Human Molecular Genetics

¹CRC Human Cancer Genetics Research Group, Box 238 and ⁴Department of Clinical Oncology, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ UK, ²Department of Medicine, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK, ³Department of Community Medicine, ⁷CRC Genetic Epidemiology Unit, Department of Community Medicine and ⁸MRC Biostatistics Unit, Institute of Public Health, University of Cambridge, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK and ⁵CRC Section of Molecular Carcinogenesis and ⁶CRC Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey SN2 5NG, UK

Received September 3, 1996; Revised and Accepted November 27, 1996

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency >1.3%. The two most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.

INTRODUCTION

Breast cancer is a common disease with a lifetime risk of 8% in women in the UK, while ovarian cancer is approximately one-tenth as frequent but remains the fifth most common cancer of women. The first human familial breast and ovarian cancer susceptibility gene, BRCA1, on chromosome band 17q21, was cloned in 1994 (1 ). The normal function of the 1863 residue protein encoded by this gene remains unknown, although two potentially functional motifs have been identified: a ring-finger domain encoded by exons 2, 3 and 5 (1 ), and a granin consensus sequence (residues 1214-1223) which indicates that the protein may be secreted (2 ). More than 100 distinct highly penetrant mutations in BRCA1 have been described (3 ,4 ). These mutations confer a 90% risk of breast or ovarian cancer by age 70 years. The majority are predicted to result in a truncated BRCA1 protein. This is consistent with other findings which suggest that BRCA1 acts as a tumour suppressor gene (5 ,6 ).

Epidemiological data suggest that the frequency of highly penetrant BRCA1 mutations in the population is between 1 in 500 and 1 in 2000 individuals (7 ), which implies that these mutations account for only ~2% of all breast cancer diagnosed before age 70. The proportion of breast cancer due to BRCA2 is likely to be of a similar magnitude (7 ). Germline p53 mutations account for a much smaller proportion of cases (8 ,9 ), whilst mutations in the ATM gene probably account for <5% of all breast cancer (10 ). In principle, a greater proportion of breast cancer incidence could be accounted for by common but less highly penetrant predisposing genes. Currently the only well-established example is the HRAS1 mini-satellite locus (11 ). So-called `rare' alleles at this locus, which have a frequency of ~0.06 in the general population, are associated with a 2-fold relative risk of breast and some other cancers; despite this small relative risk, the predisposing alleles are estimated to account for 9% of total breast cancer incidence since they are relatively common. We have used a case-control design to assess whether BRCA1 gene variants have any effect on low-penetrance predisposition to breast and ovarian cancer.

RESULTS

Individuals in the population series were genotyped for four polymorphisms in BRCA1 which result in amino acid substitutions: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly. There is strong linkage disequilibrium between the alleles of all these sites (data not shown) and, as a result of this, haplotypes can be deduced with accuracy even in unrelated individuals. There is close to complete allelic association between the alleles at residues 871, 1038 and 1613. Furthermore, 94% of the alleles encoding Arg356 are carried on a single haplotype. Thus, only three of the observed haplotypes have an overall frequency of >1.3%. The estimated haplotype frequencies are given in Table 1 . As a consequence of this strong allelic association, the effects of all three common haplotypes can be investigated by considering solely the alleles at the Gln356Arg and Pro871Leu polymorphic sites.

The genotype distribution of the Pro871Leu polymorphism does not show any consistent frequency differences between patient and control groups (Table 2 ). The Leu871 allele is marginally more frequent in the UK patients aged 36-45 years than in their matched controls [0.37 (238/642) versus 0.31 (220/700), P = 0.05], but not in any of the other groups [all breast cancer patients versus all controls: 0.34 (548/1602) versus 0.31 (362/1144), P = 0.35]. The estimated relative risk when all the breast cancer series are compared with all the controls is 1.15 [95% confidence interval (CI) 0.92-1.44] to the heterozygotes and 1.24 (95% CI 0.84-1.79) to the Leu homozygotes.

The Arg356 allele tends to be more frequent among control individuals than among breast cancer cases (all controls versus all breast cancer cases: 0.07 versus 0.05, P=0.06) and, furthermore, Arg homozygotes are only found among the controls (overall difference in genotype distribution P = 0.010, Table 3 ). This is suggestive that Arg356 may be associated with reduced susceptibility to breast cancer, the relative risk to the heterozygotes being 0.88 (95% CI 0.63, 1.23) and that to the Arg homozygotes being 0 (95% CI 0, 0.56) compared with the Gln homozygotes. Some of the differences in genotype distribution between cases and controls may be due to the unusually large number of Arg356 homozygotes in controls (seven compared with 3.1 which would be expected under Hardy-Weinberg equilibrium). However, even if the genotype distribution in controls is constrained to be in Hardy-Weinberg equilibrium, there is still a significant difference in genotype distribution between cases and controls (P = 0.019 by permutation test, Table 3 ). The Arg356 allele appears to have no effect on risk of ovarian cancer. The 95% upper confidence limit for relative risk of ovarian cancer associated with any of the polymorphisms in this study was 2.06 (Table 3 ).

DISCUSSION

This study demonstrates that >95% of individuals in the UK populations have one of three haplotypes at the BRCA1 locus. Our results indicate that none of these common haplotypes are associated with a substantially increased risk of breast (Table 1 ) or ovarian cancer. The largest upper confidence limit on the relative risk of breast cancer which could be ascribed to any common haplotype was 1.43 and that for ovarian cancer was 1.48. It is difficult to make any reliable inferences on risk associated with any of the rarer haplotypes since the numbers estimated from our data are too small.

Table 1 Estimated haplotype frequencies and observed allele frequencies in the different groups

Residue	All	Combined	Combined	Ovarian cancer	Relative risk	Relative risk
356/871/1038/1613	individuals	controls	breast cancer	cases	of breast cancer	of ovarian cancer
			cases		(95% CI)	(95% CI)
GlnProGluSer	0.572	0.591	0.542	0.587	0.92	0.98
	(482.2)a				(0.74, 1.15)	(0.76, 1.26)
GlnLeuGlyGly	0.319	0.300	0.340	0.314	1.13	1.07
	(268.5)a				(0.90, 1.43)	(0.82, 1.39)
ArgProGluSer	0.061	0.072	0.044	0.067	0.61	0.93
	(51.5)a				(0.37, 0.99)	(0.57, 1.51)
All other haplotypesc	0.048	0.037	0.074	0.032	-	-
	(40.8)a
Leu871	0.331	0.316	0.342	0.332	1.12	1.07
	(1058)b				(0.96, 1.32)	(0.85, 1.36)
Arg356	0.061	0.070	0.053	0.076	0.75	1.10
	(204)b				(0.55, 1.02)	(0.73, 1.65)

^aNumber of haplotypes estimated by maximum likelihood.^bObserved number of alleles.^cCombined frequencies of other haplotypes: GlnLeuGluGly, 0.013; GlnProGlySer, 0.012; GlnLeuGluSer, 0.011; GlnProGlyGly, 0.006; GlnProGluGly, 0.002; ArgProGlySer, 0.002; ArgLeuGlyGly, 0.001; GlnLeuGlySer, 0.001; ArgProGluGln, 0.001.

Table 2 Genotype distributions of the proline871leucine polymorphism

Genotype	ProPro	ProLeu	LeuLeu	Relative risks:		P valuea
	no. (%)	no. (%)	no. (%)	ProLeu	LeuLeu
				(95% CI)	(95% CI)
All controls	266	250	56
	(46.5)	(43.7)	(9.8)
All breast cancer	342	370	89	1.15	1.24	0.35 (n/s)
cases	(42.7)	(46.2)	(11.1)	(0.92, 1.44)	(0.85, 1.79)
Ovarian cancer	102	94	27	0.98	1.26	0.63 (n/s)
cases	(45.7)	(42.2)	(12.1)	(0.71, 1.36)	(0.76, 2.10)
East Anglian (EA)	98	106	18
controls	(44.1)	(47.8)	(8.1)
EA breast cancer	94	97	21	0.95	1.22	0.79 (n/s)
cases (<70 years)	(44.4)	(45.7)	(9.9)	(0.64,1.42)	(0.61, 2.43)
UK controls	168	144	38
	(48.0)	(41.1)	(10.9)
UK breast cancer	124	156	41	1.47	1.46	0.05
cases (36-45 years)	(38.6)	(48.6)	(12.8)	(1.06, 2.03)	(0.89, 2.41)
UK breast cancer	124	117	27	1.10	0.96	0.81 (n/s)
cases (<36 years)	(46.3)	(43.7)	(10.1)	(0.79, 1.54)	(0.56, 1.66)

^aP values are based on asymptotic [chi]² distributions with 2 degrees of freedom.

Table 3 . Genotype distributions of the glutamine356arginine polymorphism

Genotype	GlnGln	GlnArg	ArgArg	Relative risks:		P valuea
	no. (%)	no. (%)	no. (%)	GlnArg	ArgArg
				(95% CIb)	(95% CIb)
All controls	550	74	7
	(87.2)	(11.7)	(1.1)
All breast cancer	684	81	0	0.88	0	0.019*
cases	(89.4)	(10.6)	(0)	(0.63, 1.23)	(0, 0.56)
Ovarian cancer	195	35	0	1.33	0	0.38 (n/s)
cases	(84.8)	(5.2)	(0)	(0.86, 2.06)	(0, 1.98)
East Anglian (EA)	246	26	5
controls	(88.8)	(9.4)	(1.8)
EA breast cancer	167	19	0	1.08	0	0.68 (n/s)
cases (<70 years)	(89.8)	(10.2)	(0)	(0.58, 2.01)	(0, 1.63)
UK controls	304	47	2
	(85.9)	(13.3)	(0.6)
UK breast cancer	283	33	0	0.75	0	0.07 (n/s)
cases (36-45 years)	(89.6)	(10.4)	(0)	(0.47, 1.21)	(0, 2.62)
UK breast cancer	234	29	0	0.80	0	0.23 (n/s)
cases (<36 years)	(89.0)	(43.11.0)	(0)	(0.49, 1.31)	(0,3.17)

^aEmpirical P values based on 10 000 random assignments of genotypes and correcting for HWE proportions in controls.^bExact confidence intervals based on hypergeometric distribution.*P = 0.010 without correcting for HWE in controls.

Our finding of only three common haplotypes covering the coding region of BRCA1 is consistent with other studies (12 -14 ). In a recent study, Durocher et al. (13 ) reported the Leu871 allele to be significantly more frequent in 107 BRCA1 gene carriers from high risk families than in similar numbers of controls (0.42 versus 0.28, P = 0.002). We did find a higher frequency of Leu871 in cases in our series of UK breast cancer patients aged 35-45 years than in controls (0.37 versus 0.31, P = 0.05), but this was not confirmed in the other population-based series we examined. It is likely that the differences observed are an artefact of the case and control populations used. We conclude that the evidence for any effect of the Leu871 allele on breast cancer risk is not established, and that the associated increased risk, if any, must be small.

Rather than an association with increased risk, we found that homozygotes for Arg356 are less common among breast cancer cases than among controls, suggesting that haplotypes carrying this allele may confer reduced susceptibility. Although reaching formal statistical significance, this finding requires confirmation in other large case-control series. The mechanism by which the Arg356 variant might have an effect is not clear. Residue 356 is not within one of the domains of BRCA1 with recognisable function, and it is encoded by the region of exon 11 which is deleted in a common BRCA1 transcript (15 ). Furthermore, residue 356 is not evolutionarily conserved between human and mouse which has proline at the equivalent residue (16 -18 ); however, it is not possible to infer much about evolutionary conservation since these are the only species for which the sequence of this BRCA1 region is currently available. We cannot be certain that this Arg allele is the only variant carried on these haplotypes and so it may not even be directly responsible for the effect seen. The Arg356 variant does, however, generate a run of three positively charged residues (LysArgLys) and so it could conceivably alter the properties of the protein, which is composed of 16% negatively charged residues overall (2 ). Since the Arg356 allele has a frequency of only 6%, the practical implications of this finding if it is confirmed in the UK population, are likely to be limited. Nevertheless, if Arg356-carrying haplotypes are more common in other ethnic groups, they could be an important predictor of risk, particularly if the very low risk in homozygotes is borne out in other studies.

MATERIALS AND METHODS

DNA samples were collected from four studies.

East Anglian (EA) case-control series

A set of 212 consecutive, Caucasian breast cancer patients diagnosed under age 70 years (mean age at diagnosis 54.1 years, SD = 10.3) and attending the breast clinic in the Oncology Department in Addenbrooke's Hospital, Cambridge (which is in East Anglia) were compared with 277 randomly selected, anonymous, female, Caucasian controls drawn from a population-based cohort study of diet and health (the EPIC study). The cohort contains ~25 000 individuals resident in Norfolk (which also lies within East Anglia), aged 45-74 years (19 ). Women known to be suffering from breast or ovarian cancer at the time of recruitment to the original study were excluded from analysis.

UK case-control series 36-45 years old

This was a population-based case-control study based on cases diagnosed between the ages of 36 and 45 years in Yorkshire, South Thames and Oxford health regions in 1988 and 1989. A total of 644 female breast cancer cases and an equal number of unaffected controls matched for age and family doctor were interviewed. In 1992 we obtained DNA samples from 321 patients and 353 controls for this present study.

UK under 36-year-old breast cancer series

This group was drawn from a population based case-control study of breast cancer cases diagnosed below age 36 in Britain over the period 1982 and 1985. A total of 755 cases and matched controls were originally interviewed (20 ). DNA samples were obtained from 268 patients from this study who were still living in 1992. No samples were obtained from the controls in this study and we therefore used the controls from the UK series (above) for this purpose.

Ovarian cancer patients

A set of 237 consecutive Caucasian patients with epithelial ovarian cancer attending the Royal Marsden Hospital, London (mean age at diagnosis: 51.8 years, SD = 11.9) were analysed. The majority of these came from the south east of England; they were compared with combined control sets from the East Anglian and UK series (above).

Genotype detection

Polymorphisms were primarily detected by allele-specific oligonucleotides (ASOs) hybridisation. Two regions of exon 11 (encoding residues 283-440 and 712-1056) together with the whole of exon 16 of the BRCA1 gene (1 ) were PCR amplified individually or in one multiplex reaction for each of the individuals studied. The sequences of the ASOs used to detect the polymorphisms were: Gln356, aat aag cag aaa ctg; Arg356, aat aag cgg aaa ctg; Pro871, ttt gct ccg ttt tca; Leu871, ttt gct ctg ttt tca; Glu1038, ttt aaa gaa gcc agc; Gly1038, ttt aaa gga gcc agc; Ser1613, gcc cag agt cca g; Gly1613, gcc cag ggt cca g. ASOs were manufactured by Cruachem (Edinburgh, UK) and were HPLC purified. Hybridisation was carried out at 35^oC and washing at 41-43^oC. Blotting and hybridisation have been described elsewhere (21 ). PCR efficiencies varied between the regions amplified, resulting in some differences in the number of results obtained for each polymorphism.

The Gln356Arg genotyping was confirmed, in selected individuals, using AlwNI (New England Biolabs) digestion of the exon 11 PCR product encoding residues 283-440. The allele encoding arginine has no cutting site for this enzyme. All individuals indicated as having an Arg allele by ASO hybridisation together with 100 shown to be Gln homozygotes were checked by AlwNI digestion. The digest result was taken as definitive.

Statistical analysis

The haplotype frequencies were estimated by maximum likelihood using an expectation-maximisation algorithm, on S-plus. We compared allele and haplotype frequency differences in cases and controls using standard [chi]² tests, and large sample confidence intervals. Large sample approximation for a [chi]² test on 2df were also used for comparing the Pro871Leu genotype distributions, but the frequency of Arg356 was much lower and this necessitated empirical tests and exact CIs. Conditional on the number of cases and controls, we evaluated the distribution of the test statistic in each situation by 10 000 random assignments of genotypes to each subject. Because the number of Arg356 homozygotes was greater than the number under Hardy-Weinberg equilibrium, we also performed a more conservative test in which the expected number of controls with each genotype were based on Hardy-Weinberg frequencies, as suggested by Lathrop (22 ). This ensured that the observed difference is not simply an artefact of the departure of control genotypes from Hardy-Weinberg proportions.

ACKNOWLEDGEMENTS

The authors would like to thank Mark Elsdon, Patricia Harrington, Catherine Healey, Carol Houghton, Paul Russell, Tim Stonehouse and William Warren for technical assistance and Janet Brook, Beverley Nichol, Carole Pye and Mr Alastair Smellie for assistance with collection of patient and control population samples; also Drs Juliet Ellis, Gerald Laxer and Sylvie Mazoyer for helpful advice. Professors Val Beral, Clair Chilvers, Malcolm Pike, Martin Vessey and Drs Judy Deacon and Klim McPherson were principal investigators on the UK case-control studies of oral contraceptives and breast cancer. This study was supported by a programme grant from the Cancer Research Campaign (CRC). B.A.J.P. is a Gibb Fellow of the CRC.

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*To whom correspondence should be addressed

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