BRCA1 disease-associated haplotypes in Singapore Malay women with early-onset breast/ovarian cancer

Abstract

Keywords BRCA1 Haplotype Early-onset Breast OvarianTo the EditorFounder mutations are recurrent mutations with sharedcommon haplotypes arising either from a population that isestablished by a small group of individuals or from a sit-uation where the population size has decreased drastically[1]. Common shared haplotypes have been determined byanalyzing microsatellite markers in various populationgenetics studies [2].BRCA1 c.66–67delAG mutation is the most frequentlyreported mutation in about 1% of the Ashkenazi Jews andreconstruction of haplotypes in carriers has demonstratedstrong evidence for founder effects [3–6]. Identification offounder mutations has important clinical applications as itallows for a more accurate assessment on prevalence andpenetrance of BRCA1 mutations in the clinical settings [1].The Singapore Malays are a race of people of Malay orIndonesian origins and constitute 14% of Singapore’s 2.7million population [7]. Singapore Malays share genetic,cultural and historical links with Malays in PeninsularMalaysia, the coast of Borneo, on the east coast ofSumatra and the smaller islands that lie between theseareas and extends to the Southern Philippines with anestimated population of 18 million or more [8]. Virtuallyall Singapore Malays are Muslim, and their religionreflects the socio-cultural practices of this group [9]. TheBRCA1 deleterious mutation, c.2845insA, was firstreported in 2/7 unrelated Singapore Malay patients indi-cating the possible presence of a founder mutation [10].Two follow-on studies on the Singapore Malays havesince led to the identification of a common sharedhaplotype at BRCA1 intragenic markers in all BRCA1c.2845insA carriers, strongly suggesting a commonancestral origin for this mutation [11–12]. In these stud-ies, we identified the BRCA1c.2845insA mutation in 6/62(9.7%) unrelated early-onset breast/ovarian cases and 1fallopian tube cancer patient. Haplotype analysis per-formed at 3 BRCA1 intragenic polymorphic markers(D17S855, D17S1322 and D17S1323) indicated a sharedhaplotype, 142-127-159, in all BRCA1 c.2845insA muta-tion carriers [11, 13].In this study, 78 early-onset breast and ovarian cancerpatients, diagnosed before the ages of 45 and 50 yearsrespectively were recruited from the National UniversityHospital, Singapore, together with 164 unrelated age-matched normal healthy controls. This study had theinstitutional ethical committee approval and signed writ-ten informed consent was obtained from each participantbefore peripheral blood collection. All cancerous speci-mens were screened for the presence of the founder