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Carcinogenesis Advance Access originally published online on January 12, 2006
Carcinogenesis 2006 27(7):1386-1390; doi:10.1093/carcin/bgi332
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A V141L polymorphism of the human LRMP gene is associated with survival of lung cancer patients

Giacomo Manenti, Federica Galbiati, Angela Pettinicchio, Monica Spinola, Silvia Piconese, Vera Piera Leoni, Barbara Conti 1, Fernando Ravagnani, Matteo Incarbone 2, Ugo Pastorino 1 and Tommaso A. Dragani *

Department of Experimental Oncology and Laboratories and 1 Department of Thoracic Surgery, Istituto Nazionale Tumori, Milan, Italy and 2 Department of Thoracic Surgery, Istituto Clinico Humanitas (ICH), Rozzano, Italy

* To whom correspondence should be addressed at: Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy. Tel: +39 0223902642, Fax: +39 0223903237; Email: tommaso.dragani{at}istitutotumori.mi.it


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Mouse Lrmp and Casc1 genes are candidates for the pulmonary adenoma susceptibility 1 (Pas1) locus, the major determinant of strain variation in lung tumor susceptibility. These genes contain coding and non-coding single nucleotide polymorphisms (SNPs) strongly associated with lung tumor risk in mice. Analysis of LRMP and CASC1 gene SNPs in 361 lung adenocarcinoma (ADCA) patients and 327 healthy controls revealed common SNPs in LRMP (V141L and S197C) and CASC1 (R33S and three intronic variations), and none showed a significant association with lung ADCA risk. However, in the time-dependent Cox regression model, after adjustment for age, gender, smoking history and clinical stage, the carrier status of the Leu variation (V141L) of the LRMP gene was associated with higher mortality in patients with age at tumor onset ≤ 65 years [hazard ratio (HR) 2.3; 95% CI 1.4–3.7; P = 0.001]. These findings suggest that the LRMP V141L polymorphism can predict survival in lung ADCA and that the role of LRMP and CASC1 in human lung cancer risk may differ from that in mice.

Abbreviations: ADCA, adenocarcinoma; ASO, allele-specific oligonucleotide; CI, confidence interval; HR, hazard ratio; LD, linkage disequilibrium; OR, odds ratio; Pas1, pulmonary adenoma susceptibility 1; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Animal models of complex genetic diseases in humans provide a tool to dissect the genetic factors and the molecular mechanisms of the disease. In laboratory mouse inbred strains, susceptibility to spontaneous or chemically induced lung tumorigenesis is genetically determined as a complex trait. The mouse pulmonary adenoma susceptibility 1 (Pas1) locus is a major determinant (1), and additional loci may affect inherited tumor resistance (2,3) or progression (3). Indeed, meta-analysis of lung tumorigenesis in 29 laboratory inbred strains showed that high risk [odds ratio, (OR) ~12–15] of spontaneous or chemically induced lung tumors is associated with the Pas1 susceptibility allele, which is frequent (allelic frequency ~0.6) in the population of mouse inbred strains (4). Positional cloning studies have implicated a conserved haplotype block of 468 kb containing six genes in Pas1 function (5). Among the six genes, KRAS shows frequent somatic mutations in mouse lung tumors (6) and in human lung adenocarcinomas (ADCAs) (7), whereas LRMP is implicated in immune functions (8); the function of the other genes remains unclear (5).

Studies in humans to date have revealed no strong association between genetic polymorphisms in the human homologous Pas1 haplotype region and lung cancer risk (9–11), whereas two independent studies have indicated an association between an intronic polymorphism in KRAS and lung ADCA patient survival (9,10). To elucidate the role of genetic polymorphisms in the human homologous region of the mouse Pas1 locus, we focused on the possible association of LRMP and CASC1 single nucleotide polymorphisms (SNPs) with lung ADCA risk and prognosis.


   Materials and methods
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 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Paired human tissue samples and DNAs
Patients enrolled in the study had pathologically documented lung ADCA and underwent surgery at Istituto Nazionale Tumori, Milan (INT) or at Istituto Clinico Humanitas, Rozzano (ICH); personal files were recorded to obtain clinical data (Table I). Clinical stage was evaluated at diagnosis and confirmed or modified after surgical treatment. No data on chemotherapy or radiation treatments were recorded. Healthy controls (blood donors) were enrolled at INT and gender, age and smoking habit information were obtained by interview. All subjects involved in our studies signed a written informed consent and the institutional ethic committee approved the study protocol. Genomic DNAs were extracted using the automatic DNA extractor Extragen 8C (Talent, Trieste, Italy) from a small piece of non-tumor tissue excised during surgery or from peripheral blood samples.


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  		Table I. Clinicopathological characteristics of lung ADCA patients and healthy control subjects

 
Gene expression analysis
RNA was extracted from normal lung parenchyma and lung tumor tissue of seven histologically confirmed lung ADCA patients and reverse-transcribed using oligo(dT) primers and SuperscriptTM (Invitrogen, Carlsbad, CA). LRMP and CASC1 gene expression was tested using the following primers: 5'-aggaggtggaggcagaattt-3', 5'-gatttcctgtgcctggttgt-3' (LRMP) and 5'-gcagtggagcttgactcttaatg-3', 5'-tgtttcaatttctctgcttcagg-3' (CASC1). Polymerase chain reaction (PCR) products were run on agarose gels and stained with ethidium bromide.

Identification and genotyping of SNPs
SNPs in CASC1 and LRMP were identified by interrogating the public SNP databases and by nucleotide sequence analysis of the whole coding region. The 16 exons of CASC1 and the 18 coding exons of LRMP were amplified from 11 lung ADCA patients and directly sequenced. The presence of SNPs was verified by sequence alignment using the Pregap and Gap4 programs of Staden package (12).

DNA samples of 327 healthy controls and 361 lung ADCA patients were PCR-amplified and genotyped either manually using allele-specific oligonucleotide (ASO) hybridization or automatically by pyrosequencing (10,13) using a PSQ96MA system (Biotage AB, Uppsala, Sweden) and primers listed in Table II.


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  		Table II. Primers used for PCR amplification and genotyping of CASC1 and LRMP SNPs

 
Statistical analysis
Pairwise linkage disequilibrium (LD) was evaluated by calculating D' and r2 as described by Devlin and Risch (14). LD values were graphed using the Java LINkage disequilibrium plotter (JLIN) (www.genepi.com.au/projects/jlin). Consistency of genotype frequencies with the Hardy–Weinberg equilibrium was tested for each SNP locus using a contingency table of observed versus predicted genotype frequencies (15). Power of the study design was calculated according to Dupont and Plummer (16). Logistic regression was used to compute ORs and 95% confidence intervals (CIs). The Kaplan–Meier product-limit method, the log-rank test and the Cox regression model were used to evaluate the effect of the SNP genotypes on overall survival (17,18).


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
LRMP and CASC1 genes are expressed in lung normal tissue and lung ADCAs
Semiquantitative RT–PCR analysis of mRNA samples from paired normal lung and lung ADCA tissue from seven patients revealed expression of both CASC1 and LRMP genes in normal lung tissue of all samples, with slightly higher levels for the LRMP gene. No obvious differences between normal lung and lung ADCA tissue in CASC1 or LRMP mRNA expression levels were observed (data not shown).

LRMP and CASC1 genes contain coding SNPs
Two SNPs were identified in the LRMP gene: rs7969931 and rs1908946, consisting in a Val141Leu variation and in a Ser197Cys variation, respectively, with respect to the reference protein sequence NP_006143 [GenBank] .2. No additional common SNP was detected in the LRMP coding sequence nor the rare coding SNP rs6487451 leading to an A38T switch reported only in Africans (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Snp&dopt=GEN&list_uids==6487451)

Sequence analysis of the 16 exons and their relative boundaries of the human CASC1 gene identified four SNPs: intronic SNPs rs10842501 and rs10842502 located upstream and downstream exon 2, respectively, consist of a C->T transition and are 191 bp apart, whereas SNPs rs10842496 [G->T] and rs12367971 [G->A] are located in the exon 4 coding region and downstream of exon 4, respectively, and are 156 bp apart. SNP rs10842496 SNP causes a C->A transversion that generates a Arg33Ser amino acid change in the putative CASC1 protein AAQ93499 [GenBank] . Interrogation of the public databases indicated also the presence of the rs859146 SNP in CASC1, resulting in Glu2Ala substitution. However, we found no evidence of the Ala allele in 96 lung ADCA patients, consistent with the recently reported genotyping of 179 individuals in the HapMap Project (http://www.hapmap.org/).

LD pattern of the genotyped SNPs
LD pattern of LRMP and CASC1 SNPs was analyzed in 178 control samples genotyped at all six SNPs. The two LRMP SNPs, separated by only 520 bp, did not show significant LD (D' = 0.05, Figure 1). A significant LD pattern was observed between the LRMP rs1908946 SNP and the flanking CASC1 SNPs rs12367971 (D' = 0.83) and rs10842496 (D' = 0.78), but not with the more distal CASC1 SNPs rs10842501 and rs10842502 (Figure 1). Within the CASC1 gene, the closely located SNP pairs, that is, rs12367971 and rs10842496 (separated by 156 bp) or rs10842501 and rs10842502 (separated by 191 bp) showed significant LD (D' ~ 1.0), but the two intragenic SNP pairs of the CASC1 gene, separated by ~32 kbp, did not (D' = 0.2) (Figure 1).


Figure 1
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  		Fig. 1. LD pattern in the human chromosomal region containing the LRMP and CASC1 genes (genes are shown below the segment representing the DNA sequence of that region; introns are indicated by lines and exons are indicated by solid vertical bars). Positions of the alignments are based on the Ensembl database.

 
Comparison of human and mouse protein sequences
Comparison of the sequences of the mouse (NP_032537 [GenBank] , strain C57BL/6J) and human (NP_006143 [GenBank] ) LRMP proteins revealed identity in 364 of 541 (67%) amino acids. The central regions, but not the terminal regions, were quite well conserved between the two species (not shown). The amino acid variations in the mouse Lrmp protein that are highly linked with the Pas1 haplotype and strain-dependent lung tumor susceptibility (D56G, D6Int32a; L537P, D6Int8) (5) were located in exons homologous to the human exons, where no SNPs were detected. Also, the human coding SNPs that we observed (V141L, rs7969931; S197C, rs1908946) were located in exons whose homologous mouse exons do not contain SNPs.

Comparison of the mouse (AAS55696 [GenBank] , strain A/J) and human (AAQ93499 [GenBank] ) CASC1 proteins revealed an overall identity in 486 of 723 (67%) amino acid residues (not shown). The mouse Casc1 coding S60N SNP (D6Int41) of exon 4 is tightly associated with strain susceptibility to lung tumors and is located in the N-terminal region of the protein AAS55696 [GenBank] , encoded by Casc1. In the human homologous protein AAQ93499 [GenBank] , a histidine residue is present at the corresponding position, located 22 amino acids C-terminal to the R33S (rs10842496) SNP in exon 4 of the human CASC1 protein.

Association of an LRMP SNP with overall survival of lung ADCA patients
The study included 361 lung ADCA patients (75% male and 25% female) aged 36–82 years (median 64) and 327 healthy controls (81% male and 19% female) aged 25–73 years (median 57) (Table I). Hardy–Weinberg genotypic proportions were respected in both groups at all SNPs, except for the intronic rs10842502 of CASC1 in the control samples (P = 0.003); slight deviations were also seen at intronic rs10842501 (P = 0.03) of CASC1 in the control samples and at S197C (rs1908946) (P = 0.04) of LRMP in the lung ADCA samples. The reasons for such deviations, in particular the highly statistically significant deviation of SNP rs10842502 observed in controls but not in cases, are unknown.

Association analysis revealed similar frequencies of the rare allele at any of the six SNPs genotyped in cases and controls, with no significant differences; logistic regression analysis (adjusted for sex, smoking habit and age in decades) indicated no significant association with lung cancer risk (Table III). The study had 80% power to detect ORs ≥ 1.6 or ≤ 0.6 in cancer risk. Detection of smaller increases in cancer risk, that is, ORs ~1.3, would have required a sample size of ~900 cases and ~900 controls.


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  		Table III. Lung ADCA risk associated with CASC1 and LRMP gene polymorphisms

 
Median follow-up of patients alive at the end of the follow-up period was 59 months (Table I). Analysis of the six SNPs with respect to prognostic factors of lung cancer patients revealed no significant positive association of any polymorphisms with advanced clinical stage, nodal status or overall survival. However, survival analysis indicated borderline statistical effects (P ~0.07–0.08, log-rank test) for rare allele carriers of SNPs rs12367971 (CASC1), rs1908946 (LRMP) and rs7969931 (LRMP). When the analysis was limited to patients of younger age (≤65 years), only the association of SNP rs7969931 (LRMP) with survival improved its statistical significance. Indeed, Cox proportional hazard analysis of survival, adjusted for gender, smoking and age at diagnosis (in decades), showed that in patients with age at tumor onset ≤65 years, survival rates of individuals carrying either the Leu/Leu or the Val/Leu genotype differed significantly from those in Val/Val patients [hazard ratio (HR), 2.1; 95% confidence interval (CI), 1.3–3.4; P = 0.004]. When the clinical stage was also included in the adjusted analysis, individuals carrying at least one Leu allele maintained a statistically significant difference in survival, with a HR of 2.3 (95% CI, 1.4–3.7; P = 0.001) as compared with the Val/Val genotype group (Table IV, Figure 2). In Kaplan–Meier analysis, median follow-up at death was 33 months for Leu allele carrier patients and 100 months for Val/Val cancer patients (P = 0.005, log-rank, Figure 2).


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  		Table IV. Association between LRMP polymorphism rs7969931 SNP (V141L) and survival rate of Italian lung ADCA patients

 

Figure 2
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  		Fig. 2. Kaplan–Meier survival curves in Italian lung ADCA patients (age ≤ 65 years). The curves of Val/Val (n = 109) and Leu allele carrier (n = 46) patients are shown as solid and dotted lines, respectively. Small crosses indicate censored observations. Log-rank analysis indicated significant differences between curves (P = 0.005).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
We analyzed two common amino acid variations of the human LRMP gene and one amino acid and three intronic (localized in the proximity of exons) variations of the CASC1 gene for their possible association with lung ADCA risk and prognosis. Both Casc1 and Lrmp are candidate for the mouse Pas1 locus, as they contain coding and non-coding SNPs that are strongly associated with lung tumor susceptibility in mice (5).

LRMP encodes a protein with a coiled-coil domain located in the central portion of the protein and a C-terminal membrane anchor (8). LRMP expression was originally described as lymphoid cell-specific, with highest expression levels in pre-T, pre-B and mature B cells (8). However, we detected LRMP mRNA expression in human normal lung and in lung ADCA tissue, as well as in mouse normal lung and lung tumors (5). CASC1 encodes a protein with unknown functions that contains a predicted coiled-coil domain in its N-terminal region (5). CASC1 mRNA is expressed in human normal lung and in lung ADCA tissue, as well as in mouse normal lung and lung tumors (5).

We found that human LRMP and CASC1 contain common amino acid variations (i.e. frequency of the rare allele 0.14–0.48, Table III), analogous with the homologous genes of laboratory mouse inbred strains (5). Comparative analysis indicated that the human LRMP gene contains two coding SNPs in protein domains different from those in the mouse protein containing coding variations, whereas the R33S of human CASC1 was located in exon 4 as the mouse Casc1 S60N SNP (D6Int41) (5).

Comparison of human and mouse LRMP and CASC1 protein sequences revealed 67% identity for both proteins, and 97% identities for KRAS protein, suggesting the absence of a requirement for tightly conserved protein sequences for the biochemical functions of LRMP and CASC1 proteins.

Mouse coding variations at both Lrmp and Casc1 are tightly linked with strain variability in susceptibility to lung tumorigenesis, either spontaneously or chemically induced (4,5), whereas the human coding or non-coding SNPs of the homologous genes showed no significant association with lung cancer risk (Table III). On the basis of these findings and on previous results (9–11), it appears that common genetic polymorphisms in the human chromosomal region homologous to the mouse Pas1-containing region do not play a significant role in the genetic risk of lung cancer in the general human population. However, having selected patients because of their eligibility for surgery (early stage patients) may have masked the case–control association of the study. Although humans and mice might differ significantly in the genetic control of susceptibility to lung tumorigenesis at the population level, it remains possible that as-yet unidentified genetic elements of this region play a role in human lung cancer risk. Rare SNPs (i.e. frequency of the rare allele < 5%) might exist and play an important role in lung cancer risk in some individuals but might be difficult to detect in population-based association studies.

Establishing any role for the PAS1 locus in humans awaits characterization of the functional role of each of the six genes constituting the mouse Pas1 haplotype in mouse lung tumorigenesis, followed by comparative analysis of gene functions. Until the role of the homologous Pas1 genes in human lung cancer is established, the predictive value for humans of positive lung carcinogenesis bioassay results obtained in mouse strains carrying the Pas1 susceptible allele (A/J-like) remains unclear.

On the other hand, we found a significant association of the coding rs7969931 SNP (V141L) of LRMP with survival of lung ADCA patients ≤ 65 years of age at diagnosis, independently from the clinical stage. The association observed with younger patients is consistent with the reported observation supporting a major role of putative genetic factors on early onset lung cancer (19,20). Our results are in accord with those of previous association studies on the nearby KRAS gene, which is contained in the same Pas1 haplotype with Lrmp and Casc1 genes in mice (5). Indeed, we previously demonstrated a significant association between a KRAS intronic polymorphism and survival of lung ADCA patients (9,10), although no association with lung ADCA risk was observed (10,11). We can hypothesize either the functional involvement of the rs7969931 SNP (V141L) of LRMP in patients' survival rate, perhaps through modulation of patients' immune system, or the location in the human PAS1 region of one or several functional polymorphisms affecting patients' survival by different mechanisms. In the latter hypothesis, the significant association of rs7969931 SNP may also be due to LD of this SNP with not-yet identified nearby functional polymorphism(s).

Although genetic polymorphisms of the Pas1 locus that strongly modulate lung cancer risk in mice might not be present in humans, these mouse polymorphisms suggest the important role of the biochemical and biological activities of Pas1 candidate genes in mammalian lung tumorigenesis. Indeed, although the genetic polymorphisms of the human PAS1 candidate genes lack significant association with cancer risk, some of the candidate genes (i.e. LRMP, KRAS) were shown to modulate survival of lung ADCA patients. Thus, the mouse genetic model of Pas1 might provide information on the role of specific gene targets and biochemical pathways involved in the pathogenesis of lung tumors.


   Acknowledgments
 
This work was funded in part by grants from Associazione and Fondazione Italiana Ricerca Cancro (AIRC and FIRC) and Fondo Investimenti Ricerca di Base (FIRB) to T.A.D.

Conflict of Interest Statement: None declared.


   References
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 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received September 6, 2005; revised December 15, 2005; accepted December 24, 2005.


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