Linkage Of Early-Onset Familial Breast Cancer To Chromosome 17q21
Linkage of Early-Onset Familial Breast Cancer to Chromosome 17q21Author(s): Jeff M. Hall, Ming K. Lee, Beth Newman, Jan E. Morrow, Lee A. Anderson, BingHuey, Mary-Claire KingReviewed work(s):Source: Science, New Series, Vol. 250, No. 4988 (Dec. 21, 1990), pp. 1684-1689Published by: American Association for the Advancement of ScienceStable URL: http://www.jstor.org/stable/2878541 .Accessed: 03/12/2011 17:28Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at ms.jspJSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range ofcontent in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new formsof scholarship. For more information about JSTOR, please contact support@jstor.org.American Association for the Advancement of Science is collaborating with JSTOR to digitize, preserve andextend access to Science.http://www.jstor.org
Research ArticlesinkageofEarly-Onset FamilialBreasttoChromosome 17q21CancerJEFF M. HALL, MING K. LEE, BETH NEWMAN, JAN E. MoRRow,LEE A. ANDERSON,BING HUEY, MARY-CLAIRE KINGunavoidable epidemiologic realities. The disease is common, butonly a small proportion of cases in the general population areattributable to inherited susceptibility. Thus, families may havemultiple cases of breast cancer without inherited susceptibility, and"sporadic"cases may occur even in families with inherited disease. Inaddition, the disease is not completely penetrant among susceptiblepersons, with expression depending on gender, age, and nongeneticrisk factors. Finally, both epidemiological and molecular evidencesuggests heterogeneity. We have tested simultaneously for geneticlinkage and heterogeneity of breast cancer in families, and ourresults suggest both the presence of a gene for early-onset breastcancer on chromosome 17q21 and linkage heterogeneity of thedisease.Families and inheritance of susceptibility. Our genetic analysisis based on 23 extended families with 146 cases of breast cancer(Figs. 1 and 2). All persons in our analysis are Caucasian and froma variety of original ancestries. The 329 participating relatives nowlive in, and were therefore sampled from, 40 states of the UnitedStates, Puerto Rico, Canada, the United Kingdom, and Colombia., H s 'UMAN DISEASE GENES CAN BE LOCATED BY LINKAGE These families share the epidemiological features that are characteristic of familial, versus sporadic, breast cancer (2): younger age atanalysis of families in which the incidence of the disease ishigh. Linkage analysis can reveal the chromosomal loca- diagnosis, frequent bilateral disease, and more frequent occurrencetion of the genes of interest by identifying polymorphic geneticof disease among men.markersof known location that are coinherited with the disease inOur statistical model for the inheritance of susceptibility to breastfamilies (1). Among the common cancers, breast cancer is particu- cancer was derived from our previous complex segregation analysislarly suited for this approach, because family history of the disease is of a population-based series of 1500 families with breast cancer (4).a significant risk factor in all populations; epidemiological evidence Inherited susceptibility to breast cancer in that series could be fullyconsistently indicates that a woman's risk of breast cancer is inexplained by a rare autosomal dominant allele with a major effect oncreasedby the occurrence of the disease in her mother or sisters. Therisk: risk of breast cancer in genetically susceptible women wasyounger the ages at diagnosis of her relatives,the greaterthe increase estimated to be 0.37 by age 40, 0.66 by age 55, and 0.82 over thein a woman's risk (2).entire lifetime. In contrast, risk of breast cancer in women withoutThe transformation of breast ductal epithelial cells to malignant genetic susceptibility was estimated to be 0.004 by age 40, 0.028 bygrowth results from alterations in their DNA that may be either age 55, and 0.081 over the entire lifetime. Females less than 15 yearsinherited or somatic (3). Mapping genes for familial breast cancer isof age and all males had a negligible risk (less than 0.001). Theimportant because alterations at the same loci may also be respon- estimated proportion of breast cancer cases in the sample that weresible for sporadic disease. Individuals with inherited susceptibility toattributableto inherited susceptibility was only 4 percent, the greatbreast cancer are completely asymptomatic for decades before themajority of cases resulting purely from somatic events. Amongonset of disease; the effects of critical inherited alterations are thus younger patients, however, the proportion of inherited cases is likelylatent for an extended period. Among women with no inherited to be considerably higher. Disease allele frequencies (q) betweensusceptibility to the disease, these same alterations may be the initial 0.004 and 0.02 yield virtually identical results; those for q equalslesions of breast tumorigenesis, with disease expression being simi0.01 are described.larly dependent on subsequent genetic alterationsor tumor-promotDefinition of the breast cancer phenotype. For any complexing steps.disease, it is essential to adequately define the phenotype, theMapping genes for human breast cancer has been complicated byinheritance of which will be traced in families. Real linkages can bemissed and spurious linkages suggested either by defining thephenotype too broadly (so that persons without inherited susceptibility to disease are mistakenly categorized as affected) or simply byThe authors are at the School of Public Health, University of California, Berkeley, CAmaking errors in diagnosis. To minimize errors in diagnosis, we94720.Human breast cancer is usually caused by genetic alterations of somatic cells of the breast, but occasionally,susceptibility to the disease is inherited. Mapping thegenes responsible for inherited breast cancer may alsoallow the identificationof earlylesions that are criticalforthe development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of agene for inherited susceptibilityto breast cancerin families with early-onsetdisease. Genetic analysisyields a lodscore (logarithm of the likelihood ratio for linkage) of5.98 tor linkage of breast cancersusceptibilityto Dl 7S74in early-onsetfamilies and negative lod scores in familieswith late-onset disease. Likelihood ratios in favor oflinkage heterogeneity among families ranged between2000:1 and greaterthan 106:1 on the basis of multipointanalysisof four loci in the region.1684SCIENCE, VOL. 250
reviewed existing pathology records of all family members on whomaccurately estimated. Therefore, we also tested for linkage bybreast surgery had been performed. For deceased persons reported including disease information only for the affected relatives (that is,by their relatives to have had breast cancer, but for whom no the breast cancer cases) in each family; all unaffected subjects werepathology records were available, we obtained hospital records or assigned to the lowest risk class, so that only their marker informadeath certificates.For living subjects who had not undergone breast tion was incorporated. Autosomal dominance was still assumed, andsurgery, we relied on self-report of no breast cancer; for deceased lifetime risk of sporadic disease was not altered.persons with no history of breast surgery, we relied on death3) In order to evaluate linkage without imposing any specificcertificates and reports of relatives. The affected phenotype was genetic model, we counted alleles shared by descent for affectedpairsdefined as all histologic types of invasive breast cancer. No other of female relatives. This analysis was possible because one markercancer sites were included (5).was highly polymorphic. Pairs of affected relativeswere sisters (firstStatistical methods. Four approaches to evaluating linkage were degree relatives), aunt-niece and grandmother-granddaughter(secapplied:ond-degree relatives), and first cousins. (third-degree relatives).1) Lod scores (logarithms of the likelihood ratios for linkage) for Relative pairs were stratified by the average age of breast cancerlinkage of individual markers to disease were estimated with the diagnosis for the pair.LIPED program; multipoint mapping was performed with the4) We applied the affected-pedigree-membermethod to evaluateLINKAGE program; homogeneity of recombination fractions was sharing of alleles by state among the breast cancer cases in eachevaluated with the B test for two-point linkage data and direct family (7). Only cases whose markergenotypes could be determinedcomparison of likelihoods for multipoint data (1, 6). Homogeneitywith certainty were included in the analysis of affected pedigreeof linkage was tested for all families; the sample was not a priori members.subdivided. Linkage analyseswere based on an autosomal dominantTyping of DNA polymorphisms. For each of the 329 informamodel with the age- and sex-specific risks described above for tive relatives, we obtained 35 milliliters of fresh blood and preparedhypothetically susceptible and nonsusceptible individuals. (LIPED immortalized lymphocytes by Epstein-Barrviral transformation (8).was modified to incorporate four liability classes for each genotype.)Genomic DNA was prepared as described (9). Probes were labeledThe risk group (liability class) for each woman was defined by her by random primer extension (10) and hybridized to DNA accordingage at diagnosis of breast cancer, at death if deceased without breast to standardprocedures (11). Parentage was confirmed by consistentcancer, or at most recent interview if living and unaffected. All men inheritance of 183 polymorphic markers. Markers at chromosomewere assigned to the lowest risk group.17q21 include D17S74, a VNTR (variable number of tandem2) In determining a plausible model for inheritance of suscepti- repeats) defined by the probe CMM86 and Hinfi; D17S40, definedbility to a complex disease, it is always possible that the underlying by the probe LEW 101 and Msp I; D17S41, defined by the probegenetic model may be correct, but that penetrance may not be LEW 102 and Pst I; and D17S78, defined by the probe p131 and2dx44171DD66 4dx45 dx36dx3lEHBC3EHED49DDFGOv16i dx39BDdx45BA65AEBDOv72BAEA6 Od4i e643HCdx294BHCEB28EB HAH EB EB HCdx2HCdx37EFEF40HFHF5 2dx4 x2d3AAAE39BABEDEdx23 dx4ldx3AAdx25EAdx3lAC546dx47BE672BC6 BD21 DECEMBER 19904dx43BEdx32breast cancer; open circles, fe-familiesand are letteredsequentialy within each family fromlargestto smallestfragmentsize.Alleles in parenthesesare basedon reconstructedgenotypes.dx4l516 6 6leles of D17S74 are shown for alldx4562 dx41Fig. 1. BreastcancerfamiliesI to7. Solid circles, females withmaleswithoutbreastcancer;opensquares, males without breastaivencancerThe age givenfor eachcancer.womanis age at (first)breastcancer diagnosis(dx) if affected,ageat deathif deceased(deceasedindividualsarerepresentedby diagonal lines through symbols),orage at most recent interviewifalive without breast cancer. Al-BCCBDD464632(B-)DEdx45CB4dx30BD)436BD CDdx3676dx dx33BC44EBRESEARCH ARTICLES1685
Msp I (12). On the basis of analysisof the CEPH families, the orderand approximate recombination distances of the markers are:17cen-D17S78-(0. 10)-D17S41-(0.06)-D17S74-(0.12)-D17S4017qter (13).D17S74, a highly polymorphic VNTR with heterozygosity greater than 0.90, is extremely useful for linkage analysis but presentstechnical challenges that are common to VNTRs. Linkage analysisiscritically sensitive both to errors in assigning genotypes and tomarker allele frequencies. The lengths of the Hinf[ restrictionfragments that define D17S74 alleles are continuously distributedbetween 1 and 5 kilobase pairs (kb). For our analyses, D17S74alleles were identified by analyzing DNA samples from all membersof a family on the same Southern blot, placing relatives withfragments of similar size adjacentto one another (14). "Population"1098dii 4*6617561ATADdx53dx56BB6dx 32DBDdx62dx28dx5OAB(D-)(AE)dx4CHDB82 dx497271IDEEEEA94dx65DF(DE)DE46nbdx66dx6 I dx56DACGdx57(D-)ADBE70 )dx45dx49dx65BDEFGG' dx33CdxE9GGGGACACACD[D EADdx x 48(BD)dx 71CBdx49(D-)CD CEFDFD1575ADdx6lCB6CD62BCdx4Odx32FEDE4-W;66BDA[ dx58DCi dx65HJ69EJ79dx0dx302727221DHDGCH71(CD)1 dx6677GKdx 44dx35t}3dx47E*1AB51dx44? XBEGdx 8FKdx 61FKGKIEJK'* dx 1S eiAO [-odx0dx87Zodx 709179BBdx47dx45B)AAdx 7571dx49 66CF 70dx5668B dx55B FSDd501x5dx52AC14A38dx47EIHEgBBAOdx58AFEFBE 9(AC)BEEG2170AA85[Eldx64dx6620E)HETH 35DD1772dx65(DF)dx 42CDdx62CBdx6682DB(AC)GH16dx7744ACdx Ddx62dx57EEBCFig. 2. Breastcancerfamilies8 to 23. Notation as for Fig. 1, with solid Genotypes for D17S74 are shown for all families. D17S78 genotypes forsquaresin families 16 and 19 representingmales with breast cancer. family 8 and D17S40 genotypes for family 19 are also shown.1686SCIENCE, VOL. 250
frequencies of the D17S74 alleles in this sample were estimated byselecting subjects from different families whose D17S74 fragmentsappearedto be of similar size on the basis of their "familyblots," andthen analyzing the DNA from these unrelated persons in neighboring lanes on the same blots. Some samples were included severaltimes in order to identify distortions in the gels. These "populationblots" were analyzed without reference to sample numbers, in orderto determine which alleles could be consistently distinguished.D17S74 had more than 30 distinguishable fragment lengths-andhence more than 30 different alleles-in our sample, nine of whichoccurred more than once among unrelated individuals, at frequencies ranging from 0.07 to 0.13. The other D17S74 alleles were onlyrepresented once in our sample, but because extremely rare markerallele frequencies can have a major influence on estimates of lodscores and the T statistic (7), apparently unique alleles were eachassigned the frequency 0.03.Results of linkage and heterogeneity analysis in the breastcancer families. For the 23 families as a group, homogeneity oflinkage of breast cancer to D17S74 could be rejected at P equals0.01. Multipoint analysisof linkage in the intervalD17S78-D17S41D17S74-D17S40 yielded likelihood ratios in favor of heterogeneityof linkage among the 23 families between 2000:1 and 1.4 x 106 to1. After adjusting for heterogeneity among all families, the maximum two-point lod score is 3.28 at recombination distance of0.014 from D17S74, with disease linked to this locus in 40 percentof the families (Figs. 1 and 2).Heterogeneity of linkage in these families appears explicable byage of disease onset. Breast cancer is linked to markers in thischromosomal region specifically in families with early-onset breastcancer. Among the seven families with a mean age of breast cancerdiagnosis less than or equal to 45, the two-point lod score forlinkage of D17S74 and breast cancer is 5.98 at a distance of 0.001recombination units, with a 95 percent confidence interval of 0.001to 0.09 (Table 1). In contrast, total lod scores for the families withlate-onset disease are negative. It is characteristicof linkage in thepresence of heterogeneity that a modest lod score (in this case 2.35) for all families, ignoring heterogeneity, at a fairly largerecombination distance (0.20 recombination units) masks twocurves, one with a more positive lod score in the linked families( 5.98) at a smaller recombination fraction (0.001 to 0.09) and theother negative (15).Two-point lod scores for all four markers in this chromosomalregion suggest that a gene for susceptibility in the early-onsetfamilies is likely to be within approximately 10 percent recombination of D1 7S74 (Table 2). Multipoint analysis of the fourmarker interval yields a maximum lod score of 5.41 near D17S74for the earliest-onset families (Table 2). Again, total lod scores forfamilies with older ages at diagnosis are negative throughout theinterval.Linkage of breast cancer to D17S74 was also evaluated on thebasis of only the individuals with breast cancer in each family. Forthis analysis, all women without breast cancer and all men wereassigned to the lowest risk group. For the 23 families as a group, theP value for homogeneity of linkage is 0.06. For the families withaverage age at diagnosis less than or equal to 45, the maximum lodscore is 4.69 at close linkage, with a 95 percent confidence intervalfor the recombination fraction of 0.001 to 0.10. Lod scores at closelinkage to D17S74 are -2.19 for families 8 to 15 and -5.22 forfamilies 16 to 23.Analysis of alleles shared by descent among related pairs ofwomen with breast cancer also suggested linkage of early-onsetbreast cancerto D1 7S74 (Table 3). In families 1 to 7, all three classesof relatives shared more alleles by descent than expected by chance.Even in families 8 to 23, there was evidence for increased identity by21 DECEMBER 1990Table 1. Lod scoresfor linkageof breastcancerto D17S74, chromosome17q21. For eachfamily,M is the meanage of diagnosisof breastcancer.0.0010.100.200.300.40IZ at.00.001 2.36 0.50 0.40 1.14-0.50 1.38 0.70 0.75-2.56-1.71 0.65-0.85-0.07 1.89 0.35 0.29 0.91-0.25 1.06 0.58 0.02 0.03-0.06-0.41-0.03-0.09-0.18-0.08-0.56 0.04-0.38-0.93-1.01 0.50-0.13-0.02 1.38 0.21 0.19 0.64-0.08 0.73 0.40 0.02 0.06-0.08-0.13-0.02-0.02 0.01-0.02-0.20 0.07-0.18-0.45-0.56 0.34 0.04 0.00 0.82 0.09 0.09 0.35 0.00 0.41 0.21 0.01 0.04-0.08-0.03-0.01-0.03 0.06-0.01-0.07 0.05-0.07-0.20-0.28 0.18 0.05 0.00 0.28 0.02 0.03 0.11 0.03 0.14 0.05 0.00 0.01-0.05-0.00-0.00-0.04 0.04-0.00-0.02 0.01-0.02-0.05-0.11 0.05 0.02 0.00 2.36 2.86 3.26 4.40 3.90 5.28 5.98 5.98 5.67 5.63 4.12 4.06 3.65 3.00 3descent among sisters with early-onset disease, but little or noevidence for increased identity by descent for second- and thirddegree relatives. Finally, the affected-pedigree-member analysis ofalleles shared by state among all individuals with breast cancer ineach family also suggested linkage of early-onset breast cancer tomarkersin this chromosomal region (16).These analyses defined families with early-onset disease as thosewith an average age at breast cancer diagnosis of less than or equalto 45. However, "early-onset"could be defined in a variety of ways.The cumulative lod scores for linkage of breast cancer to D1 7S74, asfamilies with increasing age at disease onset are included in theanalysis, are indicated in Fig. 3 and the right-hand column of Table1. Cumulative lod scores are above 5.0 for families with an averageage at diagnosis of less than 48, remain positive for families with anaverage age at diagnosis of less than 52, and then drop sharply. Asspecific alternative ways of defining early-onset breast cancer, wedefined families with early-onset disease to be those in which (i)most breast cancers in each family were diagnosed by age 50(families 1 to 7, 9, 10, 12, 13, 21), or (ii) most breast cancersin eachfamily were diagnosed by age 45 (families 1 to 6, 10), or (iii) theaverageage at breast cancer diagnosis was less than 48, the mean forall the cases in the sample (families 1 to 10). The critical results forall definitions were the same: maximum lod scores for linkage ofbreast cancer to this chromosomal region are between 5.2 and 5.7 inthe early-onset families and negative in the late-onset families, andthe disease gene appears to be within about 0.10 recombinatioiunits of D17S74.Other risk factors for breast cancer in the families. To determine whether the linked gene is expressed in the presence of anyspecific background of nongenetic risk factors for breast cancer, wecompared breast cancer risk factors for women in families withapparentlinkage of breast cancer to chromosome 17q versus womenin families with evidence against this linkage. Ages at first pregnancy, number of children, prevalence of fertility problems, exposure tox-rays, use of oral contraceptives, and ages at menopause werefamilies, aftersimilarly distributed in "linked" and "unmlinked"'adjusting for age and birth cohort of the women. Similarly, prevaRESEARCH ARTICLES1687
Fig. 3. Linkageof D17S74to breastcancerin families,based on the autosomaldominantmodeldescribedin the test. Cumulativelodscores(Y2Z)areshownforall familiesfor which themeanage of breastcancerdiagnosis(AM)is less thanor equalto the age representedon the x-axis.Totallod scoresaregreaterthanor equalto 5.0 for familieswith M 48 and greaterthan or equal to 3.0 forfamilieswithM 50. Eachdot abovethe x-axisrepresentsa familywiththatparticularmeanonset age.6Table 3. Identity by descent of two, one, or zero alleles of D17S74among pairs of relatedindividualswith breastcancer.Mean onset is theaverageage of breastcancerdiagnosisfor the relatedpair.Familynumbersrefer to Figs. 1 and 2. Second-degree(20) relativesare aunt-nieceorgrandmother-granddaughterpairs; third-degree(30) relatives are first4cousins.Mean onset ies 1 to 72017062002010'4546-5555Families 8 to 23202087522324?56367310N. X.304050-60-2Ageof onset(years)lences of specific cancers at other sites did not differ among womenin "linked" and "unlinked" families, although male breast cancersoccurred only in "unlinked"families. The only observed differencebetween women in "linked" versus "unlinked" families was age atbreast cancer diagnosis.Linkage analysis in families and loss of heterozygosity intumors. Comparisons of breast tumor tissue with normal tissuefrom the same individual have suggested that chromosomes lp, 3p,lip, 13q, 16q, or 17p (or some combination) may harbor genesthat are important for breast tumor progression (17). An earlierlinkage analysisfrom our group, based on fewer and less-informativefamilies, suggested (with a modest lod score) that a gene for familialpremenopausal breast cancer or ovarian cancer is present on chromosome 16q (18). We have excluded the other regions suggested byloss of heterozygosity in tumors as locales of genes for inheritedsusceptibility to breast cancer (9, 19).A gene or genes on chromosome 5q appear to be responsible forinherited forms of colon cancer and quite possibly for the initialsomatic lesions of other colon cancers, with genes on 12p (K-ras),17p (p53), 18q (DCC), and possibly elsewhere being responsiblefor subsequent invasion and metastasis (20). This pattern of multiplesequential events, determined by alterations on more than onechromosome, may also apply to breast cancer.Negative lod scores in the families with late-onset breast cancersmay reflect any or all of the following: the existence of a differentlocus or loci responsible for inherited susceptibility in these families;the chance occurrence of some families with multiple cases; or aAll families019092027higher prevalence of sporadic cases in families with late-onsetinherited disease. Loci responsible for disease in families withlate-onset disease may be identifiable by continued simultaneousanalysis of linkage and heterogeneity.Candidate genes on chromosome 17q. The ultimate goal ofgene mapping of human traits is to move from a known chromosomal location to identification of the crucial gene and characterization of its critical alterations. This region of chromosome 17qincludes several plausible candidate genes (21). A gene for atruncated form of the human epidermal growth factor receptor[her2;MIM 164870 (Mendelian Inheritance in Man)] is identical toerbb2or neu (MIM 190150). The gene her2 acts as an oncogene inNIH 3T3 cells and is amplified in many primary breast tumors; her2amplification is associated with poor prognosis at least for nodepositive tumors (22). Other candidate genes in this region includethat for estradiol-17P dehydrogenase (edhbl7; MIM 264300),which is the enzyme that catalyzes the conversion of estrone toestradiol; the homeobox 2 gene (hox2; MIM 142960), which iscriticalfor murine embryological development; nm23,whose expression is associated with lymph node metastasis in primary breastcarcinomas; the gene for retinoic acid receptor ax (rara; MIM180240), a protein that binds the possible anticarcinogen retinoicacid; and wnt3 (MIM 165330), one of the integration sites activatedby the mouse mammary tumor virus and which is homologous toTable 2. Linkage analysis of breast cancer to four markerson chromosome 17q by mean age (M) of breast cancer diagnosis.Families 1 to 7 (M ' 45)Two-point lod scores at five recombination fractionsFamles 8 to 15 (46 ' M ' 51)Families 16 to 23 (M ' 4-1.54 5.98-0.65-1.12 4.83-0.16-0.71 3.47-0.04-0.36 1.97 0.00-0.14 0.65 0.36 0.10-3.33 0.95 0.51-0.80 0.81 0.43-0.18 0.48 0.26-0.05 0.14 0.94-0.12-0.35-0.34-0.04-0.16-0.12 1.36 1.01 0.63 0.30 0.07-0.49-0.12 0.01 0.06 od scores based on multipoint analysis of the interval (on recombination 800.0400.2320.256S400.2801 to 78 to 1516 to 23 2.83-0.30-6.70 3.09-0.07-5.80 3.30 0.01-5.51 4.96-3.36-5.58 4.48-2.78-5.031688 3.47 0.03-5.52 3.57-0.05-5.89 3.41-0.20-6.98 4.46-1.58-6.60 4.60-2.71-7.94 5.24-9.14-15.21 5.41-5.61-8.94 5.24-4.24-6.79SCIENCE, VOL. 250
the Drosophilawinglessness locus (23). If alterations in any of thesegenes are responsible for inherited breast cancer, polymorphisms atthe criticallocus may be in linkage disequilibriumwith the disease inthe early-onset families.REFERENCES AND NOTES1. J. Ott, Analysis of Human GeneticLinkage (Johns Hopkins Univ. Press, Baltimore,1985).2. R. Ottman, M. C. Pike, M.-C. King, J. T. Casagrande, B. E. Henderson, Am. J.Epidemiol. 123, 15 (1986); N. L. Petrakis, V. L. Ernster, M.-C. King, in CancerEpidemiology and Prevention, D. Schottenfeld and J. F. Fraumeni, Jr., Eds.(Saunders, Philadelphia, 1982), pp. 855-870; A. G. Schwartz, M.-C. King, S. H.Belle, W. A. Satariano, G. M. Swanson, J. Natl. CancerInst. 75, 665 (1985).3. A. G. Knudsen, CancerRes. 45, 1437 (1985).4. B. Newman, M. A. Austin, M. Lee, M.-C. King, Proc. Natl. Acad. Sci. U.S.A. 85,3044 (1988).5. Four women with endometrial cancer (from families 1, 4, and 9) and two womenwith thyroid cancer (from families 5 and 13) were omitted entirely from theanalysis. In family 3, two women have breast and ovarian cancer and are defined asaffected at the ages of their breast cancer diagnoses; two other women died withovarian cancer only and could not be included.6. J. Ott, Ann. Hum. Genet. 47, 311 (1983); G. M. Lathrop, J. M. Lalouel, C. Julier,J. Ott, Am. J. Hum. Genet. 37, 482 (1985); N. Risch, ibid. 42, 353 (1988).7. D. E. Weeks and K. Lange, Am. J. Hum. Genet. 42, 315 (1988).8. L. Louie and M.-C. King, ibid. 41, A174 (abstr.) (1987).9. J. M. Hall et al., ibid. 44, 577 (1989).10. A. P. Feinberg and B. Vogelstein, Anal. Biochem. 132, 6 (1983); ibid. 137, 266(1984).11. T. Maniatis, F. F. Fritsch, J. Sambrook, MolecularCloning: A LaboratoryManual(Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1982).12. Y. Nakamura et al., Genomics2, 302 (1988); J. Luty et al., Nucleic Acids Res. 16,6250 (1988).13. Centre d'Etude du Polymorphisme Humain, CEPH Version3 Database:Lod Scoresand RecombinationEstimates(CEPH, Paris, 1989).14. An example of the difficulties in typing VNTR alleles is presented by family 18, inwhich allele K is alleged to appear in cousins without pedigree evidence for identityby descent in intervening relatives. This assignment, and others like it, were madeafter analyzing several samples from the relatives on the same Southern blot,genotyping them without reference to their sample numbers or positions in thepedigree, and determining that the bands were indistinguishable among the foursamples.15. L. L. Cavalli-Sforza and M.-C. King, Am. J. Hum. Genet. 38, 599 (1985).16. For the 23 families as a whole, the method of affected pedigree members yields aT value of 1.13 (P 0.13) for the T statistic unadjusted for allele frequencies, Tequals 4.26 (P 0.001) for the inverse square root weighting function, and Tequals 5.49 (P 0.001) for the reciprocal weighting function. The T statisticamong the younger families was consistently significant, with T values of 2.60,5.18, and 5.78, and empirical P values of 0.012, 0.001, and 0.003 for the threeweighting functions, respectively.17. P. Devilee et al., Genomics 5, 554 (1989); M. Genuardi, H. Tsihira, D. E.Anderson, G. F. Saunders, Am. J. Hum. Genet. 45, 73 (1989); I. U. Ali, R.Lidereau, C. Theillet, R. Callahan, Science 238, 185 (1987); C. Lundberg, L.Skoog, W. K. Cavenee, Proc. Natl. Acad. Sci. U.S.A. 84, 2372 (1987); C. Coleset al., Lancet336, 761 (1990); T. Sato et al., Am. J. Hum. Genet. 47, A16 (abstr.)(1990).18. M.-C. King, R. C. P. Go, R. C. Elston, H. T. Lynch, N. L. Petrakis, Science208,406 (1980); M.-C. King et al., J. Natl. Cancer.Inst. 71, 463 (1
the development of breast cancer in the general popula- tion. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in fami- lies with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 tor linkage of breast cancer susceptibility to Dl 7S74
2-5 UltraLift Concept 16 3-1 Watt’s Straight Line Mechanism 19 3-2 Fully Prismatic Linkage 19 3-3 One Replace Prismatic 20 3-4 Two Replaced Prismatics 21 3-5 Fully Revolute Linkage 22 3-6 Scissors Linkage 23 3-7 Parallel Linkage 24 3-8 Parallel Linkage with a Cam 24 3-9 Constant orientation linear linkage 25 3-10 Hydraulic Mechanism 25
Onset and Rime Onset—part of the syllable prior to the vowel Rime—the vowel to the end of the syllable Examples That Onset-th Rime-at Horse Onset-h Rime-orse Match the Onset to the Rime b _ d _ tr _ s _ unk ug uck un Notes about Onset/Rime The pre
Younger-onset (or early-onset) Alzheimer's disease affects people who are under age 65. Many people with younger-onset are in their 40s and 50s. They have families, careers, or are even caregivers themselves when Alzheimer's disease strikes. Up to 5 percent of people with Alzheimer's have younger-onset. In the United States,
Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia Anne C. Goldberg, MD, FNLA, Chair*,PaulN.Hopkins,MD,MSPH,
CGIF, CLIF, or other languages, such as SQL: Define "familial relation r" as (and (Familial r) (Relation r)). Define "relation r between x and y" as (and (Relation r) (r x y)). With these definitions, the following CLCE sentence can be translated to the CLIF and CGIF sentences in the previous slide: There is a familial relation between Bob and Sue.
4-bar linkage knee mechanism has a collection of instan-taneous centers of rotation. Many physicians prescribing AK- and TK-prostheses are not familiar with the trajectory of the instantaneous center of rotation of 4-bar linkage knee mechanisms applied. A 4-bar linkage knee mechanism is intrinsically extension-stable, meaning without extension
Christen, Peter. 2012. Data matching: concepts and techniques for record linkage, entity resolution, and duplicate detection. Springer Science & Business Media. Fellegi, Ivan P and Alan B Sunter. 1969. “A theory for record linkage.” Journal of the American Statistical Association 64(328):1183–1210. Dunn, Halbert L. 1946. “Record linkage.”
America’s criminal justice system. Racial and ethnic disparity foster public mistrust of the criminal jus-tice system and this impedes our ability to promote public safety. Many people working within the criminal justice system are acutely aware of the problem of racial disparity and would like to counteract it. The pur-pose of this manual is to present information on the causes of disparity .
