The Immune System, Allergy, and Cancer · Outline • Immune system – Brief overview – Immunosurveillance and editing • Allergy – Atopic dermatitis, allergic rhinitis, asthma

The Immune System, Allergy, and Cancer

EPI 295October 16, 2009Sam S. Oh, MPH

Outline

• Immune system– Brief overview– Immunosurveillance and editing

• Allergy– Atopic dermatitis, allergic rhinitis, asthma

• Allergy and cancer• Inflammation and cancer• Potential mechanisms

– Study #1– Study #2

2

Immune System

• Human body is ideal environment for many microbes• Purpose: to discriminate and protect self from non-self• Cell surface proteins recognized by immune cells help

distinguish between self/non-self• What happens if a mass of self cells grows

uncontrollably, survives immune assault, and spreads?• Can also consider cancer as a progressive disruption of

the immune system to keep tumor growth in check

3

Immune systemAllergyAllergy and cancerInflammation and cancerPotential mechanisms

4

R

Markers of Self

Muscle cell

Nervecell

Epithelialcell

Leukocyte

Class I MHC self-marker protein

5

R

Immunity and Cancer Antibody

Helper T cell

Natural killer cell

Cancer cell

Macrophage

Cytotoxic T cell

Immunosurveillance

• Hypothesis proposed as early as 1909– Transformed cells continuously form in vivo– Immune system scans and eradicates transformed cells before

clinical manifestation• Hypothesis not widely accepted for many decades• Animal models in 1990s suggested existence of tumor-

associated antigens– Supported idea of immunosurveillance for protection of host

from transformed cells• Studies of immune-suppressed humans lent further

support for the hypothesis• But why does cancer occur in immune-competent people?

6Kim et al. Immunology 2007

Cancer Immune Editing

• Elimination of transformed cells (immuno-surveillance) results in immune selection and sculpting– Highly immunogenic tumor variants are selected out, favoring

variants with decreased immunogenicity or other mechanisms to evade/suppress immune attack

– Provides tumors mechanism to escape detection and elimination by immune system

• Preferred term over immunosurveillance– Addresses host-protecting and tumor-sculpting actions (Dunn et

al. Nat Immunol 2002;3:991-8)• Experimental evidence

– Tumors grown in mice with incompetent immune systems are more immunogenic compared to tumors grown in immunocompetent hosts (Shankaran et al. Nature 2001)

7

8

•Growth self-sufficiency•Insensitivity to anti-growth signals•Evasion of apoptosis•Limitless replication potential•Sustained angiogenesis•Tissue invasion and metastasis

Zitvogel et al. Nature Reviews Immunology 6, 715–727 (October 2006) | doi:10.1038/nri1936

Elimination Phase (Immunosurveillance)

• Once tumors reach a certain size, invasive growth disrupts surrounding tissue, inducing localized inflammation

• Immune cells (e.g., natural killer cells) recruited to the tumor site release interferon (IFN)-γ

• IFN-γ production leads to – Increased chemokine production

• Some induce cell death by preventing angiogenesis

– Recruitment of additional immune cells• Produce cytotoxins such as tumor necrosis factor, perforin, and reactive

oxygen species

9

The 3 Es of Cancer Immunoediting

10Dunn et al. Immunity 2004

Equilibrium Phase

• Dynamic equilibrium between host and tumor

• Immune cells and IFN-γ exert selective pressure

• New tumor variants arise and may be less immunogenic

• This phase may be the longest-lasting

11

Escape Phase

• Balance between immune control of tumor and tumor progression tips in favor of tumor growth

• Tumor growth continues without immune restraint

• Escape mechanisms– Reduced immunogenicity

• E.g., down-regulation of antigen presentation

– Resistance to immune-mediated killing• E.g., reduced capacity to bind cytotoxins

– Inhibition of effective immune response• E.g., down-regulation of endothelial adhesion moleules

12Prestwich et al. Clin Oncol 2008

Kim et al. Immunology 2007

Immune escape

13

Allergic Disease

• Occurs when a normally harmless material such as grass pollen is mistaken for a threat and attacked (NIAID)

• Exaggerated immune response mediated primarily by IgE and inflammatory mast cells

• Atopy: tendency to develop the “classical” allergic diseases: allergic rhinitis, asthma and atopic dermatitis (www.aaaai.org)

14NIH Publication No. 07-5423


Allergic Disease

• Prevalence has increased in last several decades– Not likely due to reporting/detection biases

• Prevalence varies widely by country• Most common are eczema, allergic rhinitis (hay fever), and

asthma, which often occur together– Eczema usually precedes onset of other conditions

• “Atopic march” theory of causal link between childhood eczema and the two later-onset airway diseases– Allergies rare during first month of life– Initial signs are atopic dermatitis and food allergies– Onset of allergic respiratory disease begins around 3yrs– Not involved in all causal mechanisms of respiratory allergies

15Burgess et al. J Asthma 2009;46:429-436Hahn & Bacharier. Immunol Allergy Clin N Am 2005;25:231-246http://www.euro.who.int/document/e79129.pdf

Prevalence of 2+ of atopic eczema, allergic rhinoconjunctivitis, and asthma

16Lancet 1998; 351:1225-32

Atopy Defined

Merriam Webster 2009 Etymology: (Greek) atopia uncommonness, from atopos out of

the way, uncommon, from a- + topos place A probably hereditary allergy characterized by symptoms (as

asthma, hay fever, or hives) produced upon exposure especially by inhalation to the exciting environmental antigen

McGraw-Hill Concise Dictionary of Modern Medicine 2002 A state of ↑ sensitivity to common antigens–e.g., house dust,

animal dander, pollen, with ↑ production of allergen-specific IgE; atopy may have a hereditary component as there is ↑ susceptibility to hay fever, asthma, and eczematoid dermatitis

Often measured in epidemiological studies by skin prick

17

Eczema• Chronic inflammatory skin disorder

– Results in itchy skin– Scratching leads to raw areas

• Blisters can form with oozing and crusting

– Leather-like skin• Onset

– Infancy: 45% of all cases within first 6mo– Childhood: 85% before age 5– Adulthood: often not IgE-sensitized

• Risk factors– Temperature/humidity extremes– Irritants (chemical and physical)– Staphylococcus aureus (exacerbates)– Stress– Hormonal changes– Family history

18

Bieber. NEJM 2008;358:1483-94Beltrani & Boguneiwicz. Derm Online Journal 2003;9(2):1Johansson et al., J Allergy Clin Immunol 2004;113:832-6

Williams. J Allergy Clin Immunol 2008;121:947-954

Williams. J Allergy Clin Immunol 2008;121:947-954

Atopic Dermatitis

• Chronic, relapsing skin disorder, often beginning in childhood and improving with age

• Often manifests in adulthood with a relapsing course

• Commonly associated with allergic rhinitis and asthma

• AD reflects an allergic (Th2) bias in response to a variety of environmental and bacterial stimuli

21Blauvelt. J Allergy Clin Immunol 2003;111:S560-70

Atopic Dermatitis

Young children

• Lesions tend to occur on face, scalp, and extensor surfaces of the arms and legs.

Old children Lesions tend to localize within

flexural areas of the extremities

22http://www.nucleusinc.com

Allergic Rhinitis

• Cold-like symptoms caused by allergic response to airborne allergens

• Affects > 500 million worldwide• Symptoms

– Runny nose– Sneezing, cough– Watery/itchy eyes– Itchy nose, roof of mouth, throat

• Risk factors– Family history– Male gender– Firstborn child– Dust mite exposure referral – Passive smoking during first year of life

23Bousquet et al. Allergy 2008;63:8-160. www.mayoclinic.com/health/hay-fever/DS00174

Asthma

• Inflammation and constriction of the airways• 13% and 14% lifetime prevalence among US adults and children• Symptoms

– Shortness of breath– Chest pain or tightness– Whistling/wheezing sounds during breathing

• Risk factors– Family history– second-hand smoke exposure– Urban living– Air pollution– Low birth weight– Overweight

24Bergeron et al. J Allergy Clin Immunol 2005;115:1102-1104www.cdc.gov/nchs/fastats/allergies.htmwww.mayoclinic.com/health/asthma/DS00021

Allergy and Cancer

• Inverse association with cancer reported over many decades

• Inconsistent results between studies– Heterogeneity across cancer site– Measurement error– Selection bias– Uncontrolled confounding

• Hypothesized that allergy sufferers have enhanced immune function to detect and eliminate tumors

25


Early Report

26Fisherman. J Allergy Clin Immunol 1960;31:74-78

Case “Control”Atopic 30 34

Not atopic 1155 260OR = 0.20, 95% CI: 0.12, 0.33

Allergy and All Cancers Combined

Study Design Study Size Effect EstimateCase-control 13,655ca 4,079co OR 0.96 (no CI)

74ca 86co 15-fold decrease in case atopy prevalence

Cohort 64,346 SMR 65.7, 95%CI (63.9-67.7)34,198 RR 1.33 (1.02-1.74) males

RR 0.79 (0.65-0.98) females1,102,247 RR 0.88 (0.83-0.93)

6,913 OR 1.40 (1.10-1.77)6,593 SIR 0.73 (0.27-1.60)6,224 SIR 0.94 (0.82-1.08)

27Merrill et al. Ann Allergy Asthma Immunol 2007;99:102-117

Allergy and Site-Specific CancersSite No. of studies RemarksBladder 2CC Increased riskBrain 5CC, 3CO Protective against gliomaBreast 1CC, 4CO MixedColorectum 4CC, 2CO Mostly protectiveLarynx 3CC ProtectiveLeukemia 8CC, 1CO Most CCs protective; increased for COLung 3CC+1, 2CO+1 Increased for asthma; decreased for AD, ARLymphoma 1CC, 1 case-only Increased riskMelanoma 1CC, 2CO Increased risk for AD, AR; null for asthmaMyeloma 5CC, 2CO Mixed but mostly increased among CCNHL 8CC, 1CO Mixed but mostly protectiveEsophagus 2CC ProtectiveOral cavity 2CC ProtectivePancreas 6CC ProtectiveProstate 2CO Increased riskStomach 1CC, 1CO ProtectiveThyroid Pooled 14CC Increased riskUterine body 1CC, 1CO ProtectiveOvary 1CO Null

28Merrill et al. Ann Allergy Asthma Immunol 2007;99:102-117

Notable Protective Associations

Inverse associations observed between…• Lung cancer

– Eczema: OR = 0.61 (0.48-0.76)

• Pancreatic cancer– Any allergy: RR = 0.82 (0.68-0.99)– Eczema: OR = 0.66 (0.46-0.93)

• Glioma– Eczema: RR = 0. 69 (0.58-0.82)

29

Castaing et al. AJE 2005Gandini et al. CEBP 2005Holly et al. AJE 2003Linos et al. JNCI 2007

30Castaing et al. AJE 2005

31

32

Gandini et al. CEBP 2005

33

Respiratory Allergies

Dermal Allergies

34Linos et al. JNCI 2007

Asthma and glioma

Eczema and glioma

Inflammation and Cancer

• Chronic inflammation associated with various cancers– Hepatitis/liver

– H. pylori/stomach

– Asbestosis/lung

– IBD/colorectal

• Inflammation mediating cells from cancers promote tumor growth in vitro

• Altered immune cytokines found in cancer cells

35


Inflammation and Cancer

• Chronic inflammation up-regulates some pro-tumor mechanisms, altering equilibrium phase by polarizing immunity toward tumor growth

• Persistent inflammatory tumor microenvironment favors – Enhanced tumor promotion– Accelerated tumor progression– Invasion of surrounding tissues– Angiogenesis– metastasis

36Lin & Karin, J Clin Invest 2007

Modulation of Immune Response

• Achieved through balance of T-helper (Th) cells via cytokine expression – Type 1: pro-inflammatory, cellular immune

response– Type 2: anti-inflammatory, humoral immune

response

• Activation of one Th-cell pathway inactivates the other

37

Chechlinska, Eur J Gastroent Hepatol 2005;17:1213-1224 38

Inflammatory Anti-inflammatory

Potential Mechanisms

• Natural killer cells from allergic asthmatics have greater anti-cell growth activity

• Low NK activity correlated with higher all-site cancer risk• Th2 cytokines have demonstrated anti-tumor activities• Low serum histamine associated with tumor occurrence and

reduced anti-tumor activity

39


Burgess et al. J Asthma 2009;46:429-436

Eczema-asthma-allergic rhinitis pathway

Chen et al. Neoplasma 1999;46:304-8Imai et al. Lance 2000;356:1795-9Mocellin et al; J Immunother 2001;24:392-407Stanciu Ann Biol Clin 1990;48:623-5

40

41Irvine. J Investigative Derm 2006;126:1200-1202

Epidermal Barrier Function

• Epidermis: physical barrier to external environment

• Barrier defects can lead to eczema

• Key cytoskeletal proteins encoded at 1q21: epidermal differentiation compex

• Filaggrin (FLG) encoded at 1q21.3

• Can filaggrin defects explain inverse association between eczema and cancer?

42

Study# 1: IARC Central Europe Lung, UADT, Kidney Cancer Study

• Case-control study– Lung (multiple histologies), UADT (squamous), and kidney (renal cell

carcinoma) cancers (3,920 cases, 2,760 controls)– Hospital-based controls (population-based in Warsaw)

• Excluded if admitted for cancer or alcohol- or tobacco-related disease• Filaggrin study also excluded controls admitted for diseases of the skin

• Face-to-face interviews• DNA extracted from blood• Genotyping (independent of case/control status)

– TaqMan: filaggrin null mutations R501X, 2282del4• Undetermined calls scored by 2 independent readers

– Sequenced or dropped

– Random 10% re-genotyping• R501X: no discordant results• 2282del4: one discordant result—dropped

43

Statistical Analysis

• Logistic regression– Odds ratios for eczema-cancer and filaggrin-cancer association

• Log-binomial regression– Risk ratios for filaggrin-eczema associations

• HWE: Pearson’s goodness of fit c2• Dominant model

– Only 3 homozygotes; no compound heterozygotes• Combined R501X and 2282del4 genotypes

– R501X and 2282del4 both result in total loss of function – Considered carriage of either variant allele equivalent exposure

• Data analyzed with SAS v9.1.3

44

Lung

(n = 2,208) UADT

(n = 811) Kidney

(n = 953) All cases

(n = 3,972) Controls

(n = 2,760) No. % No. % No. % No. % No. % Gender

Male 1715 77.7 713 87.9 564 59.2 2992 75.3 1979 71.7 Female 493 22.3 98 12.1 389 40.8 980 24.7 781 28.3

Age < 40 24 1.1 20 2.5 35 3.7 79 2.0 69 2.5 40-49 297 13.5 120 14.8 131 13.8 548 13.8 406 14.7 50-59 679 30.8 303 37.4 296 31.1 1278 32.2 839 30.4 60-69 839 38.0 248 30.6 298 31.3 1385 34.9 953 34.5 70+ 369 16.7 120 14.8 193 20.3 682 17.2 493 17.9

Study area Czech Republic 299 13.5 58 7.2 494 51.8 851 21.4 616 22.3 Hungary 313 14.2 313 7.9 244 8.8 Poland 719 32.6 206 25.4 81 8.5 1,006 25.3 842 30.5 Romania 160 7.3 142 17.5 90 9.4 392 9.9 208 7.5 Russia 407 18.4 365 45.0 288 30.2 1,060 26.7 720 26.1 Slovakia 310 14.0 40 4.9 350 8.8 130 4.7

Pack-years of tobacco Never 167 7.6 63 7.8 447 46.9 677 17.0 973 35.3 >0 - <10 83 3.8 31 3.8 106 11.1 220 5.5 314 11.4 10 - <20 191 8.7 105 13.0 103 10.8 399 10.1 357 12.9 20 - <30 412 18.7 156 19.2 122 12.8 690 17.4 398 14.4 30 - <40 525 23.8 201 24.8 86 9.0 812 20.4 317 11.5 40+ 824 37.3 249 30.7 85 8.9 1158 29.2 389 14.1 Missing 6 0.3 6 0.7 4 0.4 16 0.4 12 0.4

Alcohol drinking 1yr before interview Never 135 6.1 17 2.1 94 9.9 246 6.2 298 10.8 <1/week 89 4.0 26 3.2 92 9.7 207 5.2 185 6.7 1-2/week 286 13.0 84 10.4 150 15.7 520 13.1 457 16.6 3-5/week 397 18.0 133 16.4 147 15.4 677 17.0 419 15.2 >5/week 974 44.1 520 64.1 311 32.6 1805 45.4 1010 36.6 Missing 327 14.8 31 3.8 159 16.7 517 13.0 391 14.2

Characteristics of Participants

45

Lung UADT Kidney All cases Ca. Co. OR 95% CI Ca. Co. OR 95% CI Ca. Co. OR 95% CI Ca. Co. OR 95% CI Eczema

No 2,068 2,518 1.00 781 2,518 1.00 920 2,518 1.00 3,769 2,518 1.00 Yes 135 205 0.81 0.62, 1.04 29 205 0.59 0.38, 0.93 32 205 0.53 0.36, 0.80 196 205 0.66 0.53, 0.82

Medicated Eczema

No 2,112 2,573 1.00 786 2,573 1.00 927 2,573 1.00 3,825 2,573 1.00 Yes 91 150 0.74 0.55, 1.00 24 150 0.73 0.45, 1.20 25 150 0.61 0.38, 0.97 140 150 0.66 0.52, 0.85

Asthma No 2,096 2,605 1.00 790 2,605 1.00 927 2,605 1.00 3,813 2,605 1.00 Yes 107 117 0.91 0.67, 1.24 20 117 0.63 0.36, 1.10 25 117 0.63 0.40, 1.01 152 117 0.84 0.65, 1.09

Medicated Asthma

No 2,115 2,619 1.00 793 2,619 1.00 931 2,619 1.00 3,839 2,619 1.00 Yes 88 103 0.83 0.60, 1.16 17 103 0.67 0.37, 1.20 21 103 0.62 0.37, 1.03 126 103 0.78 0.59, 1.03

Association of Eczema and Asthma with Cancer

46

Adjusted for study area, gender, alcohol-years (for UADT), and pack-years

Distribution of FLG Null Alleles Across Potential Confounders

FLG null Covariate No Yes P for chi-square Gender

Female 4350 217 Male 1499 90 0.1501

Study area Czech Republic 1219 85 Hungary 503 21 Poland 1622 76 Romania 527 10 Russia 1557 93 Slovakia 421 22 0.0008

Pack-years of tobacco Never smoker 1400 78 0< - <10 467 22 10 - <20 662 35 20 - <30 945 46 30 - <40 997 53 40+ 1354 72 0.9784

Alcohol drinking, 1year before interview No drinking 453 24 <1/week 335 19 1-2/week 851 38 3-5/week 955 59 >5/week 2461 122 0.5721 P for chi-square

47

Filaggrin Null Alleles and Risk for Eczema and Asthma

Eczema Medicated Eczema Asthma Medicated Asthma Group FLG null No Yes RR 95% CI No Yes RR 95% CI No Yes RR 95% CI No Yes RR 95% CI Lung No 1,831 114 1,869 76 1,845 100 1,862 83 Yes 94 6 1.10 0.50, 2.43 95 5 1.37 0.57, 3.29 98 2 0.40 0.10, 1.59 99 1 0.23 0.03, 1.66 UADT No 681 24 685 20 686 19 689 16 Yes 43 3 2.13 0.66, 6.87 43 3 2.70 0.83, 8.78 45 1 0.85 0.12, 6.15 45 1 1.05 0.14, 7.57 Kidney No 795 29 801 23 804 20 807 17 Yes 44 1 0.67 0.09, 4.75 44 1 0.83 0.11, 5.93 43 2 1.88 0.45, 7.78 43 2 2.21 0.53, 9.27 Cases No 3,307 167 3,355 119 3,335 139 3,358 116 Yes 181 10 1.20 0.65, 2.22 182 9 1.50 0.78, 2.91 186 5 0.69 0.29, 1.66 187 4 0.64 0.24, 1.72 Controls No 2,190 178 2,239 129 2,270 97 2,281 86 Yes 105 10 1.16 0.63, 2.10 105 10 1.57 0.85, 2.88 108 7 1.47 0.70, 3.10 108 7 1.66 0.78, 3.51 All No 5,497 345 5,594 248 5,605 236 5,639 202 Yes 286 20 1.18 0.77, 1.82 287 19 1.55 0.99, 2.43 294 12 1.00 0.57, 1.76 295 11 1.05 0.58, 1.91

48

Adjusted for study area

Sub-analysis: Age of Onset

FLG null allele Eczema Age of onset No Yes RR 95% CI P heterogeneity Self-report No onset 5,497 286 ≤20 68 5 1.48 0.60, 3.61 >20 245 14 1.17 0.69, 1.98 0.66 Medicating No onset 5,594 287 ≤20 46 5 2.16 0.87, 5.37 >20 185 13 1.45 0.84, 2.50 0.46

49


Association of FLG with Cancer

51


Lung UADT Kidney Combined cancersFLG variant and number of risk alleles OR 95% CI OR 95% CI OR 95% CI OR 95% CI

2282del4 + R501X0 1.00 1.00 1.00 1.001 1.14 0.86, 1.51 1.58 1.09, 2.30 0.99 0.68, 1.45 1.15 0.91, 1.472 1.41 0.09, 22.92 3.58 0.15, 86.24 1.47 0.13, 16.25

Trend 1.14 0.86, 1.51 1.03 0.71, 1.49 1.16 0.91, 1.461 or 2 1.14 0.86, 1.51 1.57 1.08, 2.27 1.01 0.69, 1.47 1.16 0.91, 1.47

2282del40 1.00 1.00 1.00 1.001 1.25 0.91, 1.71 1.68 1.12, 2.52 0.97 0.64, 1.48 1.23 0.95, 1.612 1.41 0.09, 22.94 3.55 0.15, 85.10 1.47 0.13, 16.24

Trend 1.24 0.92, 1.69 1.01 0.68, 1.52 1.23 0.95, 1.601 or 2 1.25 0.91, 1.70 1.66 1.11, 2.49 0.99 0.66, 1.50 1.24 0.95, 1.61

R501X0 1.00 1.00 1.00 1.001 0.77 0.40, 1.47 1.09 0.43, 2.77 1.12 0.48, 2.59 0.86 0.50, 1.462

1 or 2 0.77 0.40, 1.47 1.09 0.43, 2.77 1.12 0.48, 2.59 0.86 0.50, 1.46

Limitations

• Self-reported eczema status– Lack of strict diagnostic criteria

– Tried to capture more severe eczema with “medicated eczema” definition

• Hospital-based controls– Excluded controls admitted for skin-related disease

– Inverse eczema-cancer association observed across different populations and study designs

52

Filaggrin

• Essential part of cornified envelope formation (outermost layer of skin)

• Null alleles present in 30-50% of eczema patients

• Expressed in oral mucosa

• Absent in kidney and bronchial, nasal, esophageal mucosa

53

Summary

• Eczema inversely associated with lung UADT, and kidney cancers

• Increased eczema risk among carriers of FLG null alleles

• Filaggrin null alleles (R501X, 2282del4) not protective of lung, UADT, or kidney cancers

• Protective association of eczema appears to work through mechanism not involving filaggrin R501X or 2282del4

54

CoauthorsIARC• Paul Brennan• Amelie Chabrier • Valerie Gaborieau• James McKay

NCI• Wong-Ho Chow• Lee Moore • Nathaniel Rothman

University of Bristol • George Davey Smith

55

IARC Central Europe Case-Control Study• Vladimir Bencko• Eleonora Fabianova• Lenka Foretova• Vladimir Janout• Jolanta Lissowska• Peter Rudnai• Dana Mates• Vladimir Matveev• Neonilia Szeszenia-Dabrowska• David Zaridze

Study #2: Los Angeles-MSKCC Study

• Investigate association of allergy with cancer– Lung, oropharynx, nasopharynx, larynx, esophagus, bladder, prostate, and

kidney cancer

• Assess whether inflammation-related SNPs mediate the allergy-cancer association

• Pooled analysis across two case-control studies– Los Angeles (LA)– Memorial Sloan-Kettering Cancer Center (MSKCC)

• All epidemiological data collected in person by trained interviewers using study-specific standardized questionnaires– Including factors associated with or known to affect study-specific cancer

risk, including age, race, medical history, education, and history of tobacco and alcohol exposure

56

LA Study

• Cases obtained from LA County cancer registry• Healthy controls matched on age, gender, and

neighborhood• Eligibility criteria

– New, histologically diagnosed cases or no history of lung cancer and head & neck cancer (controls)

– Aged 18-65 years– Resident of LA County during 1999-2005– English- or Spanish-speaking or available translator

• Recruitment rate: lung 39%, UADT 46%, control 79%

57

MSKCC Study

• Pathologically confirmed cancer cases recently diagnosed or undergone bladder surgery at MSKCC

• Controls: MSKCC blood bank donors or stable non-cancer MSKCC patients

• Recruitment rate: 95% case, 92% control

58

Results

59

Both studies pooled Los Angeles MSKCC Case Control Lung UADT Control Bladder Prostate Kidney Testes Control N = 1,650 N = 1,251 N = 611 N = 601 N = 1,040 N = 227 N = 148 N = 30 N = 33 N = 211 N % N % N % N % N % N % N % N % N % N % Age

35< 59 3.6 114 9.1 4 0.7 32 5.3 51 4.9 2 0.9 0 0 0 0 21 63.6 63 29.9 35-44 154 9.3 237 18.9 57 9.3 77 12.8 171 16.4 6 2.6 1 0.7 3 10.0 10 30.3 66 31.3 45-54 644 39.0 543 43.4 301 49.3 267 44.4 499 48.0 35 15.4 33 22.3 8 26.7 0 0 44 20.9 55+ 793 48.1 357 28.5 249 40.8 225 37.4 319 30.7 184 81.1 114 77.0 19 63.3 2 6.1 38 18.0

Gender Male 1,148 69.6 775 62.0 303 49.6 454 75.5 623 59.9 189 83.3 148 100.0 21 70.0 33 100.

0 152 72.0

Female 502 30.4 463 37.0 308 50.4 147 24.5 417 40.1 38 16.7 0 0 9 30.0 0 0 46 21.8 Missing 0 0.0 13 1.0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13 6.2

Education (years) 12 or less 686 41.6 334 26.7 265 43.4 273 45.4 300 28.9 87 38.3 42 28.4 12 40.0 7 21.2 34 16.1 16 or less 726 44.0 587 46.9 275 45.0 259 43.1 481 46.3 100 44.1 58 39.2 10 33.3 24 72.7 106 50.2 More than 16 237 14.4 329 26.3 71 11.6 69 11.5 258 24.8 39 17.2 48 32.4 8 26.7 2 6.1 71 33.7 Missing 1 0.1 1 0.1 0 0 0 0 1 0.1 1 0.4 0 0 0 0 0 0 0 0

Tobacco (pack-years) Never smoker 413 25.0 599 47.9 110 18.0 182 30.3 492 47.3 38 16.7 55 37.2 10 33.3 18 54.6 107 50.7 >0-20 320 19.4 402 32.1 102 16.7 147 24.5 353 33.9 29 12.8 33 22.3 2 6.7 7 21.2 49 23.2 >20-40 416 25.2 153 12.2 202 33.1 146 24.3 136 13.1 31 13.7 25 16.9 8 26.7 4 12.1 17 8.1 >40 465 28.2 71 5.7 197 32.2 126 21.0 58 5.6 108 47.6 28 18.9 5 16.7 2 6.1 13 6.2 Missing 36 2.2 26 2.1 0 0 0 0 1 0.1 21 9.3 7 4.7 5 16.7 2 6.1 25 11.9

Alcohol Never 343 20.8 300 24.0 170 27.8 117 19.5 264 25.4 31 13.7 13 8.8 9 30.0 3 9.1 36 17.1 Ever 1,292 78.3 933 74.6 440 72.0 482 80.2 772 74.2 187 82.4 133 89.9 21 70.0 29 87.9 161 76.3 Missing 15 0.9 18 1.4 1 0.2 2 0.3 4 0.4 9 4.0 2 1.4 0 0 1 3.0 14 6.6

60

Pooled Studies

LA Study MSKCC Study

All Cancer Sites Combined, by Smoking Status

AllNever smokerEver smoker

61

Asthma

62

Hay Fever

63

Asthma and Hay Fever

64

Asthma and/or Hay Fever

65

Asthma


Hay Fever


66

Pooled Studies

LA Study

All Cancer Sites Combined, by Age of Onset

Early onsetLate onset

MSKCC Study

Median age of onset•LA Study

•Asthma: 20, hay fever:13•MSKCC Study

•Asthma: 9, hay fever: 12

67

Asthma

68

Hay Fever

69


70


71

Asthma Hay Fever


Limitations

• Confounding– Standardized in-person questionnaires

• Information bias– Misclassification errors

• Strict inclusion/exclusion criteria• Self-report of allergic conditions

– Asked if condition was physician-diagnosed

• Differential recall between cases and controls

• Selection bias– Participation rates

72

Strengths

• Large sample size to estimate main and smoking-stratified effects

• Ability to pool across studies

• Population-based design for 6 of the 10 cancers

73

Co-authorsUCLA

Arie Belldegrun, Shen-Chih Chang, Sander Greenland, Leeka Kheifets, YC Amy Lee, Simin Liu, Jenny T Mao, Allan Pantuck, Jeanette Papp, S Lani Park, Jian Yu Rao, Donald P Tashkin, Yuko You, Zuo-Feng Zhang

Columbia University Carlos Cordon-Cardo

MSKCC

Victor E Reuter

SUNY Buffalo

Li-Na Mu

University of Michigan

Hal Morgenstern

USC

Anh Le

74

Documents

The Immune System, Allergy, and Cancer · Outline • Immune system – Brief overview – Immunosurveillance and editing • Allergy – Atopic dermatitis, allergic rhinitis, asthma