After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer

Cui J, Antoniou AC, Dite GS, Southey MC, Venter DJ, Easton DF, Giles GG, McCredie MR, Hopper JL (2001) After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am J Hum Genet 68:420-431

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years,="" ascertained="" through="" population="" cancer="" registries="" in="" melbourne="" and="" sydney,="" australia.="" extensive="" testing="" for="" deleterious="" mutations="" in="" brca1="" and="" brca2,="" to="" date,="" has="" identified="" 34="" carriers.="" our="" analysis="" suggested="" that,="" after="" other="" possible="" unmeasured="" familial="" factors="" are="" adjusted="" for="" and="" the="" known="" brca1="" and="" brca2="" mutation="" carriers="" are="" excluded,="" there="" appears="" to="" be="" a="" residual="" dominantly="" inherited="" risk="" of="" female="" breast="" cancer="" in="" addition="" to="" that="" derived="" from="" mutations="" in="" brca1="" and="" brca2.="" this="" study="" also="" suggests="" that="" there="" is="" a="" substantial="" recessively="" inherited="" risk="" of="" early-onset="" breast="" cancer.="" according="" to="" the="" best-fitting="" model,="" after="" excluding="" known="" carriers="" of="" mutations="" in="" brca1="" and="" brca2,="" about="" 1/250="" (95%="" confidence="" interval="" [ci]="" 1/500="" to="" 1/125)="" women="" have="" a="" recessive="" risk="" of="" 86%="" (95%="" ci="" 69%-100%)="" by="" age="" 50="" years="" and="" of="" almost="" 100%="" by="" age="" 60="" years.="" possible="" reasons="" that="" our="" study="" has="" implicated="" a="" novel="" strong="" recessive="" effect="" include="" our="" inclusion="" of="" data="" on="" lineal="" aunts="" and="" grandmothers,="" study="" of="" families="" ascertained="" through="" women="" with="" early-onset="" breast="" cancer,="" allowance="" for="" multiple="" familial="" factors="" in="" the="" analysis,="" and="" removal="" of="" families="" for="" whom="" the="" cause="" (i.e.,="" brca1="" or="" brca2)="" is="" known.="" our="" findings="" may="" have="" implications="" for="" attempts="" to="" identify="" new="" breast="" cancer-susceptibility="">