REVIEW ARTICLE

Hereditary Breast and Ovarian Cancer in Asia:Genetic Epidemiology of BRCA1 and BRCA2

Alexander Liede1,2 and Steven A. Narod1n

1Centre for Research in Women’s Health, University of Toronto, Toronto, Ontario, Canada; 2Women’s Cancer Research Institute,Cedars-Sinai Medical Center, Los Angeles, California

Communicated by Ellen Solomon

Ethnic differences in cancer incidence and mortality result from differences in genetic and epidemiologicrisk factors. Mutations in BRCA1 and BRCA2 account for a small proportion of all breast cancer cases, butfor a much higher proportion of cases with a strong family history of breast or ovarian cancer. Germlinemutations in BRCA1 and BRCA2 have been identified in individuals of many races and ethnic groups andthe frequency of mutations varies between these groups. Some of the differences in cancer risk betweenpopulations may be the result of founder mutations in these genes. The cost and time required for mutationanalysis are reduced considerably when founder mutations are identified for a specific ethnic group. TheBRCA2 999del5 mutation in Iceland and three BRCA mutations in Ashkenazi Jews are well characterized.However, considerably less is known about the contribution of mutations in the BRCA1 and BRCA2 genesoutside of European groups. Studies conducted on the Asian populations described here have expanded ourcurrent knowledge of genetic susceptibility and its contribution to breast and ovarian cancer rates in Asianpopulations. Hum Mutat 20:413–424, 2002. r 2002 Wiley-Liss, Inc.

KEY WORDS: Asia; breast cancer; ovarian cancer; BRCA1; BRCA2; founder effect; founder mutations; China;Japan; Philippines; Singapore; India; Pakistan; Iran

DATABASES:

BRCA1 – OMIM: 113705; GDB: 126611; GenBank: U14680BRCA2 – OMIM: 600185; GDB: 387848; GenBank: U43746www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/ (Breast Cancer Information Core Database)www.prb.org (Population Reference Bureau web-site, United Nations)

INTRODUCTION

Incidence rates of breast cancer vary as much astenfold between countries and are particularly low inEast and Southeast Asia [Parkin et al., 1997]. Thebreast cancer incidence rate in Japan is approximately20% of that of the United States (Fig. 1). Thesedifferences between Eastern and Western countriesare diminishing with time, as incidence rates of breastcancer in Asia are rising. Differences in breast andovarian cancer incidence rates may be due to severalreasons, including the distribution of hormonal,reproductive, lifestyle, and genetic factors. Anyinvestigation into the etiology of cancers of the breastor ovary should take genetic predisposition intoconsideration. The most significant risk factor forbreast or ovarian cancer is the presence of aninherited mutation in one of the two cancersusceptibility genes, BRCA1 (MIM# 113705) orBRCA2 (MIM# 600185). A germline mutation ineither of these genes confers a high lifetime risk ofdeveloping breast cancer (40–87% to age 70) or

ovarian cancer (16–60% to age 70) [Ford et al., 1994;Hopper et al., 1999; Struewing et al., 1997].

There are inherent limitations in the comparisonsof rates generated by the cancer registries of differentcountries, particularly with respect to methods,quality, and reporting of cancer incidence data.Nevertheless, the reported trends from multiplecancer registries suggest that breast cancer in EastAsia is characterized by its low incidence rate and itsearly age-of-onset. In North America, age-specificbreast cancer rates double approximately every 10years until menopause, after which the rate increases

Received 27 December 2001; accepted revised manuscript9 September 2002.

nCorrespondence to: Steven A. Narod, Centre for Research inWomen’s Health, University of Toronto, 790 Bay Street, Suite750A,Toronto, On M5G1N8,Canada.E-mail: steven.narod@swchsc.on.ca

DOI10.1002/humu.10154Published online in Wiley InterScience (www.interscience.wiley.com).

rr2002 WILEY-LISS, INC.

HUMAN MUTATION 20:413^424 (2002)

slowly. This sharp premenopausal rise is also seen inAsia, but the breast cancer risk plateaus after age 50(Fig. 1). This difference in the slope of age-specificincidence curves in Eastern and Western populationssuggests that postmenopausal breast cancer is rela-tively less common among Asian populations. Conse-quently, the mean age of breast cancer in the Far Eastis generally younger than the mean age of breastcancer in North America and Europe. Most popula-tions in the Far East are relatively young, with only10% of the female population over age 50 years(versus 27% in North America) [Parkin et al., 1997].Because of the strong association between age-of-onset and genetic susceptibility, a high proportion ofbreast cancer cases in the East may be attributable toBRCA1 and BRCA2.

Asians comprise 57% of the world’s population. Incontrast, Europeans make up only 21%. Our knowl-edge of the genetics of breast and ovarian cancer islargely based on studies from Caucasian populations inNorth America, Europe, Israel, and Australia. Ap-proximately 2% to 4% of breast cancer cases and 10%of ovarian cancer cases (non-Jewish) are attributableto mutations in the predisposing cancer genes,

BRCA1 and BRCA2 [Claus et al., 1996; Newmanet al., 1998; Risch et al., 2001]. For Asian populations,most of the data available on BRCA1 and BRCA2mutations are derived from family-based studies andcase reports. Studies of consecutive breast or ovariancancer patients, unselected for age or family history,however, provide more useful information regardingthe contribution of germline BRCA mutations tocancer occurrence in a population.

Although nongenetic factors may explain a sig-nificant proportion of the international variation inthe rates of breast and ovarian cancer, this reviewfocuses on genetic predisposition in general andmutations in BRCA1 and BRCA2 in particular asthey contribute to these cancers in Asian women. Todate, eight studies have estimated the prevalence ofBRCA1 mutations in Asian patients with breastcancer unselected for family history; four of theseexamined women with early-onset breast cancer. Onlythree studies have examined the BRCA2 gene (Table1). Mutation analysis of BRCA1 and BRCA2 islaborious because of the large size of the genes and thediversity of mutations. Consequently, studies haveoften employed limited assays to screen for mutations

Age

0.1

1

10

100

1000

0- 5- 10- 15- 20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85+

Singapore: Chinese

US, SEER:White

China, Qidong

Japan, Osaka

Canada,OntarioUS, San Francisco:

Philippines, Manila

Wor

ld S

tand

ardi

zed

Rat

e Pe

r 10

0,00

0 (L

ogar

ithm

ic s

cale

)

Filipino

FIGURE 1. Selected breast cancer incidence rates worldwide. Age-speci¢c world standardized incidence rates of breast cancer(logarithmic scale).The graphswere generated fromdata derived fromParkin et al. [1997].

414 LIEDE ANDNAROD

or have focused on small samples of early-onset breastcancer patients. The studies summarized in Tables 1and 2 include only those on relatively large popula-tions of breast or ovarian cancer patients, wheremutation analysis covered at least 60% of mutations ineither BRCA1 or BRCA2, or where population-specific founder mutations were sought. The specificmethods used for mutation detection by each studygroup are not discussed in detail.

Founder BRCA1 and BRCA2 mutations exist inethnically restricted populations due to commonancestry. Founder effects have been described forseveral European populations, including the BRCA2999del5 mutation common to the Icelandic popula-tion [Johannesdottir et al., 1996; Thorlacius et al.,1997]. Recently, a BRCA1 mutation (3452delA) wasreported in two women diagnosed with ovarian cancerfrom Mongolia, a geographically isolated population[Elit et al., 2001]. To date, Japan has the largestnumber of recurrent mutations of any Asian popula-tion. Recurrent mutations specific to Asian popula-tions are presented in Table 3, including candidate

founder mutations. Here we summarized the literaturecomprising the breast and ovarian cancer geneticsstudies conducted in Asian countries (from PubMed,2002, www.ncbi.nlm.nih.gov/entrez/query/).

JAPAN ANDKOREA

Japan has relatively low rates of breast and ovariancancer. The Hiroshima cancer registry reports thehighest breast cancer rates in Japan but these are lessthan one-third of the rates among women in theUnited States [Parkin et al., 1997]. Two studies onbreast cancer patients in Japan have estimated theprevalence of mutations in the BRCA1 gene. Throughthe analysis of exon 11 of BRCA1 on 1,000 breasttumor specimens from patients of all ages, Emi et al.[1998] estimated the prevalence of mutations to be0.8%. Katagiri et al. [1996] used a more comprehen-sive mutation detection method and estimated aprevalence of 3.9% for BRCA1 mutations among 103Japanese breast cancer patients diagnosed below age35. The latter estimate is consistent with BRCA1

TABLE 1. Studies ofBRCAMutations AmongCases of Female Breast Cancer (Non-Jewish) Unselected for FamilyHistory (N440)

Estimated prevalence

Reference CentreNo. of

patientsAges

studiedBRCA1(%)

BRCA2(%)

Total(%)

EuropeJohannesdottir et al. [1996] Iceland 459 All ages ^ 8.5 ^Thorlacius et al. [1997] Iceland 632 All ages ^ 7.7 ^Garcia-Patino et al. [1998] Madrid, Spain 109 All ages 5.7 ^ ^Peto et al. [1999] Surrey,UK 254 o36 3.5 2.4 5.9Peto et al. [1999] Surrey,UK 363 36^45 1.9 2.2 4.1Ellis et al. [2000] London,UK 110 22^35 3.6 ^ ^AnglianBreast Cancer StudyGroup [2000] Cambridge,UK 1,435 o55 0.7 1.3 2.0VanDer Looij et al. [2000] Hungary 500 All ages 3.4 0.2 3.6Yazici et al. [2000] Turkey 52 o50 3.8 1.9 5.8Papelard et al. [2000] Netherlands 642 27^91 1.6 ^ ^Syrjakoski et al. [2000] Finland 1,035 All ages 0.4 1.5 1.8Loman et al. [2001] Sweden 234 o41 6.8 2.1 9.0

NorthAmericaNewmanet al. [1998] NorthCarolina,USA 211 20^74 2.6 ^ ^Langston et al. [1996] Washington,USA 80 o35 7.5 ^ ^Malone et al. [1998] Washington,USA 193 o35 6.2 ^ ^Malone et al. [2000] Washington,USA 203 o35 5.9 3.4 9.4Tonin et al. [2001] Montreal, Canada 61 o40 6.6 6.6 13.1Chappuis et al. [2001] Montreal, Canada 127 All ages 0.0 3.1 3.1

AustraliaHopper et al. [1999] Melbourne 388 o40 2.3 2.3 4.6Southey et al. [1999] Melbourne 91 o40 3.8 ^ ^

AsiaTanget al. [1999] HongKong,China 130 All ages 3.8 ^ ^Emi et al. [1998] Tokyo, Japan 1,000 All ages 0.8 ^ ^Katagiri et al. [1996] Tokyo, Japan 103 o35 3.9 ^ ^Ho et al. [2000] Singapore 43 o36 7.0 ^ ^Sng et al. [2000] Singapore 70 o40 8.6 ^ ^De LeonMatsuda et al. [2002] Philippines 294 25^64 1.0 4.1 5.1Yassaee et al. [2002] Iran 83 o45 3.6 2.4 6.0Liede et al. [2002] Pakistan 341 All ages 4.4 2.3 6.7

BRCA1ANDBRCA2 IN ASIA 415

prevalence observed in comparable studies of early-onset breast cancer patients in other populations andconfirms age-of-onset effect in Asia.

In Japan, two founder BRCA2 mutations (S2834Xand 5802del4) are responsible for multiple breastcancer families. These two mutations accounted forover one-third of all mutations detected (11 of 29) inthe study by Ikeda et al. [2001]. Of the 101 site-specific breast cancer families (two or three cases ofbreast cancer and no ovarian cancer) studied, 21(20.7%) were attributable to a mutation in BRCA2,and eight families (7.9%) were attributable to BRCA1mutations. None of the Japanese BRCA2 familiesincluded cases of ovarian cancer and 76% had onlytwo cases of breast cancer. The data presented byIkeda et al. [2001] suggest that BRCA2 mutations areimportant in Japan and that the clinical expression ofBRCA2 mutations may differ between Asian andCaucasian carriers. Another BRCA2 mutation(6633del5) was detected in two families, one patientfrom Japan and a Japanese ovarian cancer patient inCanada [Noguchi et al., 1999; Risch et al., 2001].

Four BRCA1 mutations (L63X, 2509delAA,Q934X, and E1214X) have been described on multi-ple occasions in Japan [Ikeda et al., 2001; Inoue et al.,1995; Katagiri et al., 1996, 1998; Kijima et al., 1998;Noguchi et al., 1999; Schehl and Ostrander 1997;Sekine et al., 2001]. The most common BRCA1mutation is the codon 63 mutation (TTA to TAA)

detected in 18 independent Japanese pedigrees,reported in six studies (Table 3). The BRCA1Q934X mutation was recently reported in 13unrelated kindreds, reported in four studies [Ikedaet al., 2001; Inoue et al., 1995; Noguchi et al., 1999;Sekine et al., 2001]. Haplotype studies supportfounder effects, specifically in eastern Japan for theL63X mutation and western Japan for the Q934Xmutation [Sekine et al., 2001]. The E1214X and the2080delA mutation are the only recurrent mutationsalso reported among Caucasians (Dutch) [BIC, 2002].

The age-standardized (world) incidence rate (ASR)of female breast cancer in Korea (Kangwha) is one ofthe lowest recorded, however, breast cancer is thesecond most common cancer after gastric canceramong women and the incidence in the generalpopulation is rising [Parkin et al., 1997]. Recently,Kang et al. (2002) investigated the prevalence ofBRCA1/2 mutations among 21 Korean breast-ovariancancer families with at least two first- or second-degree relatives with breast or ovarian cancer (at leastone diagnosed below age 50 years). Nine germlinemutations (43%) (5 BRCA1, 4 BRCA2) wereidentified, demonstrating that BRCA1 and BRCA2are involved in the inherited predisposition of breastand ovarian cancer in Korea. Three BRCA1 mutationsand two BRCA2 mutations were unique to thispopulation, but none were present in more than onefamily to suggest any founder effects in this population.

TABLE 2. Studies ofBRCAMutations AmongCases of InvasiveOvarianCancer Unselected forAge ofOnset and FamilyHistory(N450)

Estimated prevalence

Reference Centre No. of patientsBRCA1(%)

BRCA2(%)

Total(%)

EuropeStratton et al. [1997] Cambridge,UK 374 3.5 ^ ^Sarantaus et al. [2001] Finland 233 4.7 0.9 5.6VanDer Looij et al. [2000] Hungary 90 11.0 ^ 11.0

NorthAmericaTakahashi et al. [1995] Philadelphia,USA 115 6.1 ^ ^Takahashi et al. [1996] Philadelphia,USA 130 ^ 3.1 ^Rubin et al. [1998] N.Carolina,USA 103 3.9 ^ ^Tonin et al. [2001] Montreal, Canada 99 5.0 3.0 8.0Risch et al. [2001] Ontario,Canada 515 7.6 4.1 11.7Smith et al. [2001] USA 258 4.6 ^ ^

AshkenaziJewishMoslehi et al. [2000] USA andCanada 208 27.4 13.9 41.3Modan et al. [2001] Israel 840 21.7 7.6 29.0Tobias et al. [2000] NewJersey,USA 92 17.4 7.6 25

AsiaMatsushima et al. [1995] Tokyo, Japan 76 5.3 ^ ^Yamashita et al. [1999] Sapporo, Japan 116 6.0 ^ ^Khoo et al. [2000] HongKong,China 53 11.3 2.1a (13.2)Khoo et al. [2002] HongKong,China 214 1.4 0.9 2.3Liede et al. [2002] Pakistan 120 13.3 2.5 15.8

a43 cases were screened forBRCA2.

416 LIEDE ANDNAROD

TABLE 3. BRCAMutations Detected inMultiple Families in South and East Asia

Reported by

No. BIC CenterNo.

familiesType ofstudy

Samplesize Reference

JapanBRCA1L63X ^ Tokyo 1 F 20 Inoue et al. [1995];

Fukutomi et al. [1997](307T4A) Osaka 2 BRCAF 33 Noguchi et al. [1999]

NiigataCity 2 F 19 Takano et al. [1997]Tokyo 2 UB 56 Kijima et al. [1998]

NiigataCity 7 F 82 Sekine et al. [2001]Osaka 4 F 113 Ikeda et al. [2001]

E1214X 5a Osaka 1 F 113 Ikeda et al. [2001](3759G4T) NiigataCity 1 F 19 Takano et al. [1997]

Osaka 2 BRCAF 33 Noguchi et al. [1999]Tokyo 1 UBT 103 Katagiri et al. [1996]Tokyo 1 UBT 1,000 Emi et al. [1998]

2080delA 17a NiigataCity 2 F 82 Sekine et al. [2001]2508delAG ^ NiigataCity 2 F 82 Sekine et al. [2001]

Sapporo 3 UO 116 Yamashita et al. [1999]2509delAA 1 Baltimore,USA 1 CR ^ Schehl andOstrander [1997]

Tokyo 1 UBT 103 Katagiri et al. [1996]Tokyo 1 UBT 1,000 Emi et al. [1998]Osaka 1 BRCAF 33 Noguchi et al. [1999]

Q934X ^ Osaka 3 BRCAF 33 Noguchi et al. [1999]Tokyo 1 F 20 Inoue et al. [1995]Osaka 1 F 113 Ikeda et al. [2001]

NiigataCity 8 F 82 Sekine et al. [2001]4237delAG ^ NiigataCity 2 F 82 Sekine et al. [2001]

BRCA2S2834X ^ Tokyo 1 F 20 Inoue et al. [1997];

Fukutomi et al. [1997]Osaka 1 BRCAF 33 Noguchi et al. [1999]Osaka 4 F 113 Ikeda et al. [2001]

5802del4 ^ Osaka 7 F 113 Ikeda et al. [2001]6633del5 ^ Osaka 1 BRCAF 33 Noguchi et al. [1999]

Ontario,Canada 1 UO ^ Risch et al. [2001]

China andTaiwan�BRCA1589delCT 2 HongKong 4 UBT 130 Tang et al. [2001,1999]IVS7-27del10 ^ Taiwan 2 F 18 Li et al. [1999]1081delG ^ HongKong andBeijing 2 UOT 214 Khoo et al. [2002]2371-2372delTG ^ HongKong andBeijing 1 UOT 214 Khoo et al. [2002]

HongKong 1 UO 53 Khoo et al. [2000]BRCA23337C4T ^ HongKong andBeijing 2 UOT 214 Khoo et al. [2002](Q1037X) HongKong 1 UO 53 Khoo et al. [2000]

Mongolia�BRCA13452delA ^ UlaanBaator 1 CR ^ Elit et al. [2001]

1 UB,UO 32 Elit et al. (personalcommunication)

Philippines�BRCA15454delC 1 Manila andHawaii 2 UB 294 De LeonMatsuda et al. [2002]

BRCA23827delGT ^ Manila 2 UB 294 De LeonMatsuda et al. [2002]4265delCT 1 Manila 3 UB 294 De LeonMatsuda et al. [2002]4859delA ^ Manila 7 UB 294 De LeonMatsuda et al. [2002]

Ontario,Canada 1 UO ^ Risch et al. [2001]

Thailand�BRCA13300delA ^ Bangkok 2 F,UB 23 Patmasiriwat et al. [2002]

Malaysia�BRCA12846insA ^ Singapore 2 UB 43 Ho et al. [2000]

Iran�BRCA1185delAG +++ Israel 1 F ^ Bar-Sade et al. [1998]

Iran 1 UB 83 Yassaee et al. [2002]

(Continued)

BRCA1ANDBRCA2 IN ASIA 417

CHINA,TAIWAN, AND SINGAPORE

Breast cancer rates among Chinese women fromChina are among the lowest recorded, although withincreased modernization and urbanization the ratesappear to be increasing. Chinese women in Singaporeand Hong Kong have higher rates than Chinesewomen in China [Parkin et al., 1997]. In Singapore,cancer is now the leading cause of death. The threemajor ethnic groups in Singapore are the Chinese(77.0%), Malay (14.0%), and Indian (7.6%). Inparticular, the Singapore Chinese have the highestrecorded rates of ovarian cancer in Southeast Asia,but the Singapore Malay and Indian are not far behind[Parkin et al., 1997]. The ASR of ovarian cancer forthe Singapore Chinese is 10.72 per 100,000 per year.This rate is significantly higher than rates reported forChina and for Chinese immigrants to North Americaand they resemble the rates observed in the CanadianProvince of Ontario [Herrinton et al., 1994; Jin et al.,1993; Parkin et al., 1997; Shu et al., 1989].

Few genetic studies have been conducted onChinese breast or ovarian cancer patients. In thestudy of 53 ovarian cancer patients in Hong Kong,the prevalence of BRCA mutations exceeded 10%[Khoo et al., 2000] and only one BRCA2 mutation(3337C>T) was identified. The study of 130 breastcancer patients in Hong Kong estimated the con-tribution of BRCA1 mutations to be 3.8% [Tang et al.,1999]. These estimates are consistent with themutation rates observed in larger studies in NorthAmerica [Newman et al., 1998; Risch et al., 2001].Two smaller studies from Singapore have examinedBRCA1 among early-onset breast cancer patients[Ho et al., 2000]. The study by Sng et al. [2000] wasbased exclusively on Chinese patients and 81% ofparticipants in the study by Ho et al. [2000] wereChinese. The estimates of BRCA1 prevalence fromthese two studies are high (8.6% and 7%, respectively)

and suggest that genetic susceptibility may be animportant contributor to Chinese breast cancerpatients in Singapore. Recently, Zhi et al. (in press)reported on two BRCA1 (1584G>T, 5028delC) andone BRCA2 (7883delTTAA) mutations among 16breast cancer families and 20 early-onset breast cancerpatients (diagnosed below age 35) from the Tianjinregion of China.

Recurrent mutations among Chinese patients areunique to this population [BIC, 2002]. Four BRCA1mutations (589delCT, IVS7-27del10, 1081delG, and2371-2372delTG) and one BRCA2 mutation(3337C>T) have been described in multiple patientsof Chinese descent. The BRCA1 589delCT mutationhas been reported in four unrelated patients fromHong Kong [Tang et al., 1999]. Haplotype studiesdetermined ancestral links for two Hong Kongpatients with the BRCA1 1081delG mutation[Neuhausen et al., 1996]. The BRCA1 2371-2372delTG and the BRCA2 3337C>T mutationshave been described in two studies by Khoo et al.[2000, 2002], but haplotype studies could not supportthese as founder mutations of the Chinese populationof Hong Kong.

A 10-bp deletion in the branch site of intron 7 ofBRCA1 (IVS7-27del10) was detected in two unre-lated patients from southern Taiwan [Li et al., 1999].However, this and the three BRCA2 mutationsidentified for Taiwanese breast cancer families havenot been reported in other Chinese populations.

THAILANDANDMALAYSIA

Recently, the first study on Thai patients withinherited germline BRCA1/2 mutations was reported.Patmasiriwat et al. (in press) examined seven breast/ovarian cancer families, seven site-specific breastcancer families, and four patients with early-onsetbreast cancer (o32 years). Among the 18 unrelated

TABLE 3 (Continued.)

Reported by

No. BIC CenterNo.

familiesType ofstudy

Samplesize Reference

India andPakistan�BRCA1185delAG +++ Ontario,Canada 1 UO ^ Risch et al. [2001]

Israel 1 F ^ Bar-Sade et al. [1998]4184delTCAA 39a UK 2 BRCAF ^ Neuhausen et al. [1996]

Karachi and Lahore 4 UB,UO 341,120 Liede et al. [2002]4284delAG 5 Karachi and Lahore 2 UB,UO 341,120 Liede et al. [2002]3889delAG 5 Karachi and Lahore 2 UB,UO 341,120 Liede et al. [2002]IVS14-1G>A ^ Karachi and Lahore 3 UB,UO 341,120 Liede et al. [2002]2080insA 1 Karachi and Lahore 3 UB,UO 341,120 Liede et al. [2002]

BRCA23337C4T 1 Karachi and Lahore 2 UB,UO 341,120 Liede et al. [2002](Q1037X)

UBT, unselected breast tumor specimens; UOT, unselected ovarian tumor specimens; UO, unselected series of ovarian cancer patients; UB, un-selected series of breast cancer patients; F, families; CR, case report; BRCAF, BRCAmutation-positive families.aReported inmultiple European families.bAlso detected inJapanese families.

418 LIEDE ANDNAROD

patients and families, two deleterious BRCA1 muta-tions (744ins20, 3300delA) and two BRCA2 muta-tions (2041delA, 6382delT) were identified—anadditional mutation in BRCA2 was suspected to bepathogenic (5527del9). Over half of the seven breast/ovarian cancer families had a BRCA1 or BRCA2truncating mutation. The BRCA1 3300delA mutationwas found in two apparently unrelated families(Patmasiriwat et al., in press).

Two patients from Singapore of Malay ethnicitywere carriers of the BRCA1 2846insA mutation [Tanget al., 1999]. There is no additional data to date onpatients or families from Malayasia.

PHILIPPINES

The Manila Cancer Registry in the Philippines hasthe highest reported incidence rate of breast cancerin Asia [Parkin et al., 1997]. The ASR of 47.7 per100,000 exceeds the rate reported for severalEuropean countries, including Spain, Italy, and mostEastern European countries. It is not yet clear why therates are high in the Philippines, but the contributionof BRCA2 mutations may be important.

De Leon Matsuda et al. [2002] estimated a 5.1%prevalence of BRCA mutations among 294 breastcancer patients at the Philippine General Hospital inManila. Of interest was the role of mutations in theBRCA2 gene, which accounted for 12 of 15 (80%)mutations. Three founder BRCA2 mutations(3827delGT, 4859delA, and 4265delCT) and oneBRCA1 mutation (5454delC) were responsible forover half of all mutations. The BRCA2 4265delCTmutation was previously reported in a Swedish family,however, the haplotypes point to independent originsfor the Filipino and Swedish mutations [BIC, 2002;De Leon Matsuda et al., 2002]. Only two casesattributable to a mutation in BRCA2 had a positivefamily history of ovarian cancer and half of themutation-positive women had no relative with breastor ovarian cancer. However, the penetrance ofdeleterious BRCA mutations in the Philippines wassimilar to the penetrance estimated using identicalmethods for the Jewish founder mutations in a studyof breast cancer patients in Canada [Warner et al.,1999].

IRAN

Among non-Ashkenazi groups, the founder BRCA1185delAG mutation was described in a patient ofIranian Jewish descent [Bar-Sade et al., 1998; Levy-Lahad et al., 1997]. A study conducted on 80 womenwith breast cancer in Shiraz, Iran did not detect thismutation in the general Iranian population [Ghaderiet al., 2001]. In a more recent study by Yassaee et al.[2002] of 83 early-onset breast cancer patients inTehran, three pathogenic mutations in BRCA1

(185delAG, 181insT, 2335delAA) and two mutationsin BRCA2 (6261insGT, 3979insA) were described.Although the 185delAG mutation was observed intheir study (1.2%), no information about specificgeographic or religious differences between subjectswas presented. The prevalence of BRCA1/2 mutationsamong early-onset breast cancer patients (o45 years)in Iran is 6% based on this study [Yassaee et al., 2002].

INDIA AND PAKISTAN

The populations in India and Pakistan include acomplex mixture of indigenous people and other racialtypes introduced with successive waves of migration.Aryans, Persians, Greeks, Pashtuns (Pathans), andMughals spread across the Indo-Gangetic Plain, whilethe Arabs conquered Sindh. The partition of BritishIndia in 1947 created Pakistan as a homeland forIndia’s Muslims. Today, breast cancer is the mostcommon cancer in women in Pakistan, followed bycancer of the oral cavity and the ovary [Bhurgri et al.,2000]. Pakistan has one of the highest rates of breastcancer in Asia, and a high proportion of cases occurbelow age 40 [Bhurgri et al., 2000; Usmani et al.,1996]. Carcinoma of the ovary is the most commoncancer of gynecologic origin in Pakistan and theincidence rates are comparable to that of NorthAmerica [Bhurgri et al., 2000; Parkin et al., 1997].

The first report on BRCA1 and BRCA2 germlinemutations among Indian women with breast cancershowed two unique BRCA1 splice variants (IVS5331+1G4T, IVS13 4476+2T4C) (Saxena et al.,in press). Before this study, only five mutations inBRCA1 had been identified for Indo-Pakistanifamilies from various sources, including case reportsor studies in Britain, Canada, and Singapore. Thesemutations include the BRCA1 2885delA, 1701del7,1768delA, and 4184del4 [Moslehi et al., 1998;Neuhausen et al., 1996; Risch et al., 2001]. TheBRCA1 4184del4 mutation, common to families inBritain, France, and Europe in general, was found intwo Indo-Pakistani families residing in Britain.Haplotype studies determined independent origins ofthe 4184del4 mutation for European and Indo-Pakistani families [Neuhausen et al., 1996]. The‘‘Jewish’’ BRCA1 185delAG mutation has been foundin non-Ashkenazi groups across the Middle East, aswell as in Greece, Turkey, Yorkshire (England), and intwo Indo-Pakistani families [Bar-Sade et al., 1998;Risch et al., 2001]. This mutation occurs in a region ofA-G repeats of BRCA1, which may explain thediffering haplotypes associated with the non-Ashke-nazi groups [Bar-Sade et al., 1998; Xu et al., 1997].

The 185delAG mutation was recently identified ina large case-control study of 341 women with breastcancer and 120 women with ovarian cancer inPakistan [Liede et al., 2002]. From this study, theprevalence of mutations among breast cancer patients

BRCA1ANDBRCA2 IN ASIA 419

(6.7%) and ovarian cancer patients (15.8%) was oneof the highest recorded outside of the AshkenaziJewish population [Liede et al., 2002]. Five candidatefounder mutations were identified in multiple patientsand their distribution appears to be specific togeographically and genetically distinct ethnic groupsin Pakistan. One of the founder mutations, theBRCA2 3337C4T mutation, has also been describedin families from southern China and Hong Kong—separate origins of the same mutation are more likelythan ancestral link. The penetrance of BRCA1/2mutations does not appear to be reduced in thispopulation.

DISCUSSION

Genetic epidemiologic studies of breast or ovariancancer in Asia advance our knowledge of thepopulation genetics of BRCA1 and BRCA2. Therehave been unique founder mutations identified inAsian populations. Until recently, most data origi-nated from studies of high-risk families and casereports. Studies on unselected breast or ovariancancer patients in Asia are emerging. Generally, theseprovide more information, despite the use of imperfectand varied methods of mutation detection. Moststudies have focused on early-onset cases of breastcancer, nevertheless the majority of cases occur beforeage 50 in most East Asian countries.

It is not yet clear how much of the variationbetween countries is attributable to genetic factors, orwhat proportion of all cases of breast cancer or ovariancancer are ‘‘familial.’’ Studies to date suggest that theprevalence of BRCA mutations may be equivalent orhigher in Asia than in most European countries(excluding Iceland). In particular, data suggest thatBRCA2 plays the principal role in genetic suscept-ibility in the Philippines and Japan [De Leon Matsudaet al., 2002; Ikeda et al., 2001], although fewer studiesexamined both BRCA1 and BRCA2 concurrently.Because of the relatively young ages of diagnosis ofbreast cancer in Asia, and because hereditary cancersoccur disproportionately in young women, it isexpected that BRCA mutations will account for agreater proportion of all breast cancers in Asia than inNorth America. However, the reason for a preponder-ance of BRCA2 over BRCA1 mutations is not known.First, it is possible that the differences are a result ofrandom sampling error in the studies to date. Second,a modifying genetic or environmental factor maymodify the penetrance of BRCA2 upwards. Third,there may be a selective advantage to carriers ofspecific BRCA2 alleles in terms of reproductivefitness. In support of this, Healey et al. [2000]reported that a specific BRCA2 variant (N372H)was associated with increased reproductive fitness inmales in the UK, and an increased breast cancer riskin females. Fourth, founder BRCA2 mutations and

genetic drift may result in a higher prevalence ofBRCA2 mutations. Finally, the penetrance or pre-valence of BRCA1 mutations may be lower in Asia.The penetrance of BRCA2 mutations was shown to bethe same in the Philippines as in Ashkenazi Jews inNorth America [De Leon Matsuda et al., 2002].Consequently, if the contribution of BRCA1 to cancerrates is lower in Asia, then the relative proportion ofbreast cancer due to mutations in BRCA2 will behigher.

There is a wide range in standards of cancerscreening and treatment in Asian countries. Devel-oped nations such as Japan and Singapore have healthcare structures similar to North America and Europe.In other countries, less resources are available—in themajority of these, breast screening is not common andcompliance is poor [Parkin et al., 2000]. Few womenperform breast self-examination or undergo regularclinical breast examination. Consequently, manywomen in the poorer countries present with advanceddisease. A high proportion of women may be seen atgovernment-sponsored hospitals. These patients typi-cally have limited resources and their treatmentoptions are restricted. In the Philippines, surgicaltreatment is provided to all patients, but radiotherapy,chemotherapy, and tamoxifen are available only tothose with sufficient means. In addition, it is oftendifficult for patients from outlying regions to attendthe hospital—in fact, patients may travel for days toconsult with specialists in urban areas. Consequently,patient follow-up is difficult and few of these womenhave private telephones.

The standard treatment of breast cancer in Asia ismastectomy, but options for women with a BRCAmutation may be extended to include bilateralmastectomy, oophorectomy, and possibly tamoxifen.Genetic testing may be valuable for newly diagnosedcases of breast cancer to decide upon appropriateclinical management, and as a means to identifyunaffected carrier relatives. It is important torecognize that the social and medical contextsurrounding genetic testing is different in the Eastthan in the West, due to different cultural values,beliefs about the origin of cancer, public awareness,and access to care.

The discovery of founder mutations in Europeanpopulations has simplified the task of screening formutations in breast and ovarian cancer patients.Mutations described for Asian patients are oftenunique and specific to these populations and a numberof candidate founder mutations have been identified.Founder mutations may reflect geographically andgenetically distinct populations in Asian countries.With this knowledge, limited resources may be betterspent in screening for a small number of founderBRCA mutations in all early-onset cancer cases,rather than to attempt comprehensive mutationscreening for the minority of cases with a strong

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family history [De Leon Matsuda et al., 2002].Because of the lack of organized breast cancerscreening programs and limited access to adjuvanttherapies, and because of the difficulties with main-taining adequate patient follow-up, prophylacticoophorectomy and mastectomy may be considered asoptions for primary prevention of breast cancer amonghealthy women who are found to carry pathogenicmutations. Counseling leading to autonomous deci-sion-making is crucial in the management of womenat high-risk for breast cancer in any country andspecial consideration should be given to those of lowersocioeconomic status.

REFERENCES

Anglian Breast Cancer Study Group. 2000. Prevalence andpenetrance of BRCA1 and BRCA2 mutations in a popula-tion-based series of breast cancer cases. Br J Cancer 83:1301–1308.

Bar-Sade RB, Kruglikova A, Modan B, Gak E, Hirsh-YechezkelG, Theodor L, Novikov I, Gershoni-Baruch R, Risel S,Papa MZ, Ben-Baruch G, Friedman E. 1998. The 185delAGBRCA1 mutation originated before the dispersion of Jews inthe diaspora and is not limited to Ashkenazim. Hum MolGenet 7:801–805.

Bhurgri Y, Bhurgri A, Hassan SH, Zaidi SH, Rahim A,Sankaranarayanan R, Parkin DM. 2000. Cancer incidence inKarachi, Pakistan: first results from Karachi Cancer Registry.Int J Cancer 85:325–329.

BIC. 2002. Breast Cancer Information Core Database.www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/.

Chappuis PO, Hamel N, Paradis AJ, Deschenes J, Robidoux A,Potvin C, Cantin J, Tonin P, Ghadirian P, Foulkes WD. 2001.Prevalence of founder BRCA1 and BRCA2 mutationsin unselected French Canadian women with breast cancer.Clin Genet 59:418–423.

Claus EB, Schildkraut JM, Thompson WD, Risch NJ. 1996.The genetic attributable risk of breast and ovarian cancer.Cancer 77:2318–2324.

De Leon Matsuda ML, Liede A, Kwan E, Mapua CA,Cutiongco EMC, Tan A, Borg A, Narod SA. 2002. BRCA1and BRCA2 mutations among breast cancer patients fromthe Philippines. Intl J Cancer 98:596–603.

Elit L, Jack E, Kwan E, Baigal G, Narod S. 2001. A uniqueBRCA1 mutation identified in Mongolia. Int J GynecolCancer 11:241–243.

Ellis D, Greenman J, Hodgson S, McCall S, Lalloo F, CameronJ, Izatt L, Scott G, Jacobs C, Watts S, Chorley W, Perrett C,MacDermot K, Mohammed S, Evans G, Mathew CG. 2000.Low prevalence of BRCA1 mutations in early onset breastcancer without family history. J Med Genet 37:792–794.

Emi M, Matsushima M, Katagiri T, Yoshimoto M, Kasumi F,Yokota T, Nakata T, Miki Y, Nakamura Y. 1998. Multiplexmutation screening of the BRCA1 gene in 1000 Japanesebreast cancers. Jpn J Cancer Res 89:12–16.

Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. 1994.Risks of cancer in BRCA1 mutation carriers. Breast CancerLinkage Consortium. Lancet 343:692–695.

Fukutomi T, Ushijima T, Inoue R, Akashi-Tanaka S, NanasawaT, Tsuda H. 1997. BRCA1 and BRCA2 germline mutationsin Japanese with hereditary breast cancer families. BreastCancer 4:256–258.

Garcia-Patino E, Gomendio B, Provencio M, Silva JM, GarciaJM, Espana P, Bonilla F. 1998. Germ-line BRCA1 mutationsin women with sporadic breast cancer: clinical correlations.J Clin Oncol 16:115–120.

Ghaderi A, Talei A, Farjadian S, Mosalaei A, Doroudchi M,Kimura H. 2001. Germline BRCA1 mutations in Iranianwomen with breast cancer. Cancer Lett 165:87–94.

Healey CS, Dunning AM, Dawn Teare M, Chase D, Parker L,Burn J, Chang-Claude J, Mannermaa A, Kataja V, HuntsmanDG, Pharoah PD, Luben RN, Easton DF, Ponder BA. 2000.A common variant in BRCA2 is associated with bothbreast cancer risk and prenatal viability. Nature Genet26:362–364.

Herrinton LJ, Stanford JL, Schwartz SM, Weiss NS. 1994.Ovarian cancer incidence among Asian migrants to theUnited States and their descendants. J Natl Cancer Inst86:1336–1339.

Ho GH, Phang BH, Ng IS, Law HY, Soo KC, Ng EH. 2000.Novel germline BRCA1 mutations detected in women inSingapore who developed breast carcinoma before the age of36 years. Cancer 89:811–816.

Hopper JL, Southley MC, Dite GS, Jolley DJ, Giles GG,McCredie MRE, Easton DF, Venter DJ. 1999. Population-based estimate of the average age-specific cumulative risk ofbreast cancer for a defined set of protein-truncatingmutations in BRCA1 and BRCA2. Australian Breast CancerFamily Study. Cancer Epidemiol Biomarkers Prev 8:741–747.

Ikeda N, Miyoshi Y, Yoneda K, Shiba E, Sekihara Y, MoritoshiK, Noguchi S. 2001. Frequency of BRCA1 and BRCA2germline mutations in Japanese breast cancer families. Int JCancer 91:83–88.

Inoue R, Fukutomi T, Ushijima T, Matsumoto Y, Sugimura T,Nagao M. 1995. Germline mutation of BRCA1 in Japanesebreast cancer families. Cancer Res 55:3521–3524.

Inoue R, Ushijima T, Fukutomi T, Fukami A, Sugimura H,Inoue S, Okonogi H, Sugimura T, Matsumoto Y, Nagao M.1997. BRCA2 germline mutations in Japanese breast cancerfamilies. Int J Cancer 74:199–204.

Jin F, Shu XO, Devesa SS, Zheng W, Blot WJ, Gao YT. 1993.Incidence trends for cancers of the breast, ovary, and corpusuteri in urban Shanghai, 1972–89. Cancer Causes Control4:355–360.

Johannesdottir G, Gudmundsson J, Bergthorsson JT, Arason A,Agnarsson BA, Eiriksdottir G, Johannsson OT, Borg A,Ingvarsson S, Easton DF, Egilsson V, Barkardottir RB. 1996.High prevalence of the 999del5 mutation in Icelandic breastand ovarian cancer patients. Cancer Res 56:3663–3665.

Kang HC, Kim I-J, Park J-H, Kwon H-J, Won Y-J, Heo SC,Lee S-Y, Kim K-H, Shin Y, Noh DY, Yang J-H, Park J-G.2002. Germline mutations of the BRCA1 and BRCA2 genesin Korean breast and/or ovarian cancer families. Hum Mutat20:235.

Katagiri T, Emi M, Ito I, Kobayashi K, Yoshimoto M, Iwase T,Kasumi F, Miki Y, Skolnick MH, Nakamura Y. 1996.Mutations in the BRCA1 gene in Japanese breast cancerpatients. Hum Mutat 7:334–339.

BRCA1ANDBRCA2 IN ASIA 421

Katagiri T, Kasumi F, Yoshimoto M, Nomizu T, Asaishi K, AbeR, Tsuchiya A, Sugano M, Takai S, Yoneda M, Fukutomi T,Nanba K, Makita M, Okazaki H, Hirata K, Okazaki M,Furutsuma Y, Morishita Y, Iino Y, Karino T, Ayabe H, Hara S,Kajiwara T, Houga S, Miki Y. 1998. High proportion ofmissense mutations of the BRCA1 and BRCA2 genes inJapanese breast cancer families. J Hum Genet 43:42–48.

Khoo US, Ngan HY, Cheung AN, Chan KY, Lu J, Chan VW,Lau S, Andrulis IL, Ozcelik H. 2000. Mutational analysis ofBRCA1 and BRCA2 genes in Chinese ovarian canceridentifies 6 novel germline mutations. Hum Mutat 16:88–89.

Khoo US, Chan KY, Cheung AN, Xue WC, Shen DH, FungKY, Ngan HY, Choy KW, Pang CP, Poon CS, Poon AY,Ozcelik H. 2002. Recurrent BRCA1 and BRCA2 germlinemutations in ovarian cancer: a founder mutation of BRCA1identified in the Chinese population. Hum Mutat 19:307–308.

Kijima G, Murakami Y, Ohuchi N, Satomi S, Sekiya T. 1998.Nonsense mutation at codon 63 of the BRCA1 gene inJapanese breast cancer patients. Jpn J Cancer Res 89:837–841.

Langston AA, Malone KE, Thompson JD, Daling JR,Ostrander EA. 1996. BRCA1 mutations in a population-based sample of young women with breast cancer. New Engl JMed 334:137–142.

Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, HornreichG, Lishinsky E, Shohat M, Weber BL, Beller U, Lahad A,Halle D. 1997. Founder BRCA1 and BRCA2 mutations inAshkenazi Jews in Israel: frequency and differential pene-trance in ovarian cancer and in breast-ovarian cancerfamilies. Am J Hum Genet 60:1059–1067.

Li SS, Tseng HM, Yang TP, Liu CH, Teng SJ, Huang HW,Chen LM, Kao HW, Chen JH, Tseng JN, Chen A, Hou MF,Huang TJ, Chang HT, Mok KT, Tsai JH. 1999. Molecularcharacterization of germline mutations in the BRCA1 andBRCA2 genes from breast cancer families in Taiwan. HumGenet 104:201–204.

Liede A, Malik IA, Aziz Z, Rios Pd Pde L, Kwan E, Narod SA.2002. Contribution of BRCA1 and BRCA2 mutations tobreast and ovarian cancer in Pakistan. Am J Hum Genet71:595–606.

Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A.2001. Family history of breast and ovarian cancers andBRCA1 and BRCA2 mutations in a population-based seriesof early-onset breast cancer. J Natl Cancer Inst 93:1215–1223.

Malone KE, Daling JR, Thompson JD, O’Brien CA, FranciscoLV, Ostrander EA. 1998. BRCA1 mutations and breastcancer in the general population: analyses in women beforeage 35 years and in women before age 45 years with first-degree family history. JAMA 279:922–929.

Malone KE, Daling JR, Neal C, Suter NM, O’Brien C,Cushing-Haugen K, Jonasdottir TJ, Thompson JD, OstranderEA. 2000. Frequency of BRCA1/BRCA2 mutations in apopulation-based sample of young breast carcinoma cases.Cancer 88:1393–1402.

Matsushima M, Kobayashi K, Emi M, Saito H, Saito J,Suzumori K, Nakamura Y. 1995. Mutation analysis of theBRCA1 gene in 76 Japanese ovarian cancer patients: four

germline mutations, but no evidence of somatic mutation.Hum Mol Genet 4:1953–1956.

Modan B, Hartge P, Hirsh-Yechezkel G, Chetrit A, Lubin F,Beller U, Ben-Baruch G, Fishman A, Menczer J, Ebbers SM,Tucker MA, Wacholder S, Struewing JP, Friedman E, Piura B.2001. Parity, oral contraceptives, and the risk of ovariancancer among carriers and noncarriers of a BRCA1 orBRCA2 mutation. N Engl J Med 345:235–240.

Moslehi R, Soledhin F, Malik I, Narod S. 1998. Analysis ofBRCA1 mutations in a Pakistani family with hereditarybreast and ovarian cancer syndrome. Am J Med Genet78:386–387.

Moslehi R, Chu W, Karlan B, Fishman D, Risch H, Fields A,Smotkin D, Ben-David Y, Rosenblatt J, Russo D, Schwartz P,Tung N, Warner E, Rosen B, Friedman J, Brunet JS, NarodSA. 2000. BRCA1 and BRCA2 mutation analysis of 208Ashkenazi Jewish women with ovarian cancer. Am J HumGenet 66:1259–1272.

Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K,Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, KelsellD, Solomon E, Weber B, Couch F, Struewing J, Tonin P,Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O,Ponder B, Stoppa-Lyonnet D, Easton D, King MC, GoldgarDE. 1996. Haplotype and phenotype analysis of six recurrentBRCA1 mutations in 61 families: results of an internationalstudy. Am J Hum Genet 58:271–280.

Newman B, Mu H, Butler LM, Millikan RC, Moorman PG,King M-C. 1998. Frequency of breast cancer attributable toBRCA1 in a population-based series of American women.JAMA 279:915–921.

Noguchi S, Kasugai T, Miki Y, Fukutomi T, Emi M, Nomizu T.1999. Clinicopathologic analysis of BRCA1- or BRCA2-associated hereditary breast carcinoma in Japanese women.Cancer 85:2200–2205.

Papelard H, de Bock GH, van Eijk R, Vliet Vlieland TP,Cornelisse CJ, Devilee P, Tollenaar RA. 2000. Prevalence ofBRCA1 in a hospital-based population of Dutch breastcancer patients. Br J Cancer 83:719–724.

Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. 1997.Cancer incidence in five continents, vol VII. Lyon: IARC.Scientific Publication No. 143.

Parkin DM, Pisani P, Gibson LJ, Esteban DB, Ngelangel CA,Laudico AV. 2000. Screening for cancer of the breast in thePhilippines. IARC Biennial Report, 1998/1999. Lyon: IARC.p 129–130.

Patmasiriwat P, Bhothisuwan K, Sinilnikova OM, Chopin S,Methakijvaroon S, Badzioch M, Padungsutt P, VattanaviboonP, Vattanasapt V, Szabo CI, Saunders GF, Goldgar D, LenoirGM. 2002. Analysis of breast cancer susceptibility genesBRCA1 and BRCA2 in Thai familial and isolated early-onsetbreast and ovarian cancer. Hum Mutat, in press.

Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N,Easton DF, Evans C, Deacon J, Stratton MR. 1999.Prevalence of BRCA1 and BRCA2 gene mutations inpatients with early-onset breast cancer. J Natl Cancer Inst91:943–949.

Risch HA, McLaughlin JR, Cole DEC, Rosen B, Bradley L,Kwan E, Jack E, Vesprini DJ, Kuperstein G, AbrahamsonJLA, Fan I, Wong B, Narod SA. 2001. Prevalence andpenetrance of germline BRCA1 and BRCA2 mutations in a

422 LIEDE ANDNAROD

population series of 649 women with ovarian cancer. Am JHum Genet 68:700–710.

Rubin SC, Blackwood MA, Bandera C, Behbakht K, BenjaminI, Rebbeck TR, Boyd J. 1998. BRCA1, BRCA2, andhereditary nonpolyposis colorectal cancer gene mutationsin an unselected ovarian cancer population: relationship tofamily history and implications for genetic testing. Am JObstet Gynecol 178:670–677.

Sarantaus L, Vahteristo P, Bloom E, Tamminen A, Unkila-Kallio L, Butzow R, Nevanlinna H. 2001. BRCA1 andBRCA2 mutations among 233 unselected Finnish ovariancarcinoma patients. Eur J Hum Genet 9:424–430.

Saxena S, Szabo C, Chopin S, Barjhoux L, Sinilnikova O,Lenoir G, Goldgar D, Bhatanager D. 2002. BRCA1 andBRCA2 in Indian breast cancer patients. Hum Mutat,in press.

Schehl CM, Ostrander GK. 1997. Identification of BRCA1germline mutation, 797delAA, in a Japanese breast-ovariancancer patient. J Natl Cancer Inst 89:1547–1548.

Sekine M, Nagata H, Tsuji S, Hirai Y, Fujimoto S, Hatae M,Kobayashi I, Fujii T, Nagata I, Ushijima K, Obata K, SuzukiM, Yoshinaga M, Umesaki N, Satoh S, Enomoto T,Motoyama S, Tanaka K. 2001. Mutational analysis ofBRCA1 and BRCA2 and clinicopathologic analysis ofovarian cancer in 82 ovarian cancer families: two commonfounder mutations of BRCA1 in Japanese population. ClinCancer Res 7:3144–3150.

Shu XO, Brinton LA, Gao YT, Yuan JM. 1989. Population-based case-control study of ovarian cancer in Shanghai.Cancer Res 49:3670–3674.

Smith SA, Richards WE, Caito K, Hanjani P, Markman M,DeGeest K, Gallion HH. 2001. BRCA1 germline mutationsand polymorphisms in a clinic-based series of ovarian cancercases: a Gynecologic Oncology Group study. Gynecol Oncol83:586–592.

Sng JH, Chang J, Feroze F, Rahman N, Tan W, Lim S, LehnertM, van der Pool S, Wong J. 2000. The prevalence of BRCA1mutations in Chinese patients with early onset breast cancerand affected relatives. Br J Cancer 82:538–542.

Southey MC, Tesoriero AA, Andersen CR, Jennings KM,Brown SM, Dite GS, Jenkins MA, Osborne RH, Maskiell JA,Porter L, Giles GG, McCredie MR, Hopper JL, Venter DJ.1999. BRCA1 mutations and other sequence variants in apopulation-based sample of Australian women with breastcancer. Br J Cancer 79:34–39.

Stratton JF, Gayther SA, Russell P, Dearden J, Gore M, Blake P,Easton D, Ponder BA. 1997. Contribution of BRCA1mutations to ovarian cancer. N Engl J Med 336:1125–1130.

Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M,McAdams M, Timmerman MM, Brody LC, Tucker MA.1997. The risk of cancer associated with specific mutations ofBRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med336:1401–1408.

Syrjakoski K, Vahteristo P, Eerola H, Tamminen A, KivinummiK, Sarantaus L, Holli K, Blomqvist C, Kallioniemi OP, KainuT, Nevanlinna H. 2000. Population-based study of BRCA1and BRCA2 mutations in 1035 unselected Finnish breastcancer patients. J Natl Cancer Inst 92:1529–1531.

Takahashi H, Behbakht K, McGovern PE, Chiu HC, Couch FJ,Weber BL, Friedman LS, King MC, Furusato M, LiVolsi VA,

Menzin AW, Liu PC, Benjamin I, Morgan MA, King SA,Rebane BA, Cardonick A, Mikuta JJ, Rubin SC, Boyd J.1995. Mutation analysis of the BRCA1 gene in ovariancancers. Cancer Res 55:2998–3002.

Takahashi H, Chiu HC, Bandera CA, Behbakht K, Liu PC,Couch FJ, Weber BL, LiVolsi VA, Furusato M, Rebane BA,Cardonick A, Benjamin I, Morgan MA, King SA, Mikuta JJ,Rubin SC, Boyd J. 1996. Mutations of the BRCA2 gene inovarian carcinomas. Cancer Res 56:2738–2741.

Takano M, Aida H, Tsuneki I, Takakuwa K, Hasegawa I,Tanaka H, Saito M, Tsuji S, Sonoda T, Hatae M, Chen JT,Takahashi K, Hasegawa K, Toyoda N, Saito N, Yakushiji M,Araki T, Tanaka K. 1997. Mutational analysis of BRCA1gene in ovarian and breast-ovarian cancer families in Japan.Jpn J Cancer Res 88:407–413.

Tang NLS, Pang C-P, Yeo W, Choy K-W, Lam PK, Suen M, LawLK, King WWK, Johnson P, Hjelm M. 1999. Prevalence ofmutations in the BRCA1 gene among Chinese patients withbreast cancer. J Natl Cancer Inst 91:882–885.

Tang NL, Choy KW, Pang CP, Yeo W, Johnson PJ. 2001.Prevalence of breast cancer predisposition gene mutations inChinese women and guidelines for genetic testing. Clin ChimActa 313:179–185.

Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G,Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjord JE. 1997.Study of a single BRCA2 mutation with high carrierfrequency in a small population. Am J Hum Genet60:1079–1084.

Tobias DH, Eng C, McCurdy LD, Kalir T, Mandelli J, DottinoPR, Cohen CJ. 2000. Founder BRCA 1 and 2 mutationsamong a consecutive series of Ashkenazi Jewish ovariancancer patients. Gynecol Oncol 78:148–151.

Tonin PN, Perret C, Lambert JA, Paradis AJ, Kantemiroff T,Benoit MH, Martin G, Foulkes WD, Ghadirian P. 2001.Founder BRCA1 and BRCA2 mutations in early-onsetFrench Canadian breast cancer cases unselected for familyhistory. Int J Cancer 95:189–193.

Usmani K, Khanum A, Afzal H, Ahmad N. 1996. Breast cancerin Pakistani women. J Environ Pathol Toxicol Oncol 15:251–253.

Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B,Pulay T, Toth J, Devilee P, King MC, Olah E. 2000.Prevalence of founder BRCA1 and BRCA2 mutationsamong breast and ovarian cancer patients in Hungary. Int JCancer 86:737–740.

Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J,Paterson C, Ozcelik H, Goss P, Allingham-Hawkins D,Hamel N, Di Prospero L, Contiga V, Serruya C, Klein M,Moslehi R, Honeyford J, Liede A, Glendon G, Brunet JS,Narod S. 1999. Prevalence and penetrance of BRCA1and BRCA2 gene mutations in unselected AshkenaziJewish women with breast cancer. J Natl Cancer Inst 91:1241–1247.

Xu CF, Chambers JA, Nicolai H, Brown MA, Hujeirat Y,Mohammed S, Hodgson S, Kelsell DP, Spurr NK, Bishop DT,Solomon E. 1997. Mutations and alternative splicing of theBRCA1 gene in UK breast/ovarian cancer families. GenesChromosomes Cancer 18:102–110.

Yamashita Y, Sagawa T, Fujimoto T, Sugawara T, Yamada H,Hoshi N, Sakuragi N, Ishioka C, Fujimoto S. 1999. BRCA1

BRCA1ANDBRCA2 IN ASIA 423

mutation testing for Japanese patients with ovarian cancer inbreast cancer screening. Breast Cancer Res Treat 58:11–17.

Yassaee VR, Zeinali S, Harirchi I, Jarvandi S, Mohagheghi MA,Hornby DP, Dalton A. 2002. Novel mutations in the BRCA1and BRCA2 genes in Iranian women with early-onset breastcancer. Breast Cancer Res 4:R6.

Yazici H, Bitisik O, Akisik E, Cabioglu N, Saip P, MuslumanogluM, Glendon G, Bengisu E, Ozbilen S, Dincer M, Turkmen S,

Andrulis IL, Dalay N, Ozcelik H. 2000. BRCA1 and BRCA2mutations in Turkish breast/ovarian families and youngbreast cancer patients. Br J Cancer 83:737–742.

Zhi X, Szabo C, Chopin S, Suter N, Wang Q-S, Ostrander EA,Sinilnikova OM, Gilbert M. Lenoir GM, Goldgar D, Shi Y-R.2002. BRCA1 and BRCA2 sequence variants in Chinesebreast cancer families. Hum Mutat, in press.

424 LIEDE ANDNAROD