M 1010 cases T 1829 cases
Collectively 4th commonest cancers in both men and women
Lymphoma Aetiology
Still largely unknown, but much better understood than ten years ago Occupational exposures Farming Viruses, notably Hepatitis B, C, HIV, HTLV I, SV40
and especially EBV Bacteria H pylori Sunlight, but not occupational sunlight exposure Older hair dyes Being male Many different SNPs
The problem
The lymphomas are a group of closely related disorders
As they are studied more closely, in particular using gene expression studies, each pathological disorder reveals clinically relevant heterogeneity
The classifications were rather a mess, but this is now well sorted out
There are a group of cases for whom leading experts will not find a consensus diagnosis
The problem (2)
There were large numbers of studies Many were quite small They used inconsistent exposure assessments,
and classifications
The solution?
A solution anyway
Interlymph NCI supported consortium with investigators
originally from Europe, Australia and North America, now including China, Japan, other parts of Asia, Africa, and the Middle East
Started at an informal meeting of several case-control studies which were using similar methodologies and the WHO classification
Interlymph
Consortium of case-control study investigators Studies in adults and adolescents only, so far Closely associated with Interlymph are a
Hodgkin's lymphoma consortium, and a myeloma consortium (IMMC)
Activities
Annual meeting Data centre Clear protocol for data sharing and authorship Many pooling studies Largely responsible for the improvement in our
understanding of the aetiology of the lymphomas
Plasma cells and myeloma
Normal Plasma Cells
Myeloma Cells
Patterns of myeloma
Class switch recombination
Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and
susceptibility to myeloma. A team lead by Mark Lawler and Prerna Tewari
used data from Epilymph and from an Irish study to look at CSR genes and myeloma
We found 2 SNPs in XRCC4 and XRCC5 with significant, and likely robust, associations with an increased risk of myeloma
Epidemiology & Etiology
More than 10% of all haematological malignancies
1% of all cancers, around 2/100,000 in the UK & Ireland
Increases with age, 40% of patients around 60 yrs
Big variation in rates internationally Highest in Caribbean Highest in American Blacks, about 2X rate in
Whites and Hispanics
Myeloma in Ireland0
2040
6080
rate
/ 10
0,00
0
30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 >84
Males Females
Myeloma in Ireland
About 320 cases a year (M > F) About 210 deaths a year (M > F) Five year survival 200-2004 is 35% (F > M) Modest improvement since 1994 (about 30%)
Aetiology?
There are lots of studies There are lots of reviews There was little clarity
Myeloma tended to be reported towards the bottom of table 3
We really did not know what we needed to know
What did we do?
A large systematic review A case-control study A pooled case-control study
A large systematic review
Multiple myeloma and farming. A systematic review of 30 years of research. Where next?
Perrotta C, Staines A, Cocco P. J Occup Med Toxicol. 2008 Nov 17;3:27.
Systematic review
Case-control studies Cohort studies Systematic literature search Formal meta-analysis methods Pooled effect estimate
Allow for heterogeneity
Meta-analysis
NOTE: Weights are from random effects analysis
.
.
Overall (I-squared = 53.2%, p = 0.002)
La Vecchia 1986
Eriksson 1992
Pearce 1986
Death certificate studies
Pahwa 2003
Boffetta 1989
Incident case studies
Nanni 1998
Nandakumar 1989
Subtotal (I-squared = 33.9%, p = 0.147)
Brown 1993
Brownson 1989
Subtotal (I-squared = 61.3%, p = 0.003)
Gallagher 1983
ID
Demmers 1993
Fristchi 2002
Cantor 1984
Mester 2006
Forastieri 1993Heineman 1992 (men)
Sonoda 2005
Study
Cuzik 1988
Baris 2004
Costantini 2001
Flodin 1987
1.39 (1.18, 1.65)
2.00 (1.10, 3.50)
1.68 (1.23, 2.33)1.70 (1.00, 2.90)
1.37 (1.00, 1.88)
2.70 (1.30, 5.70)
1.20 (0.50, 3.10)
1.36 (0.75, 2.47)
1.25 (1.03, 1.52)
0.70 (0.50, 1.20)
1.40 (0.87, 2.24)
1.57 (1.19, 2.06)
2.20 (1.20, 4.00)
ES (95% CI)
1.40 (0.90, 3.30)
1.00 (0.60, 1.60)
1.40 (1.00, 1.80)
9.20 (2.60, 33.10)
0.95 (0.33, 2.79)1.10 (0.90, 1.50)
3.50 (0.70, 17.45)
1.60 (0.87, 2.94)
1.86 (0.76, 4.59)
0.70 (0.50, 1.20)
1.40 (0.79, 2.50)
100.00
4.66
7.585.10
7.63
3.46
2.56
4.51
48.41
6.11
5.71
51.59
4.46
Weight
4.08
5.52
7.91
1.49
2.008.41
0.99
%
4.40
2.62
6.11
4.69
1.39 (1.18, 1.65)
2.00 (1.10, 3.50)
1.68 (1.23, 2.33)1.70 (1.00, 2.90)
1.37 (1.00, 1.88)
2.70 (1.30, 5.70)
1.20 (0.50, 3.10)
1.36 (0.75, 2.47)
1.25 (1.03, 1.52)
0.70 (0.50, 1.20)
1.40 (0.87, 2.24)
1.57 (1.19, 2.06)
2.20 (1.20, 4.00)
ES (95% CI)
1.40 (0.90, 3.30)
1.00 (0.60, 1.60)
1.40 (1.00, 1.80)
9.20 (2.60, 33.10)
0.95 (0.33, 2.79)1.10 (0.90, 1.50)
3.50 (0.70, 17.45)
1.60 (0.87, 2.94)
1.86 (0.76, 4.59)
0.70 (0.50, 1.20)
1.40 (0.79, 2.50)
100.00
4.66
7.585.10
7.63
3.46
2.56
4.51
48.41
6.11
5.71
51.59
4.46
Weight
4.08
5.52
7.91
1.49
2.008.41
0.99
%
4.40
2.62
6.11
4.69
1.0302 1 33.1
Farming case-control studies
0.2
.4.6
.81/
stan
dard
err
or
-1 0 1 2Odds ratio
Death certificate studies Incident case studiesLower CI Upper CIPooled
Farming case-control studies
NOTE: Weights are from random effects analysis
Overall (I-squared = 45.2%, p = 0.090)
Boffetta 1989
Heineman 1992 (Men)
Study
Baris 2001
ID
Pearce 1986
Pottern 1992 (females)
Morris 1990
Eriksson 1992
1.43 (1.14, 1.79)
2.10 (1.04, 4.20)
1.10 (0.90, 1.40)
1.22 (0.77, 1.94)
ES (95% CI)
1.30 (0.70, 2.50)
1.30 (0.80, 2.10)
2.90 (1.50, 5.50)
1.55 (1.15, 2.26)
100.00
8.14
26.05
%
14.26
Weight
9.34
13.54
9.06
19.62
1.43 (1.14, 1.79)
2.10 (1.04, 4.20)
1.10 (0.90, 1.40)
1.22 (0.77, 1.94)
ES (95% CI)
1.30 (0.70, 2.50)
1.30 (0.80, 2.10)
2.90 (1.50, 5.50)
1.55 (1.15, 2.26)
100.00
8.14
26.05
%
14.26
Weight
9.34
13.54
9.06
19.62
1.182 1 5.5
Pesticides
NOTE: Weights are from random effects analysis
Overall (I-squared = 68.6%, p = 0.023)
Boffetta 1989
Mester 2006
Study
ID
Baris 2004
Demmers 1993
2.13 (1.06, 4.29)
4.30 (1.50, 12.50)
8.60 (1.80, 40.00)
ES (95% CI)
1.25 (0.82, 1.91)
1.30 (0.80, 2.80)
100.00
20.95
13.56
%
Weight
35.06
30.43
2.13 (1.06, 4.29)
4.30 (1.50, 12.50)
8.60 (1.80, 40.00)
ES (95% CI)
1.25 (0.82, 1.91)
1.30 (0.80, 2.80)
100.00
20.95
13.56
%
Weight
35.06
30.43
1.025 1 40
Farming > 10 years
NOTE: Weights are from random effects analysis
Overall (I-squared = 30.6%, p = 0.164)
Demers 1993
Boffetta 1989 (Maids)
Study
Costantini 2001 (cleaners)
Baris 2004 ( janitors)
ID
Baris 2004 (cleaning, building)
Mester 2005 (Maids)
Boffetta 1989 (janitor)
Miligi 1999 (cleaners, women)
Pottern 1992 (cleaners)
Mester 2005 (cleaners)
1.34 (1.02, 1.77)
1.10 (0.80, 1.90)
5.00 (1.20, 21.10)
0.70 (0.10, 3.50)
1.02 (0.66, 1.59)
ES (95% CI)
1.16 (0.79, 1.70)
2.90 (1.10, 7.40)
2.70 (0.80, 9.00)
1.40 (0.60, 3.40)
0.90 (0.40, 1.90)
3.10 (1.00, 10.10)
100.00
19.48
3.41
%
2.29
19.18
Weight
21.68
6.90
4.61
8.02
9.45
4.99
1.34 (1.02, 1.77)
1.10 (0.80, 1.90)
5.00 (1.20, 21.10)
0.70 (0.10, 3.50)
1.02 (0.66, 1.59)
ES (95% CI)
1.16 (0.79, 1.70)
2.90 (1.10, 7.40)
2.70 (0.80, 9.00)
1.40 (0.60, 3.40)
0.90 (0.40, 1.90)
3.10 (1.00, 10.10)
100.00
19.48
3.41
%
2.29
19.18
Weight
21.68
6.90
4.61
8.02
9.45
4.99
1.0474 1 21.1
Cleaners and related occupations
NOTE: Weights are from random effects analysis
Overall (I-squared = 36.6%, p = 0.162)
Bethwaite 1990
Demers 1993
ID
Heineman 1992 (males)
Study
Cuzick 1988
Baris 2004
Pottern 1992 (women)
1.48 (1.03, 2.12)
1.95 (1.05, 3.65)
2.50 (1.30, 4.70)
ES (95% CI)
1.00 (0.50, 2.10)
1.91 (0.80, 4.55)
1.33 (0.63, 2.77)
0.80 (0.40, 1.60)
100.00
19.45
18.76
Weight
16.37
%
12.60
15.72
17.11
1.48 (1.03, 2.12)
1.95 (1.05, 3.65)
2.50 (1.30, 4.70)
ES (95% CI)
1.00 (0.50, 2.10)
1.91 (0.80, 4.55)
1.33 (0.63, 2.77)
0.80 (0.40, 1.60)
100.00
19.45
18.76
Weight
16.37
%
12.60
15.72
17.11
1.213 1 4.7
Painters
Systematic review conclusions
Farmers – but not sure why Other workers who might be exposed to
solvents and cleaners Lot of heterogeneity
A case-control study
Epilymph Seven countries
France, Germany, Spain, Italy, Czech Republic, Finland and us
Led by Paul Brennan and Paolo Boffetta in IARC
Looked at occupation, viruses, medical history, family history, genes and sunlight mostly
Power calculation
Odds Ratio
Matching ratio1 to 1 2 to 1 3 to 1 4 to 1
1.4 0.31 0.42 0.48 0.521.5 0.43 0.57 0.64 0.681.6 0.55 0.7 0.77 0.81.7 0.67 0.81 0.86 0.89
Epilymph - participants
Country Controls Cases Total
Czech Republic 303 (12.3%) 32(11.6 %) 335(12.2%)
France 276 (11.2 %) 43(15.5 %) 319(11.7%)
Germany 710 (28.8 %) 75(27.1 %) 786(28.7 %)
Ireland 206 (8.4 %) 27(9.8%) 233(8.5%)
Italy 336 (13.7 %) 16(5.8%) 352(12.9%)
Spain 631 (25.6%) 84(30.3%) 715(26.1%)
Total 2462 277 2739
Exposure Assessment
Based on job history, coded AND Job/Exposure specific questionnaires Coded by national experts, including
agronomists Code for
Frequency of exposure Intensity of exposure Confidence of exposure
Epilymph - FarmersOccupation group
(ISCO Codes)Duration ofoccupation Cases Controls OR 95%CI
All Farmers ISCO codes 60000 to 62990
All
Less than 10years
10 years ormore
69
24
45
433
194
239
1.22
.98
1.45
0.88-1.68
.61-1.56
1.00-2.10
General FarmersISCO codes 61000 to 61999
All
Less than 10years
10 years ormore
22
4
18
255
33
67
1.79
.79
2.21
1.08-2.96
.23-2.66
1.26-3.87Agriculture andHusbandry workersISCO codes62000-62999
All
Less than 10years
10 years ormore
45
27
18
232
166
173
.90
.78
1.00
0.62-1.29
0.46- 1.32
0.63- 1.59
Gardeners ISCO codes:62700-62790
All
More than tenyears
5
4
29
9
1.82
3.16
0.67- 4.92
0.94- 10.62
Epilymph - PesticidesCases Controls OR ( CI) Univariate
analysisOR ( CI) Multivariate
analysis 1
Organic pesticides (level of confidence 2 and 3)
All 20 113 1.70 (0.96-2.9) 1.28(0.82-2.01)
1-10 years 9 42 1.34(0.75-2.39) 1.25 (0.69-2.28)More than 10 years 11 71 1.56(0.83-2.93) 1.32 (0.69-2.54)
Inorganic pesticides (level of confidence 2 and 3)
All inorganic pesticides 11 68 1.45(0.76-2.78) 1.10 (0.54-2.22)
Specific pesticides
Carbamates 3 15 1.03 (0.98-1.08) 2.71 (0.74-8.92)
Carbon tetrachloride 7 36 1.74 (0.77-3.86) 1.43 (0.61-3.31)
Phenoxyacetics 3 24All pesticides (organic and inorganic) 29 159 1.69 (1.11-2.57) 1.49 (0.96-2.31)
Epilymph – Other agricultural exposures
Cases Controls OR ( CI) Univariateanalysis
OR ( CI) Multivariateanalysis 1
AnimalsAll
1-9 years10 years or more
508
42
31882236
1.48 (1.07-2.06)0.92 (0.44-1.92)1.68 (1.17-2.31)
1.17 (0.77-1.59)0.80 (0.91-1.79)1.21 (0.81-1.79)
Benzene All
1-9 years10 years or more
331518
24114496
1.24 (0.84-1.83)0.94 (0.54-1.64)1.70 (1.01-2.87)
1.08 (0.71-1.62)0.85 (0.48-1.51)1.40 (0.81-2.40)
Organic Solvents (all levels of confidence,no difference) 96 1.04 (.80-1.33) 0.85(.64-1.14)
Toluene 46 333 1.27(.90-1.78) 1.18 ( .81-1.71)Xylene 44 309 1.31(.93-1.85) 1.20 (.82-1.77)Styrene 6 58 .91 (.39-2.14) .81(.36-2.09)
Epilymph conclusions?
Farmers are at some risk, but really only for long exposures
Pesticides may be the problem Limits to exposure assessment Limited power - but this is the biggest ever
single study of Myeloma
Interlymph
Pooled study Based on individual level data From five studies
the Population and Health Study (USA) the SEES Study (USA) the Italian Study (Italy) the Los Angeles County Study (USA) the Epilymph Study (Europe)
Interlymph
The systematic review was based on published odds ratios and counts
This analysis is based on anonymised raw data from these five studies
All data were recoded by Silke Kleefeld, the Irish coder for Epilymph, with support from Gigi Cocco (U. Cagliari), and the coders for the participating studies
Exposure assessment
We do not have exposure data, only jobs data These are coded to the ISCO frame, and
exposure is estimated using a job-exposure matrix from Gigi Cocco
Not ideal, but that was what was available to us
Analysis
Can be tricky There are several options The method we chose was a two-stage
analysis, which carries out individual analyses, using unconditional logistic regression, from the raw data, and combining these using a random-effects model
Study details
Study Identification, country Years Cases Controls
SEER 1977 - 1980 Study, USA 1977 - 1981 689 1,681
Population and Health Study, USA 1986 - 1989 573 2,131
Italian Study, Italy 1991 - 1993 270 1,161
Los Angeles County Study, USA 1999 - 2002 150 111
Epilymph Study, 6 European countries
1999 - 2004 277 1,108
Total 1971 - 2004 1,959 6,192
NOTE: Weights are from random effects analysis
.
.
Overall (I-squared = 8.2%, p = 0.367)
SEES (1977-1981)
Italy (1991-1993)
Study
Italy (1991-1993)
SEES (1977-1981)
Epilymph (1999-2004)
Epilymph (1999-2004)
Population and Health (1986-1989)
Subtotal (I-squared = 0.0%, p = 0.455)
Males
Subtotal (I-squared = 0.0%, p = 0.544)
Population and Health (1986-1989)
Females
ID
1.00 (0.84, 1.19)
1.08 (0.58, 2.03)
0.92 (0.60, 1.42)
0.60 (0.37, 0.99)
1.06 (0.75, 1.50)
1.42 (0.93, 2.17)
0.83 (0.48, 1.43)
1.49 (0.24, 9.11)
0.79 (0.58, 1.09)
1.09 (0.90, 1.33)
1.05 (0.72, 1.53)
ES (95% CI)
100.00
7.37
14.69
%
11.46
22.01
15.11
9.56
0.92
29.31
70.69
18.88
Weight
1.00 (0.84, 1.19)
1.08 (0.58, 2.03)
0.92 (0.60, 1.42)
0.60 (0.37, 0.99)
1.06 (0.75, 1.50)
1.42 (0.93, 2.17)
0.83 (0.48, 1.43)
1.49 (0.24, 9.11)
0.79 (0.58, 1.09)
1.09 (0.90, 1.33)
1.05 (0.72, 1.53)
ES (95% CI)
100.00
7.37
14.69
%
11.46
22.01
15.11
9.56
0.92
29.31
70.69
18.88
Weight
1.11 1 9.11
Farmers (by gender)
NOTE: Weights are from random effects analysis
Overall (I-squared = 7.1%, p = 0.366)
Population and Health (1986-1989)
SEES (1977-1981)
Italy (1991-1993)
Epilymph (1999-2004)
ID
Los Angeles County (1999-2002)
Study
1.53 (1.02, 2.30)
1.13 (0.51, 2.52)
2.13 (1.31, 3.45)
1.33 (0.18, 2.19)
0.64 (0.17, 1.93)
ES (95% CI)
1.46 (0.13, 16.78)
100.00
23.05
53.80
10.00
10.43
Weight
2.71
%
1.53 (1.02, 2.30)
1.13 (0.51, 2.52)
2.13 (1.31, 3.45)
1.33 (0.18, 2.19)
0.64 (0.17, 1.93)
ES (95% CI)
1.46 (0.13, 16.78)
100.00
23.05
53.80
10.00
10.43
Weight
2.71
%
1.0596 1 16.8
Painters
NOTE: Weights are from random effects analysis
Overall (I-squared = 20.0%, p = 0.290)
Study
Population and Health (1986-1989)
SEES (1977-1981)
ID
Italy (1991-1993)
Epilymph (1999-2004)
1.31 (0.99, 1.75)
1.17 (0.73, 1.87)
1.83 (1.15, 2.89)
ES (95% CI)
1.06 (0.72, 1.56)
1.88 (0.55, 6.42)
100.00
%
28.03
29.31
Weight
37.49
5.17
1.31 (0.99, 1.75)
1.17 (0.73, 1.87)
1.83 (1.15, 2.89)
ES (95% CI)
1.06 (0.72, 1.56)
1.88 (0.55, 6.42)
100.00
%
28.03
29.31
Weight
37.49
5.17
1.156 1 6.42
Organic solvents
Other occupations
Occcupation Exposed Cases
Exposed Controls
Pooled OR (95% CI)
Cleaners(ISCO55)
135 377 1.01 (0.81 - 1.26)
Females 54 125 1.32 (1.00 - 1.76)
Males81 252 0.91 (0.62 - 1.33)
Painters(ISCO 93)
60 116 1.52 (1.03 - 2.25)
Discussion
In this pooled analysis of five case-control studies, we observed a statistically significant increased risk of MM among painters. This is nice, but not too surprising
Our results showed no real evidence of an increased risk among crop farmers and farmers. This is quite surprising.
Why is this surprising?
Well, quite a few smaller studies have shown risks with farming
Our systematic review confirmed this Our large pooled analysis does not
Why is this surprising?
Well, quite a few smaller studies have shown risks with farming
Our systematic review confirmed this Our large pooled analysis does not
Lessons for epidemiologists
Epidemiology has difficulties with rare disease caused by low-level exposures
Much of the difficulty comes from measurement error
Exposure assessment is critical
Lesson for epidemiologists
The next big question is how do genetics and exposures interact
GxE studies, in the jargon We don't know if there is a big difference
between lymphoma subtypes, but there probably is
Current studies are too small, possibly by a factor of twenty or so
The team
The Irish team included :- Epidemiologists
Me, Dominique Crowley, Carla Perrotta Haemaologists
Paul Browne, Pat Hayden, Helen Geneticists
Mark Lawler, Prerna Tewari
Acknowledgements
The doctors, nurses, and laboratory staff who supported our data collection
The patients and their families
Acknowledgements
Carla Perrota, who has just been conferred with her PhD, whose work this is
Prerna Tewari, Pat Hayden, and Mark Lawler, who did the genetic work
The Epilymph group, led by Paolo Boffeta and Paul Brennan from IARC
The IMMC group led by Wendy Cozen of USC, Dalsu Baris of NCI, and Brenda Birmann of Harvard