Localization of a Breast Cancer Susceptibility
`Gene, BRCA2, to Chromosome 13q 12-13
`Richard Wooster,* Susan L. Neuhausen,* Jonathan Mangion,*
`Yvette Quirk,* Deborah Ford,* Nadine Collins, Kim Nguyen,
`Sheila Seal, Thao Tran, Diane Averill, Patty Fields, Gill Marshall,
`Steven Narod, Gilbert M. Lenoir, Henry Lynch, Jean Feunteun,
`Peter Devilee, Cees J. Cornelisse, Fred H. Menko, Peter A. Daly,
`Wilma Ormiston, Ross McManus, Carole Pye, Cathryn M. Lewis,
`Lisa A. Cannon-Albright, Julian Peto, Bruce A. J. Ponder,
`Mark H. Skolnick, Douglas F. Easton,t David E. Goldgar,
`Michael R. Stratton
`
`A small proportion of breast cancer, in particular those cases arising at a young age, is
`due to the inheritance of dominant susceptibility genes conferring a high risk of the
`disease. A genomic linkage search was performed with 15 high-risk breast cancer families
`that were unlinked to the BRCA 1 locus on chromosome 17q21. This analysis localized a
`second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chro(cid:173)
`mosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of
`breast cancer but, unlike BRCA 1, does not confer a substantially elevated risk of ovarian
`cancer.
`
` on May 16, 2014
` on May 16, 2014
` on May 16, 2014
`
`p53 gene on chromosome 17p cause a wide
`range of neoplasms including early-onset
`breast cancer, sarcomas, brain tumors, leuke(cid:173)
`mias, and adrenocortical cancer (3). Certain
`rare abnormalities of the androgen receptor
`appear to be associated with breast cancer in
`men (4), and epidemiological studies have
`suggested that heterozygotes for the ataxia
`telangiectasia gene, AT, on chromosome
`11q are at elevated risk of breast cancer
`(5). However, mutations in p53 and AT
`can only be responsible for a small minor(cid:173)
`ity of breast cancer families that are un(cid:173)
`linked to BRCAl (6).
`To localize other genes that predispose
`to breast cancer, we performed a genomic
`linkage search using 15 families that had
`multiple cases of early-onset breast cancer
`and that were not linked to BRCAl. These
`families were classified according to the
`number of cases of female breast cancer,
`male breast cancer, and ovarian cancer (Ta(cid:173)
`ble 1). In addition to a negative lod score
`(logarithm of the likelihood ratio for link(cid:173)
`age) with markers flanking BRCAl, all but
`one of the families used for this study had at
`least one breast cancer case diagnosed be(cid:173)
`fore age 50 that did not share a BRCAI
`haplotype with other breast cancer cases in
`the family. The exception, CRC 136, had
`an obligate sporadic case diagnosed at age
`53. Families were genotyped with polymor(cid:173)
`phic microsatellite repeat markers (7, 8).
`Typing of the markers DI3S260 and
`D 13S263 provided provisional evidence for
`the presence of a susceptibility gene on
`chromosome 13, which was subsequently
`confirmed by analysis of additional poly(cid:173)
`morphisms in the region.
`
`www.sciencemag.org
`www.sciencemag.org
`www.sciencemag.org
`
`Downloaded from
`Downloaded from
`Downloaded from
`
`variants. Furthermore, probe cyclization
`reactions depend on an intramolecular
`reaction as opposed to reaction between
`pairs of independent probe molecules as
`in amplification by the polymerase chain
`reaction. Thus, there should be fewer prob(cid:173)
`lems with nonspecific reactions resulting
`from interactions between noncognate pairs
`of probe segments with cyclizable probes.
`The present probe design should permit the
`simultaneous analysis of multiple gene se(cid:173)
`quences in a DNA sample.
`In conclusion, the nucleic acid probe pre(cid:173)
`sented here permits highly specific detection
`of nucleotide sequences and, although the
`target is not amplified, highly sensitive detec(cid:173)
`tion is possible through efficient reduction of
`nonspecific signal. Circularizable probes
`should be applicable in a number of other
`contexts, including the detection of specific
`RNA molecules expressed in tissue sections as
`T4 DNA ligase can assist in ligation reactions
`involving RNA strands (8). Moreover, immo(cid:173)
`bilized padlock probes could be useful for pre(cid:173)
`parative purposes, such as trapping circular
`target molecules from solution when screen(cid:173)
`ing gene libraries.
`
`REFERENCES AND NOTES
`
`1. U. Landegren, R. Kaiser, J. Sanders, L. Hood, Sci(cid:173)
`ence 241, 1077 (1988); A.M. Alves and F. J. Carr,
`Nucleic Acids Res. 16, 8723(1988); F. Barany, Proc.
`Nat/. Acad. Sci. U.S.A. 88, 189 (1991).
`2. D. Y. Wu and R. B. Wallace, Gene 76, 245 (1989).
`3. A. Jaschke, J. P. FOrste, D. Cech, V. A. Erdmann,
`Tetrahedron Lett. 34,301 (1993).
`4. G. Prakash and E. T. Kool, J. Am. Chern. Soc. 114,
`3523 (1992); N. G. Dolinnaya et at., Nucleic Acids
`Res. 21, 5403 (1993).
`5. The upper faint bands observed in lanes 3 and 4
`probably represent small amounts of linear dimer
`molecules, appearing as a consequence of ligation
`of one end each of two different probe molecules.
`This material proved susceptible to exonuclease,
`digestion. The extra lower bands in these lanes
`were not reproducible between experiments.
`Small amounts of uncatenated, circular probes ap(cid:173)
`pearing in lane 7 most likely were a consequence
`of endonuclease activity in the exonuclease prep(cid:173)
`aration. With increasing amounts of exonuclease,
`catenated probes are lost and more free circular
`probes appear (M. Nilsson et at., unpublished
`data).
`6. J. R. Riordan et at., Science 245, 1066 (1989).
`7. H. F. Willard and J. S. Waye, Trends Genet. 3, 192
`(1987). A. G. Matera and D. C. Ward, Hum. Mol.
`Genet. 7, 535 (1992). A. Baldini et at., Am. J. Hum.
`Genet. 46, 784 (1990).
`8. N. P. Higgins and N. R. Cozzarelli, Methods Enzymol.
`68, 50 (1979).
`9. T. Maniatis, E. F. Fritsch, J. Sambrook, Molecular
`Cloning: A Laboratory Manual (Cold Spring Harbor
`Laboratory, Cold Spring Harbor, NY, 1982).
`10. C. Sund, J. Ylikoski, P. Hurskainen, M. Kwiatkowski,
`Nuc/eos. Nuc/eot. 7, 655 (1988).
`11 . D. Pinkel et at., Proc. Nat/. Acad. Sci. U.S.A. 85,
`9138 (1988).
`12. We thank E. Johnsen for technical assistance and T.
`Hansson for molecular modeling. U. Pettersson of(cid:173)
`fered critical comments on this manuscript. Support(cid:173)
`ed by the Beijer, Precordia, and Borgstrom founda(cid:173)
`tions; by NUTEK, the Technical and Medical Re(cid:173)
`search Councils of Sweden; and by the Swedish
`Cancer Fund.
`
`18 July 1994; accepted 1 September 1994
`
`In 1990, a breast cancer susceptibility gene,
`known as BRCAl, was localized to chromo(cid:173)
`some 17q (1 ). Subsequent studies demonstrat(cid:173)
`ed that BRCAl accounts for most families
`with multiple cases of both early-onset breast
`and ovarian cancer and about 45% of families
`with breast cancer only, but few if any families
`with both male and female breast cancer (2).
`Several other genes can confer susceptibility
`to breast cancer. Germline mutations in the
`
`R. Wooster, J. Mangion, Y. Quirk, N. Collins, S. Seal, M.
`R. Stratton, Section of Molecular Carcinogenesis, Insti(cid:173)
`tute of Cancer Research, Sutton, Surrey 8M2 5NG, UK.
`S. L. Neuhausen, K. Nguyen, T. Tran, P. Fields, C. M.
`Lewis, M. H. Skolnick, D. E. Goldgar, Department of
`Medical Informatics, University of Utah, Sa~ Lake City, UT
`84108, USA.
`D. Ford, D. Averill, G. Marshall, J. Peto, D. F. Easton,
`Section of Epidemiology, Institute of Cancer Research,
`Sutton, Surrey 8M2 5NG, UK.
`S. Narod, Department of Medicine, Division of Medical
`Genetics and Division of Human Genetics, McGill Univer(cid:173)
`sity, Montreal, Canada H3G 1A4.
`G. M. Lenoir, International Agency for Research on Can(cid:173)
`cer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08,
`France.
`H. Lynch, Department of Preventive Medicine and Public
`Health, Creighton University School of Medicine, Omaha,
`NE 68178, USA.
`J. Feunteun, Institute Gustav-Roussy, Villejuif, France.
`P. Devilee and C. J. Comelisse, Departments of Pathol(cid:173)
`ogy and Human Genetics, University of Leiden, 2333 AL
`Leiden, Netherlands.
`F. H. Menko, Department of Clinical Genetics, Free Uni(cid:173)
`versity of Amsterdam, 1007 MB Amsterdam, Nether(cid:173)
`lands.
`P. A. Daly, W. Ormiston, R. McManus, Department of
`Medicine, Trinity College Medical School, St. James Hos(cid:173)
`pital, Dublin 8, Ireland.
`C. Pye and B. A. J. Ponder, CRC Human Cancer Genet(cid:173)
`ics Group, Department of Pathology, Universrty of Cam(cid:173)
`bridge, Cambridge CB2 1QP, UK.
`L. A. Cannon-Albright, Department of lntemal Medicine,
`University of Utah, Salt Lake City, UT 84132, USA.
`*These authors contributed equally to this study.
`tTo whom correspondence should be addressed.
`
`2088
`
`SCIENCE
`
`• VOL 265
`
`• 30 SEPTEMBER 1994
`
`GeneDX 1022, pg. 1
`
`

`

`Two-point lod scores were calculated
`for a set of closely spaced markers on
`chromosome 13q (Table 2) (9). Ten other
`markers were typed to confirm the seg(cid:173)
`regation of haplotypes. The order of
`markers and intervals between them (in
`is 13cen-D 13S283-(3 )(cid:173)
`centimorgans)
`D 13S221-(2)-D 13S 120-(2)-D 13S217-
`(5)-D 13S289/D 13S290-(3 )-D 13S260-( 1 )(cid:173)
`D 13S 171-(2)-D 13S267 -( 2)-D 13S220/
`D 13S219-(5 )-D 13S218-(5 )-D 13S263-
`(8)-D 13S 155-(2)-D 13S 153-13qter (1 0).
`The maximum total multipoint lod score
`with markers D 13S260 and D 13S267 was
`9.58 at a location 5 eM proximal to
`D 13S260. However, the admixture test
`indicated significant evidence of hetero(cid:173)
`geneity (P = 0.001) with an estimated
`proportion of 13q-linked families of 74%
`(95% CI 35 to 97%). Under the assump(cid:173)
`tion of heterogeneity, the maximum total
`lod score was 11.65 and the most likely
`location for BRCA2 was coincident with
`D 13S260. Multipoint lod scores at
`D 13S260 for each family are shown in
`Table 2. The haplotypes confirmed coseg(cid:173)
`regation of chromosome 13q markers with
`the disease (an example from CRC 186 is
`shown in Fig. 1). Two recombinants place
`BRCA2 telomeric to D13S289, in breast
`cancer cases diagnosed at ages 43 and 39
`(in families IARC 2932 and CRC 186,
`respectively). One recombinant in a bi(cid:173)
`lateral breast cancer case diagnosed at
`ages 38 and 41 in Utah 107 places the
`gene centromeric to D 13S267. The dis(cid:173)
`tance between these two markers is esti(cid:173)
`mated to be 6 eM (7), and these flanking
`markers place BRCA2 in a physical region
`defined by 13q12-13.
`
`The proximal part of chromosome 13 in
`which BRCA2 is situated commonly shows
`loss of heterozygosity (LOH) in sporadic
`breast and ovarian cancers, suggesting that
`BRCA2 is inactivated during oncogenesis
`(10). However, the tumor suppressor gene
`RB 1 is also located in this region and may
`account for the LOH observed. Indeed, so(cid:173)
`matic mutations in RBI have been reported
`in sporadic breast cancers ( 11 ). However,
`the presence of numerous recombinants be(cid:173)
`tween RBl [the marker Dl3S153 is within
`the RB 1 gene (12)] and the disease in
`linked families indicates that BRCA2 is not
`RB 1. Other candidate genes within 13q 11-
`14 include members of a family of tyrosine
`
`kinase genes that are related to the FMS
`proto-oncogene ( 13) and the FTE 1 gene,
`which may act as an effector of the v-fos
`oncogene and is a mammalian homolog of a
`yeast gene involved in protein import into
`mitochondria (14).
`Like BRCAl, BRCA2 appears to confer
`a high risk of early-onset breast cancer in
`females; previous segregation analysis of the
`largest BRCA2-linked family (Utah 107)
`indicated a risk of 87% by age 80 (15),
`which is comparable to the BRCAl pen(cid:173)
`etrance. However, other aspects of the
`BRCA2 phenotype may differ from the
`BRCAl phenotype. For example, in the two
`families showing the strongest evidence of
`
`Table 1. Breast cancer families used in the genome search for BRCA2. FBC, female breast cancer; MBC,
`male breast cancer; OvC, ovarian cancer.
`
`Family
`
`Number
`of FBCs
`
`Number of
`FBCs under
`age 50
`
`Number
`ofMBCs
`
`Number
`ofOvCs
`
`Lod score
`at BRCA1*
`
`Number of
`sporadic
`casest
`
`0
`0
`5
`7
`CRC007
`0
`0
`3
`5
`CRC 018
`0
`CRC 028
`1
`2
`3
`4
`CRC 135
`0
`6
`0
`0
`0
`4
`6
`CRC 136
`1
`1
`15
`16
`CRC 186
`0
`0
`10
`15
`IARC 2932
`4
`1
`4
`4
`Leiden 49
`6
`3
`25
`38
`Utah 107
`Utah 1001
`0
`0
`11
`14
`0
`0
`4
`4
`Utah 1929
`4
`4
`0
`0
`Utah 2027
`1
`1
`2
`2
`Utah 2043
`Utah 2044
`4
`1
`6
`9
`0
`0
`5
`5
`Utah 9018
`*Multipoint lod score based on D17S250 and D17S579, which flank BRCA 1 in an interval of approximately 6 eM, or
`closer flanking markers.
`tMinimum number of cases affected with breast cancer under age 60 or ovarian cancer that
`do not share a 17q haplotype.
`
`-1.45
`-0.41
`0.04
`-0.49
`-0.02
`-2.61
`-2.02
`-1.11
`-3.57
`-0.48
`-0.41
`-1.14
`-0.44
`-1.40
`-0.53
`
`2
`1
`1
`1
`1
`7
`3
`1
`7
`2
`1
`1
`1
`4
`1
`
`Table 2. Two-point and multipoint lod scores for chromosome 13q markers in breast cancer families showing evidence against linkage to BRCA 1.
`
`Two-point lod scores at recombination fractions of 0.00 and 0.05
`
`Family
`
`013$289
`
`013$260
`
`013$267
`
`013$219
`
`013$263
`
`0.00
`
`0.05
`
`0.00
`
`0.05
`
`0.00
`
`0.05
`
`0.00
`
`-0.81
`-1.23
`0.29
`0.16
`0.22
`0.65
`0.77
`CRC 007
`0.10
`0.21
`0.26
`0.67
`0.78
`0.62
`0.73
`CRC 018
`-0.02
`0.26
`0.02
`0.21
`0.00
`0.00
`0.00
`CRC028
`-0.06
`0.12
`0.14
`0.12
`0.15
`0.36
`0.43
`CRC 135
`-1.07
`-1.26
`-0.42
`-0.28
`-0.57
`-0.75
`-0.84
`CRC 136
`-0.30
`1.00
`2.08
`2.35
`1.60
`1.84
`0.03
`CRC 186
`-0.03
`1.62
`0.67
`0.80
`1.22
`1.33
`0.10
`IARC 2932
`-0.37
`-0.65
`-0.16
`-0.21
`0.08
`-0.65
`Leiden 49
`0.06
`0.24
`-0.23
`-0.86
`2.11
`1.84
`1.11
`0.24
`Utah 107
`-1.99
`-3.25
`-0.41
`-0.81
`-1.63
`-0.39
`-0.96
`Utah 1001
`-0.16
`-0.37
`-0.47
`-0.26
`-0.33
`-0.33
`-0.46
`Utah 1929
`0.19
`-0.05
`-0.06
`0.13
`0.14
`0.34
`0.39
`Utah 2027
`-0.01
`-0.27
`-0.39
`0.74
`0.85
`0.81
`0.93
`Utah 2043
`-0.44
`1.37
`1.54
`-0.59
`Utah 2044
`0.88
`1.15
`0.99
`-0.11
`0.00
`0.12
`0.16
`0.19
`0.23
`Utah 9018
`0.00
`2.67
`1.98
`1.00
`5.78
`4.80
`0.34
`-2.39
`Total
`"Multipoint lod scores were calculated at D13S260, the most likely position of BRCA2 in the heterogeneity analysis.
`
`SCIENCE . VOL 265 . 30 SEPTEMBER 1994
`
`0.05
`
`0.24
`0.08
`0.01
`-0.04
`-0.10
`0.84
`1.38
`-0.25
`0.20
`-0.17
`-0.14
`0.16
`-0.02
`0.76
`-0.09
`2.87
`
`0.00
`
`-0.30
`-0.48
`-0.67
`-0.54
`-1.06
`4.08
`-0.72
`-0.75
`1.26
`-1.91
`-0.25
`0.69
`-1.13
`-1.29
`-0.86
`-3.95
`
`0.05
`
`-0.11
`-0.27
`-0.41
`-0.32
`-0.71
`3.67
`-0.17
`-0.37
`1.66
`-1.02
`-0.19
`0.59
`-0.52
`-0.72
`-0.47
`0.65
`
`Multipoint
`lod
`score*
`
`013$260-
`013$267
`
`0.97
`0.84
`0.15
`0.29
`-1.24
`3.70
`1.93
`-0.44
`3.48
`-3.40
`-0.45
`-0.11
`0.86
`2.11
`0.00
`
`2089
`
`GeneDX 1022, pg. 2
`
`

`

`- -
`
`283
`Br45
`
`285
`Br52
`
`/ 0138283
`//0138221
`
`~ ! // 0138289
`- ~ 0138260
`...........
`0135171
` 3
`7 1 - 0138267
`
`1 a- 0135220
`
`4 4 '
`0138219
`2 2
`a 11~ 0138218
`54 ~ 0135263
`5 1
`\ " 0135155
`\0135153
`
`11
`
`10 12
`7 8
`
`11
`
` 4
`a a
`7 3
`1 a
`4 2
`2 2
`3 5
`5 1
`
`788
`Br42
`
`10 1a
`7 4
`8 2
`
`I l l 5 1
`
`10 20 I! ~
`
`7 7
`
`4 4
`2 2
`3 1
`5 4
`
`-Br34
`I~ l 1 4
`
`10 5
`7 4
`
`11
`
` 2 •• 7 1
`
`1 3
`4 4
`2 3
`3 1
`1 1
`
`10 4
`7 7
`8 2
`
`5 8
`
`5 4
`diagnosis. Unaffected individuals who are potential gene carriers have been
`omitted. Marker numbers are shown on the right adjacent to the haplotype of
`indMdual 285. The black bar indicates the haplotype shared by all affected
`individuals. Genotypes in square brackets are inferred.
`
`211
`Ul85
`
`1 1
`
`7 1
`1 3
`4 4
`
`-I! !
`
`311 -5 7
`
`714
`Br38
`
`20 12
`
`• 1 In 7 1
`
`8 4 -
` 5 • •
`
`7 1
`
`11
`
`7 7
`7 1
`7 1
`1 1
`1 3
`1 1
`1 1
`1 1
`4 a
`4 2
`4 2
`4 2
`4 3
`4 3
`2 a
`2 a
`2 3
`2 3
`2 1
`2 1
`a 11
`a 1
`3 1
`3 1
`3 •
`3 8
`5 1
`5 8
`5 5
`5 5
`5 8
`58
`5 5
`5 4
`7 5
`5 5
`5 3
`5 3
`Fig. 1. Pedigree of CRC 186. Half shading (right side), breast cancer; full shading,
`bilateral breast cancer; half shading (bottom), ovarian cancer; quarter shading,
`other cancer. Types of cancer: Br, breast; Ov, ovary; Pa, pancreas; La, larynx; St,
`stomach; OM, ocular melanoma. The number after the cancer type is the age of
`
`•
`
`•
`
`ll ll
`
`5
`5
`
`5
`5
`
`344
`Br41
`
`1 1
`• 4
`
`• 2 I! !
`
`305
`301
`-
`Br33 Br34 Br41
`Br33
`
`1 1
`
`1 1
`
`• • • •
`
`310
`Br32
`Br33
`1 1
`
`1 1
`
`-Br41
`• 4 In 7 1
`I!: I!:
`
`linkage to BRCA2 (multipoint lod score
`greater than 3.0), there are 49 reported
`cases of breast cancer, 39 under age 50, and
`only 3 ovarian cancers (excluding 5 cases of
`breast cancer and 4 of ovarian cancer in
`Utah 107 that do not carry the linked hap(cid:173)
`lotype). This suggests that the risk of ovar(cid:173)
`ian cancer attributable to BRCA2 may be
`lower than that for BRCAl, which confers
`an estimated 63% risk by age 70 (16). There
`may also be a difference in the risk of male
`breast cancer. In the same two families,
`there were four cases of male breast cancer
`and three more cases in other families
`showing some evidence of linkage
`to
`BRCA2. By contrast, no male breast can(cid:173)
`cers have been observed in families showing
`strong evidence of linkage to BRCAl.
`Thus, the risk of breast cancer in men car(cid:173)
`rying BRCA2 mutations, though still small,
`is probably greater than in men carrying
`BRCAl mutations. However, the absolute
`risk of male breast cancer is still small, and
`many families where the risk of breast can(cid:173)
`cer is attributable to BRCA2 will be char(cid:173)
`acterized by female breast cancer only (for
`example, IARC 2932).
`Although in the majority of families in
`our data set breast cancer can now be
`attributed to BRCAl or BRCA2, it is
`likely that these genes still do not account
`for all breast cancer caused by high-risk
`susceptibility genes (of the order of 5% of
`all cases). Both the overall evidence for
`genetic heterogeneity and inspection of
`haplotypes in individual families indicate
`
`that an additional gene (or genes) confer(cid:173)
`ring susceptibility to breast cancer re(cid:173)
`mains to be discovered.
`
`REFERENCES AND NOTES
`
`1. J. M. Hallet a/., Science 250, 1684 (1g9Q); S. A.
`Narod eta/., Lancet 338, 82 (1gg1).
`2. D. F. Easton, D. T. Bishop, D. Ford, G. P. Crockford,
`and the Breast Cancer Unkage Consortium, Am. J.
`Hum. Genet. 52, 678 (1gg3); M. R. Stratton eta/.,
`Nat. Genet. 7, 103 (1994).
`3. J. M. Birch eta/., Cancer Res. 54, 12g9 (1994); D.
`Malkin et a/., Science 250, 1233 (1ggo); S. Srivas(cid:173)
`tava, Z. Zou, K. Pirollo, W. Blattner, E. H. Chang,
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`8. Genotyping was performed independently at the In(cid:173)
`stitute of Cancer Research [R. Wooster eta/., Nat.
`Genet. 6, 152 (1gg4)] and the University of Utah [L. A.
`Cannon-Albright eta/., Science 258, 1148 (1gg4)].
`g, Lod scores were computed with the FASTUNK version
`of the UNKAGE program [G. M. Lathrop, J. M. Lalouel,
`C. Julier, J. Ott, Proc. Nat!. Acad. Sci. U.S.A. 81, 3443
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`for familial breast cancer derived from the segregation
`analysis of the Cancer and Steroid Hormone Study
`(CASH). Under this model, susceptibility to breast can(cid:173)
`cer is conferred by an autosomal dominant gene with
`population frequency 0.0033, and the risk of breast
`cancer by age 70 in carriers is 0.67 compared to 0.05 in
`noncarriers. Penetrances for ovarian cancer in carriers
`of the breast cancer susceptibility gene were derived
`from E. B. Claus, J. M. Schildkraut, W. D. Thompson,
`and N.J. Risch [Am. J. Hum. Genet. 53, A787 (1993)],
`which estimated a cumulative frequency of 1 0% by age
`60. The effects of age were incorporated into the anal-
`
`2090
`
`SCIENCE
`
`• VOL. 265
`
`• 30 SEPTEMBER 1994
`
`yses as in (2 ). Male breast cancer cases were assigned
`to the same liability classes as female breast cancer
`cases diagnosed below age 30. All cancers other than
`breast and ovarian cancer were ignored in this analysis.
`Allele frequencies were those reported in the Genome
`Data Base and were based on 56 CEPH (Centre
`d'Etude du Polymorphisme Humain) chromosomes.
`Evidence for heterogeneity was evaluated by the ad(cid:173)
`mixture model [J. Ott, Analysis of Human Genetic Unk(cid:173)
`age (Johns Hopkins Univ. Press, Baltimore, 1985), pp.
`200-203]. Lod scores for linkage to BRCA 1 were com(cid:173)
`puted as in (5).
`10. C. Lundberg, L. Skoog, W. K. Cavenee, M. Norden(cid:173)
`skjold, Proc. Nat/. Acad. Sci. U.S.A. 84, 2372 (1g87);
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`16. D. F. Easton, D. Ford, D. T. Bishop, and the Breast
`Cancer Linkage Consortium, unpublished data.
`17. All studies were carried out with the full informed
`consent of the families. We thank the Cancer Re(cid:173)
`search Campaign, the Medical Research Council,
`the Committee for Clinical Research of the Royal
`Marsden Hospital, the National Institutes of Health
`(grants CA-48711, HG-00571, CN-05222, and RR-
`00064), grant DAMB17-g4-J-4260 from the U.S.
`Army, Myriad Genetics, the European Community
`Concerted Action on Genetics and Epidemiology of
`Hereditary Breast Cancer Unkage (PL9208go), the
`Chetwood Aiken fund, and the Ugue Nationale cen(cid:173)
`tre le Cancer for their support. We also thank the
`families for their encouragement and cooperation,
`the many clinicians who have helped in the identifi(cid:173)
`cation of cases, in particular the late Dr. E. Gardner,
`all the members of the International Breast Cancer
`Linkage Consortium, F. Lennard, M. Ponder, and T.
`Harrington.
`
`25 July 1gg4; accepted 26 August 1gg4
`
`GeneDX 1022, pg. 3
`
`