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Alpha₁-Antitrypsin Deficiency Allele Carriers among Lung Cancer Patients¹

Mayo Clinic and Foundation, Rochester, Minnesota 55905

	Abstract

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Lung cancer (LC) and chronic obstructive pulmonary lung diseases (COPDs; including emphysema and chronic bronchitis) share a common etiology. Despite the known associations of alpha₁-antitrypsin deficiency (₁AD) with COPD and COPD with LC, few studies examined the association of ₁AD alleles and LC. We hypothesize that heterozygous individuals who carry a deficient allele of the ₁AD gene Pi (protease inhibitor locus) are at an increased risk of developing LC. The Pi locus is highly polymorphic with >70 variants reported. There are at least 10 alleles associated with deficiency in alpha₁-antitrypsin. Using an exact binomial test, we compared the ₁AD carrier rate in 260 newly diagnosed Mayo Clinic LC patients to the reported carrier rate in Caucasians in the United States (7%). ₁AD carrier status, determined by isoelectric focusing assay, was examined with respect to the history of cigarette smoking, COPD, and histological types. Thirty-two of the 260 patients (12.3%; 95% confidence interval, 8.6–16.9%) carried an ₁AD allele, which was significantly higher than expected (P = 0.002). Twenty-four of the 32 carriers had allele S, 6 had allele Z, and 2 had allele I. Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. Patients with squamous cell or bronchoalveolar carcinoma had a significantly higher carrier rate than expected (15.9% and 23.8%, P 0.01, respectively). Our preliminary findings suggest that individuals who carry an ₁AD allele may have an increased risk for developing LC, specifically squamous cell or bronchoalveolar carcinoma.

	Introduction

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An unresolved paradox of LC³ is that, although a majority of the patients are tobacco users, only a minority of long-term smokers develop LC. In addition to cigarette smoking, another well-known risk factor for LC is COPD, which includes emphysema and chronic bronchitis (1) . COPD not only increases LC risk in both smokers and nonsmokers, but also shares common risk factors with LC (1, 2, 3, 4) . Both diseases are strongly associated with tobacco use (1 , 5) , and both aggregate in families (4, 5, 6) . Individuals who are homozygous for the ₁AD gene (7) or who are heterozygous for this gene (₁AD carriers) are predisposed to the development of COPD (8, 9, 10) . However, it is not known whether ₁AD individuals and carriers are at increased risk of LC.

₁AT, a secretory glycoprotein produced in the liver, is a protease inhibitor and neutralizes the effects of proteases in several organ systems, mainly the lung. It is believed that COPD develops in ₁AD individuals as a result of an imbalance between neutrophil elastase (a protease) and ₁AT in lung tissue (8 , 11 , 12) . This imbalance could be due to an excess of elastase and/or a lack of functional ₁AT (8 , 13) . Normal plasma ₁AT concentration or level is 110–200 mg/dl, and ₁AD individuals have ₁AT levels ranging from 0–60 mg/dl (7 , 14) . The ₁AT level is marginally normal in those who are heterozygous for the deficient alleles (70–110 mg/dl; Refs. 14 and 15 ). Tobacco smoke disturbs the balance between protease and protease inhibitor activity in lung tissue by stimulating neutrophils to secrete more elastase (16) and inactivating ₁AT (17 , 18) , thereby leading to elastolytic destruction of lung tissue (19) . Because of debilitating consequences (7 , 14 , 19) , individuals with known ₁AD usually have minimal or no tobacco smoke exposure (20) . ₁AD carriers do not normally suffer from severe ₁AD-related diseases; however, they may be especially vulnerable to tobacco smoke-related diseases. Whether an individual with elastolytically destroyed lung tissue is more susceptible to respiratory carcinogens has not been properly evaluated. As an initial step to test this hypothesis, we attempt to answer the following question: Are LC patients more likely to carry ₁AD alleles than the general population?

	Materials and Methods

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Study Subjects.
Patients were selected from an ongoing comprehensive LC study at the Mayo Clinic in Rochester, Minnesota. The goals of this study are to examine the roles of genes and environmental exposures in LC etiology, to search for susceptibility and risk-modifying genes, and to identify at-risk individuals. Since March 1997, all patients who were newly diagnosed with primary LC have been identified and evaluated for study eligibility. Our eligibility criteria were developed to efficiently achieve our goal of a balanced case group by over-sampling cases with characteristics indicative of other risk factors besides smoking: (a) all cases with a positive FH of LC in at least one first-degree relative, and all cases with a positive FH of other cancers in at least two first-degree relatives; (b) all cases who are diagnosed at age 50 or younger; (c) all cases who are lifetime nonsmokers (smoked <100 cigarettes during lifetime); (d) all cases who have uncommon tumor types; and (e) a 20% sample of those LC patients who do not meet criteria 1–4 (i.e., the sporadic group). Group 5 can serve as an internal comparison for groups 1–4 and can be used to derive a complete patient ascertainment. The sporadic cases were selected in such a way that every fifth sporadic case identified was enrolled to achieve a 20% sample of the patients in this category. The rationale for our sampling strategy is as follows: although a majority of all cases are cigarette smokers, LC presents as a very heterogeneous disease with regard to clinical presentation, histopathological features, age at diagnosis, and FH of cancer. On average, one-half of the patients are so-called "sporadic" cases who seem to be typically smoking-related, develop a common type of LC after 50 years of age, and have no significant FH of lung or other cancer. Common types of LC include adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, and unspecified non-small cell LC.

New patients were ascertained daily from our computerized pathology reporting system, which identifies approximately 95% of all LC cases seen at our institution. The re-maining 5% of the patients were identified directly from the patient-care physicians. Medical records for each patient were reviewed to determine study eligibility, except for a small number of patients who denied research authorization for review of their medical records (<1%). After informed consent, each patient was interviewed by a certified genetic counselor (K. A. W.) for complete FH (a five-generation pedigree). Patients who were classified as nonsmokers were confirmed at the interview, and a detailed passive smoking history was obtained. From each consenting patient, a 28-ml blood sample and environmental exposure information (tobacco consumption, dietary pattern, and occupational exposures) were requested for study.

Due to the dynamic nature of an ongoing study, this report presents preliminary results based on cases identified during the first 9 months of our study. Between March and November 1997, 597 eligible patients were identified. Among these, 400 (67.3%) were interviewed and 68 (11.4%) declined. Three hundred eighty-eight of the interviewed patients (97%) agreed to donate blood, 302 blood samples have been received, and ₁AT allele types were tested on 260 patients in the study period defined for this early report. Because the ₁AD allele frequency has been well documented worldwide and varies greatly from Caucasians to other populations (7 , 21, 22, 23) , only patients of European origin were included in the current report. Among the 42 patients (i.e., the difference between the 302 and 260), for whom we have collected blood samples but were not included in this early report, 3 were non-Caucasian of European origin and 39 did not have a pathological report from our institution.

Data Collection.
Information abstracted from the patients’ medical records includes pathology, clinical staging, treatment, history of previous diseases, lifestyle (tobacco, alcohol, and coffee use), education, occupation, a brief FH, demographics, and follow-up data. History of COPD was based on explicit diagnosis (24) or abnormal pulmonary function tests (25) that were recorded in the patients’ medical histories. During the patient interview, a five-generation pedigree was constructed for each patient. Data collected for each relative in the pedigree included: vital status and health history concerning malignant and nonmalignant diseases (age at diagnosis and/or cause of death). Information on tobacco use and major occupation was collected for all first-degree relatives.

₁-AT Allele Determination and Plasma Concentration Measurement.
₁AD is a common autosomal recessive disorder caused by mutations of the protease inhibitor locus Pi, located on chromosome 14q32.1 (7 , 21) . Pi is highly polymorphic with >70 variants reported (7 , 26 , 27) . Each variant is designated by a letter corresponding to the migration of the ₁AT protein in isoelectric focusing assay, the standard clinical diagnostic test for more than 20 years (28, 29, 30, 31, 32, 33) . M (including subtypes M₁, M₂, and M₃) is the most common, with most normal individuals being homozygous for this allele (designated as MM or PiMM with the subtypes, e.g., M₁M₁). Of the variants that lead to a deficiency of ₁AT, only Z and S alleles are common. Uncommon deficient alleles include I, M_Malton, M_Pittsburgh, null, and other rare alleles (7) . Isoelectric focusing assay, performed in the Mayo Clinic Protein and Immunopathology Laboratory (33 , 34) , was used to type ₁AT alleles, and the concentration of plasma ₁AT was determined by nephelometry using standard protocol by Beckman Instruments, Inc. (35) .

Data Analysis.
An exact binomial test (36) was used to compare the ₁AD carrier rate among LC patients with the expected frequency of 7%. An observed to expected ratio was calculated. Although Pi allele frequencies vary substantially across geographic regions and ethnic groups in Europe, they are fairly homogeneous in the United States white population (22 , 23 , 37 , 38) . The Z allele is found in 1–2%, and the S allele in 2–4% of all Caucasians of European descent, but <1% for both alleles combined in Asians and Africans (7 , 8 , 23 , 39) . Previous studies in Minnesota populations reported a prevalence of 1.4% for the Z allele and 2.3% for the S allele (37, 38, 39) . Assuming Hardy-Weinburg equilibrium (40) , the proportion of heterozygous individuals is estimated at 7%. The I allele, which causes moderate ₁AD (60–70% of normal level), is very rare with a frequency of <0.003 in United States whites (38 , 41) . Results were also stratified by history of COPD and tobacco smoking (coded as binary variables). Smoking status was divided into never- and ever-smoked in this analysis. ² statistics were used in comparing carriers to noncarriers for smoking and COPD history, and the Wilcoxon rank sum test was used to compare ages and ₁AT levels of the carriers and noncarriers (42) . The 95% CIs are exact intervals based on Feller (43) .

	Results

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Our study group, as shown in Table 1 , included 164 men and 96 women with a gender ratio of 1.7 males to 1 female and a mean age at diagnosis of 63.27 (± 12.67) years. Eligible patients not included in the current analysis did not differ significantly with respect to gender, mean age at diagnosis, study eligibility criteria, or histological type of tumor. Thirty-two (12.3%) of the 260 patients studied were found to be ₁AD carriers (19 males, 13 females). When compared with the 7% carrier rate expected for the United States white population, the overall 12.3% carrier rate in our sample was significantly higher (P = 0.002). The carrier rate among female patients (13.5%) was not significantly different from that among male patients (11.6%), each higher than expected (P < 0.05). Patients who never smoked cigarettes were three times more likely to carry a deficient allele (20.6%; P = 0.008), although smokers had a higher carrier rate (11.1%; P = 0.025) when compared with the 7% rate. FH of LC or other cancers did not differ in the ₁AD carrier rate from the sporadic group in our study sample (12.8%, 13.3%, and 10.9%, respectively).

Carrier rates were compared with respect to age at diagnosis, history of COPD, and cigarette smoking (Table 2) . In the older age group, a significantly higher carrier rate was seen in smokers (12.0%) and marginally significant in nonsmokers (20%), compared with the expected rate. In contrast, a higher carrier rate was not observed in the younger age group. Prior history of COPD (16 of 32 or 50.0% versus 91 of 225 or 40.4%; P = .305) and cigarette smoking (25 of 32 or 78.1% versus 201 of 228 or 88.2%, P = 0.115) were not significantly different between the carriers and noncarriers, respectively. Also shown in Table 2 is the significantly higher carrier rate in patients who had a COPD history (15.0%; P = 0.003). Among patients without a COPD history, only nonsmokers had a significantly higher carrier rate (18.8%; P = 0.022).

View this table: [in this window] [in a new window]   Table 3 1AD carrier rate by histologic type and by cigarette smoking history

	Discussion

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Our preliminary results demonstrate that LC patients, both smokers and nonsmokers, were more likely to carry an ₁AD allele than the general United States white population. Specifically, patients with squamous cell or BAC were much more likely to be carriers than expected. An association between LC and ₁AD carrier state has not been reported previously.

Our results were based on an expected carrier rate of 7%, which was the most commonly quoted Pi allele frequency for the United States white population (7 , 21) . These allele frequencies were derived from the results of multiple studies, one of which included 904 healthy blood donors in the state of Minnesota (38) . As shown in Table 4 , Pi allele frequencies vary substantially across geographic regions and ethnic groups in Europe (22 , 23) , but are fairly homogeneous in the United States white population (23 , 37) . Nonetheless, further investigation with age-, gender-, and race-matched control groups is needed.

On the basis of our results, it is plausible to hypothesize that the damage in lung tissue resulting from an imbalance between neutrophil elastase and ₁AT is a predisposing condition for LC development. Two alternative mechanisms are postulated. First, carrying an ₁AD allele may be an indirect cause or a "paraneoplastic" marker (46) for LC. Individuals with varying degrees of lung tissue damage may have longer exposures due to air trapping, thereby increasing absorption and enhancing the action of carcinogens present in tobacco smoke. Second, specific alterations in the Pi gene might directly predispose an individual to higher LC risk. The Pi gene is highly polymorphic and its functional domains are now characterized (27 , 47) . The alterations causing Z and S alleles are in exons 5 and 3, respectively. Interestingly, in exon Ib of the Pi gene, there are two binding sites capable of interacting with the c-jun (AP-1) proto-oncogene products (14 , 48 , 49) . The role of the combinations of Pi gene mutations and/or c-jun (AP-1) activities should be studied.

We would expect to observe a stronger association between smokers and ₁AD carriers than that in nonsmokers based on the first of our postulated mechanisms (the presence of lung tissue damage and carcinogen exposure). For nonsmokers, when sample size increases substantially, we could further test whether passive smoking and undiagnosed mild lung dysfunctions (as shown in pulmonary function tests) are significant risk factors. However, it was not surprising to observe a stronger association between nonsmokers and ₁AD carriers than that in smokers based on our alternative hypothesis that there may be an interaction between the Pi locus and a proto-oncogene, c-jun. It is also possible that the role of the deficient Pi allele differs in smokers from that in nonsmokers in LC development.

Although within the normal range, the mean serum ₁AT level was significantly lower in carriers than in noncarriers. It is known that ₁AT increases in several conditions, including malignancies, and this elevation in ₁AT concentration has been considered a physiological reaction. Our findings were consistent with the reported literature and suggested a compromised reactive ₁AT level among ₁AD carriers compared with the noncarriers. It is not clear whether a proper reactive response might be part of the protective mechanism in certain adverse situations such as malignancies.

We did not observe a single patient who was homozygous for ₁AD alleles. The relative rarity of homozygous individuals in United States whites (1/2500; Refs. 7 and 21 ), coupled with their associated higher mortality (50) , reduced exposure to tobacco smoke (20) , and the generally late onset of LC, are explanations.

In conclusion, markers for genes coding organ- or tissue-specific functional products (for example, protease and protease inhibitors) and their interaction with environmental exposures have not been adequately studied in LC etiology. Our findings suggest that ₁AD carriers may have an increased risk for developing squamous cell or BAC of the lung. We hope that our findings will stimulate further investigations in searching for genetic markers and their roles in LC development.

	Acknowledgments

 
We thank additional contributors Drs. Claude Deschamps, Eric S. Edell, James Jett, Daniel L. Miller, Ashokakumar M. Patel, Daniel J. Schaid, Stephen J. Swensen, Henry Tazelaar, and Victor F. Trastek for valuable input at various stages of this research project. We also acknowledge Marilyn Goodman for secretarial support and Amy Knutson for manuscript editing.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Partially funded by Mayo Clinic/Foundation and National Cancer Institute Grant CA77118.

² To whom requests for reprints should be addressed, at Mayo Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905. Phone: (507) 266-5369; Fax: (507) 284-1516; E-mail: yang.ping{at}mayo.edu

³ The abbreviations used are: LC, lung cancer; COPD, chronic obstructive pulmonary diseases; ₁AT, alpha₁-antitrypsin; ₁AD, alpha₁-antitrypsin deficiency; BAC, bronchoalveolar carcinoma; CI, confidence interval; FH, family history.

Received 6/30/98; revised 12/ 7/98; accepted 3/ 8/99.

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