High activation of immune system maylead to lower risk of several diseases.

It had been shown that history of atopicallergic conditions (Allergy) such as asthma, hay fever,eczema and food allergies could be related with several types of cancer,although the evidence is not entirely conclusive.  The aim of current review is to summarize thecurrent knowledge about association betw­­een allergy and the risk of cancers withparticular emphasis on case-controls and cohort studies to estimate of the cancer risk incase with allergy.       Keywords: Allergy, Atopy, Asthma, Cancer, Tumor , Rhinitis    Introduction:Allergic disorders (Allergy)such as asthma, eczema, hay fever, allergic rhinitis and food allergies are commonhealth problems around the world and as a result of immune system response to innocuousenvironmental antigens which is mainly mediated by TH2 response. In contrast toTH2 cells, TH1 cells produce pro inflammatory cytokines and are the majorplayer in immunity against infections, eliminating cancerous cells as well asautoimmune disorders (1). Imbalance ofthese Th1/Th2 pathways is responsible for multiple immunological disordersincluding allergies, autoimmune disorders and hypersensitivity reactions, consequentlymanipulating and deviation one pathway toward the other is a promising strategyfor management of many immune-associated disorders, although there are somecontroversies (1-4).

As the TH1 and TH2cells down regulate each other, over activation of one system, may exacerbate orrelieve symptoms. In this regard inverse relationship between atopic dermatitis(AD) and insulin-dependent diabetes mellitus as well as  different cancers reported (5). At the momentthere is controversy about the relationship between allergy and cancers. Some evidencessupported the protective role of Allergy against glioma (GM) (6), pancreaticcancer (PC) (7), andhematological malignancies (8), while a positiveassociation has been demonstrated between Allergy and lung cancer (LC) risk (9) and for Allergyand gastrointestinal  (GI) cancers theresults has been inconclusive (10).

Two hypotheses suggestthe plausible mechanism for allergic conditions and tumor: immune surveillanceand the antigenic stimulation. The immune surveillance theory is frequentlyused to demonstrate the inverse relationships between atopic diseases and many tumors(8,11, 12). It has been shown that T helperType 2 (Th2) cytokines, which participate in the pathophysiology of atopic disorders,may contribute in antitumor immunity(13) by attractingand activating eosinophils, macrophages, natural killer (NK) cells, and Type 2CD8+ T cells. IgE as the essential player ofallergic reactions has the pivotal role in response to allergens and up-gradingallergic symptoms but recently researchers have concerned on its anti-cancerproperties and several studies demonstrated high tumoricidic effects of IgE (14,15).

On the other hand, theantigenic induction hypothesis suggests that overactive immune conditions stimulatechronic cellular inflammation, causing DNA mutation in dividing cells and consequentlytumor initiation and propagation (16). In addition,cytokines originated from Th2 cells such as interleukin 4 (IL-4), and IL-13 mediatesome biological effects, such as tumor proliferation, cell adhesion, cellsurvival and lymph node-metastasis (17,18). Studies publishedbefore 1985 provided evidences for reduced risk of cancer in allergic diseases (19). Finding ofepidemiological studies since 1980s are more complicated, implicating that theassociation might rely on both particular Allergy and specific organs.Inthis review, we discuss the existing data on the association between Allergy anddifferent type of cancers. A critical evaluation of the literature in this matteris essential to clarify previous controversial findings and to determine futureresearch directions.HematologicalmalignanciesAllergy has beenassessed as protective factors for several cancers including childhood leukemia.

Evaluationof 1842 children with acute lymphoblastic leukemia (ALL) disclosed that ahistory of eczema correlated with a significant reduced risk for cancer (oddsratio (OR)=0.7, 95% CI:0.5 to 0.9) in a case–control study in the USA(20). Also, historyof AD was related with significantly 50% lower risk for ALL and not-significantly20% decrement in the risk of acute myeloid leukemia (AML) (21). Controversy, astudy including 180 childhood ALL patients in Taiwan demonstrated nosignificant association of childhood ALL with history of eczema (OR 1.1, 95% CI:0.6to 2.

0) (22). Studies evaluatingassociation in adult leukemia have mixed results. A non-significant risk of chroniclymphocytic leukemia (CLL) in adults with a history of eczema was announced inUSA population (23).

A case-controlrecord and population-based study reported that any allergy and asthma wasrelated with an greater odds of childhood ALL (24).Specifically,in a meta-analysis performed in 2010 on childhood/adolescent ALL, the risks ofatopy/allergies, asthma, hay fever and eczema were 0.7, 0.8, 0.5, and 0.7 (95%CI: 0.5 to 0. 9; 95% CI: 0.

6 to 1.0; 95% CI:0.4 to 0.5; and 95% CI:0.6 to 0.9)respectively (8). Recently, acohort population- based study in UK revealed that atopy is linked with a 50 %lower risk of CLL (relative risk (RR)=0.

5, 95 % CI: 0.3 to 0.8)(25).Hodgkin lymphoma (HL) ,malignancy of B-cell, is one of the most prevalent cancers in younger adults (26). It has been proposedthat Allergy might be related with an increased risk of HL, particularly inyounger cases (27). It has reportedthat history of allergic rhinitis was correlated with a non-significantly lowerrisk of HL (OR = 0.8, 95 % CI: 0.

6 to 1.0; P = 0.09)(28). Similarly, self-reportedof hay fever, was associated with a 14% lower risk of non-Hodgkin (NHL) in alarge population-based study (29). Breast cancerBreast cancer (BC) isthe second most frequent cause of cancer related mortality among womenworldwide. In 1985s, a study reported no association between BC risk and hayfever, but the risk of BC was rather decreased in women with history of hivesor other allergies (19). But in otherstudy, a history of allergies or hay fever was related with a 20% lower risk ofBC (95 % CI: 0.7 to 0.

9) (30). Also, among youngAmerican women, an allergic condition was associated with a low risk of BC (31). Other severalstudies of allergies and BC risk represented no association, although may nothave had enough power to evaluate this association (32-34). Case control studies evaluating relationshipsof allergy and BCs was shown in table1.

Petridou and collogues found serumIgE level positively associated with BC in Greek population(35). Moreover, there was positive relationshipbetween history of allergy and serological test. In a meta-analysis conductedin 2009, there was no association between IgE and BC (36). Recently, ithas been shown that serum IgE levels were significantly lower in BC patients thanhealthy subjects (37). Conflicting results whichdiscussed above might be as a result of interfere effect of many variedallergic factors.In Canadian individuals,asthma was not related with BC risk overall; but, a significant decrement in BCrisk was observed only in premenopausal women (30). The reason maybe explained by difference in pattern of asthma among pre- and postmenopausal women,as allergic asthma is usually occur earlier compared to non-allergic asthma (38,39) which affectsolder people (40-43).

PancreaticcancerPancreatic cancer (PC) asa fourth cause of cancer related mortality worldwide has extremely poorprognosis. A meta-analysis of 14 PC studies showed the 30% and 45% lower riskin subjects with history of any allergies and nasal allergies, respectively (44). Other review exploring11 published studies reported reduced risk of PC in respiratory allergyconditions such as allergies to plants or pollen or hay fever (45). In PanGenEU studyconducted on 1297 pancreatic ductal adenocarcinoma (PDAC) cases and 1024 normalcontrols above 18 years old revealed that asthma was related with 40 % reducedrisk of PDAC (95% CI:0.5-0.9) which consist with a result of meta-analysis of10 case–control studies (OR=0.7, 95% CI:0.6- 0.

9). Nasal allergies and associatedsymptoms were protective factor for PDAC (OR=0.7, 95% CI: 0.5 to 0.

8 and OR= 0.6,95% CI: 0.5 to 0.8, respectively) which confirmed by a meta-analysis of nasalallergy studies (OR=0.6, 95% CI: 0.5 to 0.

7) (46).Controversy, cohortstudies performed in different countries (34,47, 48) reported no association between PCrisk and serum Ig E levels, history of Allergy, or skin prick tests. Theseinconclusive results may be attributed to young studied population and short followup, resulting to only a small number of cases; Furthermore, data were notadjust for potentially confounding factors.The underlying mechanismsof association between Allergy and PDAC risk are unclear. It has been proposedthat hyperactive immune system involved in subjects with Allergy(10). Furthermore,susceptibility and severity of asthma and allergies are known to be affected bygenetic factors and interactions between gene and environment (49-51). Further researches are needed toclarify the role of genetics in these relationships. In addition, it has been foundthat cromolyn as an anti-allergic agent can suppress proliferation and propagationof human PC cells invitro and invivo (52).

Gastrointestinal(GI) cancers Studies reporting theassociation of Allergy and GI cancers have had different results (10).Allergywere described to be protective factors in a case–control studies on CRC patients(53,54). Although, thesestudies used self-reported history of atopy and did not differ between differenttypes of allergies; so, it may be lead to misclassification. In contrast,cohort studies did not advocate the protective effect of atopy against CRC (33,55). A prospective dataanalysis of first National Health and Nutrition Examination Survey (NHANES I) showednon-significant higher risk  (RR=1.

7, 95%CI: 0.9 to 3.1) among 45 CRC patients regarding to any type of allergy(34). The Busselton cohortstudy noted that Allergy is a protective factor, although non-significant forCRC (33). Cohortstudies investigating association between Allergy and CRCs was presented intable 2.

A meta-analysis of 16studies in 2009 found no association between Allergy and CRC risk (36). A study amongcolon and rectum cancer patients in Taiwan reported an inverse relationshipbetween allergic rhinitis and only rectum cancer (56). The IowaWomen’s Health study highlighted history of two or more atopic conditions correlatedwith a 42% decrement in CRC risk (57). More recentcohort study among different ethnic population explained that Allergy were aprotective effect against CRC among both men and women (RR = 0. 9, 95% CI: 0.8to 0.9) in all populations except Latinos. Also, Allergy cases had a 20% fewerCRC-related mortality (58).

Ye et al.reported that higher risk of esophageal and gastric cancers in asthmaticpatients which may be due to the more gastro-esophageal reflux in thesepatients (59). Several case-controlstudies have reported inverse relationships between esophageal tumor and historyof allergy (60-62). Kallen et al. reported a50% lower risk of stomach cancer mortality among asthmatics; but, cohortstudies reported no significant relationships(63).

The biological mechanismfor the correlation of Allergy with CRC is not understood but could be as aresult of antitumor functions of type I Ig E-mediated immune activity. Thiseffect leads to migration of immune cells such as eosinophils and mast cells tointestinal mucosa. Allergens can enter the body through respiratory system andthe digestive system, where mast cells and eosinophils are widespread (64). This can resultto type I Ig E-mediated hypersensitivity reactions, due to the high activationof eosinophils and mast cells and over response of T-helper cell type II. Complexesof Ig E and cancer cell can degranulate mast cells which release factors to enhancepermeability and inflammation (65).

Eosinophillevels are speculated to have cytotoxic effects and antitumor activity onprecancerous cells that drive from high proliferating tissues, such as the gutlining (57,66, 67). Due to the high presence ofeosinophils and degranulation of mast cell in the respiratory mucosal lining ofasthmatic cases, leukocytes in the gut of subjects with atopic conditions ismore (68). Another theory,termed the prophylaxis hypothesis proposed that immune responses andinflammation in mucosal layer can cause to further rapid clearance of mutagenicstimulators (10).Brain cancerSince early 1990s, manystudies reported that Allergy may be related with a lower risk of brain tumors (55,69-73).In a case–control studyin Boston displayed an inverse association of glioblastoma with medications forany kind of allergies (RR= 0.

6, 95% CI: 0.4–1.0) (74). In a multicenterinternational case–control research recruited data among 1178 patients historyof allergy was a protective factor (OR=0.4, 95% CI: 0.

5–0. 7) for GM. (75-78). Several case–control and cohort studieshighlighted the protective effect of Allergy against GM (Table1)(21,79, 80).

It has been presented a lowerrisk of GM among people with a history of allergy in Swedish twins cohort and hospitaldischarges cohort (21). Ameta-analysis published in 2009 disclosed that meningioma (a low-grade tumor)did not display inverse relationship with Allergy in adults (70).INTERPHONE is a largepopulation based case–control study performed among 13 country included 2103patients with different type of brain tumor, as well as  2520 normal controls. Finding of this studyindicated an significant inverse association between a history of any allergyand GM (OR = 0.7, 95 % CI: 0.

6 to 0.9), acoustic neuroma (OR = 0.6, 95 % CI:0.5to 0.8) , and meningioma (OR = 0.8, 95 % CI: 0.

6 to 0.9), but not parotid glandtumors (OR = 1.2, 95 % CI: 0.7 to 2.

0) (81). Brenneret al. in a multicenter hospital-based study among adults reported a 2.4-foldincreased risk of having a history of hay fever for acoustic neuroma (95 % CI1.4 to 4.0)(80). Also, it hasbeen shown that  an inverse relationshipbetween prediagnostic IgE levels and GM risk (73,82). In anotherpopulation-based case–control study (CEFALO), among children and adolescents wasnot observed any relationship between Allergy and all type of brain tumor (OR=1.

0;95% CI: 0.7 to 1.3)(83). Recently, Porcelli et al in a cross sectional studyinvestigated allergic condition may protect against pediatric brain tumors(PBT) development in individuals with Neurofibromatosis type 1 (NF1).

Non-significant inverserelationships between asthma and PBTs were reported. Although, this association wasstrongly more in the younger than in the older age group (84).Lung cancer (LC)Almost all scientificfindings indicated that history of allergic disease related with greater riskof LC. Multiple case–control studies among never-smoker reported risks of LCassociated with asthma to be 1.1–2.7 (85-88). A population-based case–controlstudy among Missouri woman found the asthma was a non-significant risk factor (OR=1.2,95% CI: 0.

8 to 2.1) in smokers and significant risk factor (OR=2.7, 95% CI: 1.4to 5.

4) in non-smokers (86). This findingis compatible with finding of study conducted among never-smoking women in fivecity areas of the USA with risk of 1.7 (95% CI: 1.1 to 2.5) for history ofasthma (87). A study in 98female cases of small cell lung cancer (SCLC) and 204 controls reported historyof asthma related with statistically significant increased risk of LC afteradjustments (89). A study inChina reported the increased risk of asthma (OR=2.

0, 95% CI: 0.9 to 4.2) among nonsmokerseven adjusting for smoking history (OR=2.1, 95% CI: 1.5 to 3.0) (88).

In a case–control studyincluding 437 nonsmoking cases and 437 controls was revealed no significant associationamong nonsmokers, however a higher risk was found after adjusting for smokinghistory (OR=2.1, 95% CI: 1.0 to 4.1)(90). In two studiesin USA were not observed any association between history of asthma and LC afteradjusting age and smoking history (91,92).

It have beenshown a %50 reduced risk for LC among 217 case–control pairs women with asthmaor hay fever from the Californian nested case–control study (93). Similarly, prospectivecohort studies displayed a higher risk of LC among asthmatic patients. In aprospective study on a Finnish twin cohort, the risk of LC-mortality was higherin men with asthma (94).

In a large ancientstudy covering 78000 participants, the risk of LC was increased (StandardizedIncidence Ratio (SIR) = 1.3 in men and SIR = 1.7 in women) among asthmatic patients(95).

In Swedishpatients which hospitalized for asthma (96), the SIR was1.6 (95% CI: 1.5–1.

7) during 8.5-years follow up.Bladder cancer(BlC)An early case-controlstudy expressed that a history of atopic condition was associated to higherrisk of BlC in men, but with a lower risk in women (97). Other case-controlstudies have demonstrated positive relationships of having history of asthmaand either urothelial tumor (98) or BlC (99). Interestingly,risk of BlC increased in asthmatics with the glutathione S-transferase (GSTM1)or glutathione S-transferase (GSTT1) null genotypes. This finding was speculatedto be as a result of a lack of the detoxification of reactive asthma medicationintermediates by a deficiency of these enzymes (99). In cohortstudies was reported no significant associations (55) or advancedrisk for BlC in asthmatics patients only among men (95).Rhabdomyosarcoma  Rhabdomyosarcoma (RMS)is a scarce and high malignant cancer of developing skeletal muscle which can happenanywhere in the body.

Lupo et al in a case-control study of 322 RMScases and 322 controls found that allergies and hives were negatively relatedwith childhood RMS (OR = 0.6, 95% CI: 0.4 to 0.9) (100). Prostate cancer Prostate cancer (PrC)is one of most frequent malignancy in men and remains a main public healthproblem(101). There are severalstudies exploring possible effect of systemic inflammation conditions onprostate carcinogenesis.

In a study was assessed single-nucleotidepolymorphisms (SNP) between patients with PrC and normal controls revealed that4 genes (TLR1, TLR6, OAS1, and OAS2) participate in innate inflammationpathways were associated to higher risk of Prc (102). Also, it hasbeen found that increased white blood cell count, as a marker of systemicinflammation, was significantly associated with advance PrC risk (103). Results from large-scalecohort study including 16,934 men which performed by Severi and coworker revealeda small increment in PrC risk in asthmatic patients compared to controls (HR:1.

2, 95% CI: 1.05 to 1.5) (104). Furthermore,the risk was further elevated in cases allocating antiasthma medications suchas inhaled glucocorticoids, systemic glucocorticoids, and bronchodilators.In a prospective questionnaire-basedcohort study reported that men with a history of asthma had a 30% low risk oflethal PrC (101). In contrast, Zhaoet al reported 86 of 1552 asthmatics were diagnosed PrC during follow-up (33). In the large nationwidestudy, asthma was an independent risk factor for PrC and was associated to a136% higher risk after adjustment for possible confounding variables.

Also, therewas no direct relationship between history of glucocorticoids consumption and PrCdiagnosis. Glucocorticoids joined with mutated androgen receptors which may leadto development and progression of androgen-independent PrC (105). Although,there is inadequate document to establish this theory associated to prostatecarcinogenesis.

In a large,population-based case-cohort study including 4124 cases with asthma and8248 full-matched healthy control subjects, asthma was significantly associatedwith PrC (OR= 2.4, 95% CI: 1.2 to 4.6) and its independent risk factors wereage and hypertension (106).Head and neckcancer (HNC)Head and neck cancer(HNC) (tumors of the oral cavity, larynx oropharynx, and hypopharynx) is thefifth most frequent cancer worldwide.

A meta-analysis of 14 studies showed an protectiveeffect of allergy symptoms for HNC (OR=0.8, 95 % CI: 0.6 to 0.9) (107). In contrast,cohort studies showed that higher serum IgE levels were related with an higherrisk of HNC (108). In a cohort studywith 14,849 participants subjects with positive tests for serum specific IgE forinhalant allergens had higher risk of HNC (OR=1.7, 95 % CI: 1.0–3.

1). In othercohort including 37747 subjects, high IgE levels was linked with an higher riskof oral and pharyngeal cancer (OR=1.4, 95 % CI:1.0 to 1.8) (25).Recently, Liao et alreported that elevated serum total IgE levels was related with a significantly 1.7-foldhigher HNC.

Symptomatic allergy was related with a significantly 40% decrementof HNC risk. Notably, asymptomatic atopic cases had a higher risk of HNC thansubjects with normal serum IgE level and no allergy symptoms(109).Squamous cell carcinoma (SCC) and earlyonset basal cell carcinoma (BCC)There are limited dataabout the contribution of atopic and allergic conditions in the etiology ofkeratinocyte tumors. In 2003, Twin Cohort study reported that females with ahistory of AD prone to be more likely to affect a basal cell carcinoma (BCC), butit was non-significant (OR=1.8, 95% CI:0.

8 to 3.9) (110). A Danishnationwide cohort study reported that increased risk of both squamous cellcarcinoma (SCC) and BCC among subjects who had a history of AD (111). Results from anested case–control study of skin cancer patients demonstrated that cases whodeveloped a new primary cutaneous SCC had higher prediagnostic IgE levels thancontrols who did not (112).

Similarly, ahigher risk of SCC was reported in asthmatics subjects compared with non-asthmaticssubjects (Table2) (113). Other studiespresented positive (113), negative (19,56, 63, 114), and null association between BCCand SCC and allergic condition (19,114, 115). In a population-basedcase–control study including 375 early onset BCC patients and 251 controls, aswell as 254 SCC patients and 432 controls, an overall inverse association wasreported between an allergic conditions and risks of early onset BCC but notSCC. Interestingly, reduced risks of either early onset BCC or SCC related toatopic history was noticed only in women (116). Although,almost all studies was discussed above had limited data about possiblemodifying factors, for instance age at onset, type of allergy and its severity,as well type of medications. Cervical Cancer(CC)Cervicalcancer (CC) is a malignant cancer of the cervix with nearly 277,000 newdiagnosed cases and 266,000 deaths annually (117).

A case-control study among USA individuals reportedthat an odds of history of any allergy was 0.7 (95 % CI: 0.6 to 0.

9) forsquamous cell SCC. Also, they estimated the risk of CC related with SNPs in thechromosome 5 cytokine cluster genes(118).DiscussionDespite the hesitantresults, the currently available data from case-control and cohort studies indicatethat Allergy is related with a lower risk of cancer. Further research shouldfocus on a more carefully defined atopy status and manifestation of differentatopic diseases, to advance our understanding of the role that allergies mightplay in the risk of developing cancer.  Prophylaxis hypothesis may be the more probablyexplain the inverse association between Allergy and certain cancers.

Actually,relationship between cancer risk and allergy symptoms was more commonlyhighlighted in malignancies of tissues or organs which interface the externalenvironment such as GI cancers than others such as breast and prostate tumors.Many of previousreports above collected data of allergy symptoms retrospectively; so recallbias is plausible. Also, study participants may mistake non-allergic symptomsand over-estimated the allergy symptoms. Additionally, an ongoing chemoradiotherapymay influence the manifestation of Allergy (119), which couldaffect recall when subjects declaring history of atopic diseases. The involvements ofallergic inflammatory pathways in growth and development of cancer provide anopportunity for further evaluation and consideration.

Moreover, establishmentof the genetic mechanisms behind the association between Allergy and cancersmight allow a novel insight to development of primary prevention and promisingapproach for effective treatments for cancer patients.


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