Carcinogenesis

Carcinogenesis Advance Access originally published online on October 26, 2005
Carcinogenesis 2006 27(3):606-609; doi:10.1093/carcin/bgi248

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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.

Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant

Bernd Frank ^1, *, Kari Hemminki ^1, 2, Barbara Wappenschmidt ^3, 4, Alfons Meindl ⁵, Rüdiger Klaes ⁶, Rita K. Schmutzler ^3, 4, Peter Bugert ⁷, Michael Untch ⁸, Claus R. Bartram ⁶ and Barbara Burwinkel ¹

¹ Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany, ² Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden, ³ Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Germany, ⁴ Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Germany, ⁵ Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany, ⁶ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany, ⁷ Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessia, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany and ⁸ Department of Gynaecology and Obstetrics at the Ludwig-Maximilians-University, Munich, Germany

^* To whom correspondence should be addressed. Tel: +49 6221 421802; Fax: +49 6221 421810; E-mail: b.frank{at}dkfz.de

	Abstract

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Dysregulation of apoptosis plays a crucial role in carcinogenesis. As part of death receptor- and mitochondrion-mediated apoptosis, the homologues caspases 10 and 8 may act as low-penetrance breast cancer (BC) susceptibility genes. In death receptor-mediated apoptosis, engagement of death receptors by their ligands involves the assembly of the death-inducing signalling complex (DISC). In mitochondrion-mediated apoptosis, the release of cytochrome c into the cytosol results in apoptosome formation. Recruitment of both caspases 10 and 8 (CASP10 and CASP8, respectively) to DISC and apoptosome leads to their activation by dimerization. We investigated the influence of the coding CASP10 variant V410I (G1228A) by performing a case–control study — using 511 familial BC cases and 547 control subjects — on BC risk and revealed a significant association of V410I with a reduced risk (OR = 0.62, 95% CI = 0.43–0.88, P = 0.0076) related to the number of variant alleles (P_trend = 0.0039). As CASP10 and CASP8 functionally co-operate during apoptosis, we analysed the mutual effect of both CASP10 V410I and CASP8 D302H, resulting in a significant association between the number of the variant alleles I410 and H302 and a highly decreased familial BC risk (OR = 0.35, P_trend = 0.007), pointing to the interaction between the CASP10 and CASP8 polymorphisms in breast carcinogenesis.

Abbreviations: BC, breast cancer; CASP8, caspase 8; CASP10, caspase 10; CFLAR, CASP8 and FADD-like apoptosis regulator; 95% CI, 95% confidence interval; DED, death effector domain; DISC, death-inducing signalling complex; FADD, Fas-associating protein with death domain; HWE, Hardy–Weinberg equilibrium; OR, odds ratio; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism; TNF, tumour necrosis factor

	Introduction

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Programmed cell death, apoptosis, is a physiological mechanism that eliminates damaged cells from an organism, thus controlling cell numbers and tissue size, and sustaining homeostasis. Caspases are important mediators of the apoptotic process. They function as cysteine aspartyl proteases that cleave numerous intracellular substrates initiating cell dissolution (1). Suppression of apoptosis due to mutations involves an illegitimate cell survival and predisposition to cancer (2). Death receptor-mediated apoptosis provokes the formation of the death-inducing signalling complex (DISC), comprising both the death receptors and adaptor proteins as well as the initiator caspase 10 (CASP10) and caspase 8 (CASP8) (3–7). Mitochondrion-mediated apoptosis involves the release of cytochrome c into the cytosol upon activation by DNA damage-inducing or DNA repair-inhibiting agents, leading to the formation of apoptosome-containing cytochrome c, Apaf-1 and caspase 9. Recruitment of both caspases 10 and 8 to DISC and apoptosome leads to their activation by dimerization.

We pursued the hypothesis that genes involved in the initiation of apoptosis might act as low-penetrance familial breast cancer (BC) susceptibility genes. The non-synonymous coding SNPs (single nucleotide polymorphisms) in CASP10, V410I (G1228A; rs13010627) and the common I522L (A1564T; rs13006529), were drawn from the NCBI dbSNP database (http://www.ncbi.nlm.nih.gov/). CASP10 I522L affects the very last amino acid of the protein and has been described not to be associated with BC risk (8,9) and was, therefore, not considered for further analysis. Recent studies, however, have reported an association between the common CASP8 variant D302H and a reduced BC risk dependent on allele dosage [(DH) versus (DD): odds ratio (OR) = 0.83, 95% confidence interval (CI) = 0.74–0.94 (Ref. 9); and OR = 0.87, 95% CI = 0.65–1.17 (Ref. 10); (HH) versus (DD): OR = 0.58, 95% CI = 0.39–0.88 (Ref. 9); and OR = 0.49, 95% CI = 0.17–1.44 (Ref. 10)].

This is the first study to investigate the effect of the CASP10 V410I genotype as well as the mutual effect of CASP10 V410I and CASP8 D302H genotypes on familial BC risk, revealing a reduced risk for carriers of the CASP10 I410 allele and a highly reduced risk for individuals carrying CASP10 I410 in combination with CASP8 H302.

	Materials and methods

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Subjects
Case patients were recruited during the years 1996–2005 by the familial BC centres of Heidelberg (Institute of Human Genetics), Cologne (Department of Gynaecology and Obstetrics) and Munich (Department of Medical Genetics). About 3% refused to spend their blood samples for research purposes. Our familial BC cohort comprised 566 unrelated German women without BRCA1 and BRCA2 mutations. We obtained CASP10 V410I genotype data for 511 women (mean age = 45.3 years, range = 19–87 years). Genotyping for the remaining failed. According to the German Consortium for Hereditary Breast and Ovarian Cancer, they were classified into five categories based on family history: (A1) families with two or more BC cases including at least two cases with onset below the age of 50 (38.9%); (A2) families with at least one male BC case (0.4%); (B) families with at least one BC and one ovarian cancer case (24.9%); (C) families with at least two BC cases comprising one case diagnosed before the age of 50 (27.4%); (D) families with at least two BC cases diagnosed after the age of 50 (8.4%) (11). All recruited women gave written consent to the molecular analysis of the BRCA1 and BRCA2 genes and potential new BC susceptibility genes. Prior to DNA extraction, their blood (EDTA) was frozen at –20°C. The DNA was isolated using a conventional phenol–chloroform protocol. Mutations in the open reading frame of BRCA1 and BRCA2 were excluded using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. The control group included 552 healthy, unrelated female blood donors. CASP10 V410I genotype data were obtained for 547 individuals (mean age = 50.8 years, range = 26–68 years), while genotyping for the remaining failed. The controls were recruited in 2004 and 2005 by the Institute of Transfusion Medicine and Immunology (Mannheim, Germany) and share their ethnic backgrounds with the BC case patients (Caucasian populations). Control subjects were invited for regular blood donation on a daily basis. According to the German guidelines for blood donation, all blood donors were examined by a standard questionnaire. Offers of blood donation from approximately 5% of donors were refused due to various reasons not related to the research study. Buffy coat samples were taken from the anti-coagulated blood donations and were used for DNA isolation (FlexiGene® DNA Kit; Qiagen, Hilden, Germany). All subjects who donated blood gave written consent to the use of their blood samples for research purposes. The study was approved by the Ethics Committee of the University of Heidelberg (Heidelberg, Germany).

Genotyping
CASP10 and CASP8 genotyping was carried out using TaqMan allelic discrimination assays. TaqMan probes and primers were provided by the assay-by-design service (Applied Biosystems, Foster City, CA). Of the genotyping results >5% were confirmed by sequencing, and genotype distributions were consistent with Hardy–Weinberg equilibrium (HWE), respectively. Allelic discrimination, PCR amplification and sequencing were performed as previously described (12). Primer design was based on the GenBank CASP10 (accession nos NT_005403 [GenBank] , NM_032977 [GenBank] and NP_116759 [GenBank] ) and CASP8 (accession nos NT_005403 [GenBank] , NM_001228 [GenBank] and NP_001219 [GenBank] ) sequences.

Statistical analysis
HWE test was undertaken using a ²-‘goodness-of-fit’-test. Genotype-specific ORs, 95% CIs and P-values were computed by unconditional logistic regression using a tool offered by the Institute of Human Genetics, Technical University Munich, Munich, Germany (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl) (13–15) and SAS version 9.1 (SAS Institute, Cary, NC). A two-sided Cochran–Armitages trend test with one degree of freedom was performed to evaluate the trend across the genotype combinations. P < 0.05 was deemed significant.

	Results

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CASP10 V410I is associated with a reduced familial BC risk
The present study revealed a significant association of the CASP10 V410I variant with a decreased familial BC risk (OR = 0.62, 95% CI = 0.43–0.88, P = 0.0076; Table I). In addition, the Cochran–Armitage trend test pointed to an association between the number of variant alleles and BC risk (P_trend = 0.0039; Table I). Thus, the comparison of the rare with the wild type homozygotes showed an extremely decreased OR with a borderline significance (OR = 0.16, 95% CI = 0.02–1.39, P = 0.06). Adjustment for age did not change the respective ORs.

View this table: [in this window] [in a new window]   Table I. Genotype frequencies of CASP10 V410I (G1228A) in unrelated German BRCA1/2 mutation-negative BC patients and healthy, unrelated female control subjectsa

 
CASP10V410I/CASP8 D302H genotype interaction and familial BC risk
We tested for interaction between the CASP10 V410I and CASP8 D302H variants and observed a significantly decreased risk for the heterozygous carriers of both variants (OR = 0.39, 95% CI = 0.16–0.94, P = 0.029; Table II) and a significant trend for a decreased risk with an increasing number of the CASP10 I410 allele (OR = 0.35, ² = 7.27, P_trend = 0.007; Table II). We would expect the same trend for an increasing number of CASP8 H302 allele. Due to the small numbers of homo- and heterozygotes for the H302 allele, however, only a non-significant trend was noted (P_trend = 0.88, Table II). Investigating the combined effect comparing genotype combinations bearing the protective alleles of both CASP10 (I410) and CASP8 (H302) (410VI-302DH, 410VI-302HH, 410II-302DH and 410II-302HH) with the most common genotype combination (410VV-302DD), we detected a significant association with a decreased risk (OR = 0.37, 95% CI = 0.16–0.83, P = 0.013).

View this table: [in this window] [in a new window]   Table II. Joint effect of CASP10 (V410I) and CASP8 (D302H) genotypes on familial BC risk in unrelated German BRCA1/2 mutation-negative BC cases and healthy, unrelated female control individuals

 

	Discussion

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Apoptosis is a major form of cell death, characterized by a series of distinct morphological and biochemical alterations and is perturbed in many cancers (9,16). We pursued the hypothesis that coding polymorphisms of the caspases 8 and 10 genes might act as familial breast cancer risk factors. Recent studies on independent cohorts have considered the CASP8 variant D302H to be inversely associated with BC risk (9,10). The functional effect of D302H is so far unknown. However, the aspartate residue is conserved between mouse and human. Due to its exposed position on the surface of the protein, the D302H change could have an effect on CASP8 interactions with the antiapoptotic molecule CFLAR or on autoprocessing of procaspase 8 molecules. Like CASP8, CASP10 comprises two death effector domains (DEDs). It has been assumed that, in the latent state, both DEDs bind to each other, thus preventing activation. Upon activation of the Fas-associating protein with death domain (FADD) by CD95 or tumour necrosis factor (TNF) receptors, the FADD DED conformation changes, facilitating its binding to one of the DEDs of the caspase and allowing its caspase domain to undergo autocatalytic activation (16–19). Mature CASP10 is derived from a single-chain polypeptide proenzyme by cleavage at D415 located between the large p17 and the small p12 subunits. CASP10 V410I is located five amino acids upstream of this cleavage site as well as seven amino acids downstream of the conserved QACXG pentapeptide active-site motif which contains the catalytic cysteine residue (7). Thus, the V410I change could affect CASP10 activation and impair caspase function. We revealed a significant association of this variant with a decreased familial BC risk dependent on the number of variant alleles (Table I). The observed association indicates that CASP10 V410I is either itself a causative variant or is in strong linkage disequilibrium with an unknown functional variant residing in CASP10 or in neighbouring genes. There have been no in vivo studies investigating the function of the variant so far. An in vitro expression study using human embryonic kidney cells (HEK293 cells) showed an attenuation of apoptotic function upon transfection with mutant cDNA (20). Transfection experiments with MCF7 BC cells or the use of an animal model would help to elucidate the impairment of this variant on breast carcinogenesis. Investigating the mutual effect of the CASP10 V410I and CASP8 D302H polymorphisms, we observed a significantly decreased risk for the heterozygous carriers of both variants and a significant trend for a decreased risk with an increasing number of the CASP10 I410 allele (Table II), supporting the hypothesis of a joint effect. Although the observed OR is strongly decreased, the influence of these genotype combinations on general familial BC risk is, due to the rareness of both variants, rather small.

The choice of blood donors as control group might have somewhat influenced our results, for this group probably consists of women that are more health-conscious than the case patients. However, the use of blood donors in a study testing the association of a SNP with a disease is justified as long as the controls are drawn from the same ethnic population and as long as the HWE holds (21,22). Furthermore, we preferred blood donors, because, for a fixed budget, it allowed a maximal sample size. The strengths of the present study also include a sound sample size of a single ethnic group comprising women selected for familial BC. Only BRCA1 and BRCA2 mutation negative familial BC cases were considered in order to avoid effects derived from these high-penetrance susceptibility genes. With our present sample size, we had a power of 80% at a significance level of 0.05 to detect an OR of 0.59 for V410I. The power of an association study based on cases with a family history is at least twice higher compared to a study using unselected cases (23–25). In addition, the effect of CASP10 V410I on familial BC risk depends on gene dosage, suggesting our observation to be no chance finding. However, functional studies would elucidate the impact of V410I on the function of CASP10.

In summary, our results indicate a decreased risk of developing BC for carriers of the CASP10 I410 allele. Moreover, the individual susceptibility for breast carcinogenesis is altered by combined effects between the protective CASP10 I410 and CASP8 H302 variants.

	Acknowledgments

 
The authors are grateful to Kerstin Wagner for helpful comments on the manuscript and Justo Lorenzo Bermejo for statistical advice. The German BC samples were collected within a project funded by the Deutsche Krebshilfe, supported by the Center of Molecular Medicine Cologne (CMMC), and coordinated by Prof. Rita K. Schmutzler.

Conflict of Interest Statement: none declared.

	References

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Received July 24, 2005; revised September 20, 2005; accepted October 18, 2005.

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