112 C376T, which is associated with an amino acid substitution from Gln to a stop codon at codon 126 (Gln126stop), was detected in only two placental samples (1.0%) as TABLE 1 Genetic polymorphism in the BCRP gene in Japanese placentas (n ϭ 100) Location Positiona Reference Alleleb Variant Allele Amino Acid Substitution Genotype Frequency of Variant Allele R/R R/V V/V 5Ј-Flanking region -20445 gtctCctcc gtctTctcc 98 2 0 0.010 -20296 agctAttaa agctGttaa 80 18 2 0.110 -19781 aaaaAttat aaaaGttat 99 1 0 -19572_-19569 ctcaCTCAcaaa ctca--caaa 60 33 7 0.235 Exon 2 34 cccaGtgtc cccaAtgtc Val12Met 70 24 6 0.180 Intron 2 203 ϩ 16 tttaAttta tttaGttta 70 24 6 0.180 Intron 3 263 ϩ 10 tataAgaga tataGgaga 85 14 1 0.080 263 ϩ 72 ttttGtgtg ttttTGtgtg 99 1 0 0.005 Exon 4 376 ggtaCaagt ggtaTaagt Gln126stop 98 2 0 0.010 Exon 5 421 cttaCagtt cttaAagtt Gln141Lys 42 45 13 0.355 Intron 5 532-16 ttatAatat ttatGatat 99 1 0 0.005 Exon 9 1098 aggaGatca aggaAatca Synonymous 98 2 0 0.010 Intron 10 1277 ϩ 95 atagTgtaa atagAgtaa 97 3 0 0.015 Exon 11 1322 agcaGtgtt agcaAtgtt Ser441Asn 99 1 0 0.005 Intron 11 1367 ϩ 20 ttctAggaa ttctGggaa 71 25 4 0.165 Exon 12 1465 tataTttac tataCttac Phe489Leu 99 1 0 0.005 Intron 12 1492 ϩ 49 ctatGggtg ctatCggtg 44 45 11 0.335 Exon 13 1515 atgcCttct atgc-ttct Phe506Ser 99 1 0 0.005 Phe507Leu Val508Leu Met509stop Intron 13 1648-42 tgaaAttac tgaaTttac 99 1 0 0.005 1648-21 gactCttag gactTttag 71 25 4 0.165 Intron 14 1738-46 tcttAaaat tcttGaaat 24 52 24 0.500 3Ј-UTR 2332 cttcAgtct cttcTAgtct 86 14 0 0.070 2364 tgccAttat tgccCttat 99 1 0 0.005 2512 agaaCttac agaaTttac 99 1 0 0.005 R, reference allele; V, variant allele.

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ABCG2 p.Val508Leu 15475413:112:1357

status: VERIFIED

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116 Another polymorphism, a C1515 deletion, which results in a frame shift (Phe506Ser, Phe507Ser, Val508Leu, and Met509stop), was extremely rare (0.5%) in our samples.

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ABCG2 p.Val508Leu 15475413:116:94

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250 It should be noted that many xeno- and endobiotic BCRP Figure 5 Predicted membrance topology of BCRP (ABCG2) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 5 for allele frequencies and description of funtional consequences. NH2 COOH NBD Val12Met Gly51Cys Gln126* Ala149Pro Gln141Lys Thr153Met Arg160Gln Arg163Lys Gln166Glu Phe506Ser Phe507Leu Val508Leu Met509* Phe489Leu Ser441Asn Phe431Leu Glu334* Ile206Leu Ala315del Thr316del Phe208Ser Asp296His Ser248Pro Pro269Ser Phe571Ile Arg575* Asn590Tyr Asp620Asn in out Membrane BCRP (ABCG2) NBD Val12Met NBDNBD Val12Met substrates are also transported by other efflux transporters, especially P-glycoprotein, thus extrapolating BCRP related in vitro data to the in vivo situation may be difficult.

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ABCG2 p.Val508Leu 18464048:250:413

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290 In addition, loss or 339 Table5BCRP(ABCG2)singlenucleotidepolymorphisms.Location,allelefrequencyandfunctionaleffects. Positionin coding sequence Amino acidexchangeLocation Allelefrequency Effect NCBIID ReferenceAfCaJpothers 34G>AVal12MetExon26[1] 4[2] 4[1] 2[2] 2[3] 10[4] 17[1] 18[5] 15[2] See[2]noinfluenceonproteinexpression,localization[6] andtransportintransfectedcells[5-8] rs2231137 noassociationwithmRNAexpressioninventricular andauricularheardtissue[9] increaseddrugaccumulationandlossofdrug resistanceinvitro[4] lossinmembranelocalization[4] higherdrugresistanceinvitro(SN-38)[7] 151G>TGly51CysExon2---Originnotcitedin[10]impactonMTXandporphyrintransportin transfectedcellsunclear[11] 376C>TGln126*Exon40[1]0[1] 0[4] 1[1] 1[5] -expressionoftruncatedproteinintransfectedcells,lossof MTXandporphyrintransportintransfectedcells[11] 421C>AGln141LysExon52[1] 0[2] 1-5 [12] 11[1] 14[2] 10-12 [12] 9[4] 30[1] 26[5] 35[2] See[2,13] 34Chinese[12] lowerproteinexpressioninplacenta[1]rs2231142 noassociationwithmRNAexpressioninheart[9] ormRNAandproteinexpressioninintestine[2] lowerproteinexpressionintransfectedcells[5-7] conflictingdataonmembranelocalizationin transfectedcells[7,8] decreaseinin-vitrotransport[8,14] increaseddrugaccumulationandlossofdrug resistanceinvitro[4,7] higherdiflomotecanplasmalevels[15] nosignificantchangesinirinotecanpharmacokinetics [12,13] greateraccumulationofgefitinib[16]andassociation withgefitinib-induceddiarrhea[17]increaseAUC andcmaxofrosuvastatin[18] (Continued) Table5(Continued) Positionin coding sequence Amino acidexchangeLocation Allelefrequency Effect NCBIID ReferenceAfCaJpothers 445G>CAla149ProExon5---originnotcitedin[6]noinfluenceonproteinexpressionandtransportin transfectedcells[6] 458C>TThr153MetExon5-0[4]--noeffectonMTXandporphyrintransportin transfectedcells[11] 479G>AArg160GlnExon5-0.5c[19]--- 488G>AArg163LysExon5---originnotcitedin[6]noinfluenceonproteinexpressionandtransport intransfectedcells[6] 496C>GGln166GluExon5----noinfluenceonproteinexpressionandtransport intransfectedcells[6] rs1061017 616A>CIle206LeuExon60[2]0[2]0[2]10inHispaniclivers[2], see[2] noinfluenceonmembranelocalizationintransfected cells[20] 623T>CPhe208SerExon6----lowproteinexpressionandnomembrane localizationintransfectedcells,drugresistance similartomock[7] rs1061018 lowproteinexpressionintransfectedcells,lossofMTX andporphyrintransportintransfectedcells[11] 742T>CSer248ProExon7----noinfluenceonproteinexpressionandlocalizationin transfectedcells,drugresistancesimilartoWT[7] rs3116448 decreaseinMTXandporphyrintransportin transfectedcells[11] 805C>TPro269SerExon7---4Chinese[21]noinfluenceonproteinexpressionandtransport intransfectedcells[6] 886G>CAsp296HisExon8-----rs41282401 944-49delAla315del Thr316del Exon8/9----noinfluenceonproteinexpressionandtransport intransfectedcells[5] 1000G>TGlu334*Exon9----expressionoftruncatedproteinintransfectedcells,loss ofMTXandporphyrintransportintransfectedcells[11] rs3201997 341 1291T>CPhe431LeuExon12--0.8[22]-noinfluenceonproteinexpressionandlocalizationin transfectedcells,drugresistancesimilartoWT[7] decreaseinMTXtransportintransfectedcells[11] 1322G>TSer441AsnExon11--0.5[1]-intracellularlocalizationanddecreaseintotalBCRP expressionintransfectedcells[6,7] lowerdrugresistance[7]anddecreaseinMTXand porphyrintransportintransfectedcells[11] 1465T>CPhe489LeuExon12--0.5[1]-noinfluenceonproteinexpressionandlocalizationin transfectedcells[7] 0.8[22] 1515CdelPhe506SerExon13--0.5[1]-- Phe507Leu Val508Leu Met509* 1711A>TPhe571IleExon14-----rs9282571 1723C>TArg575*Exon14-0.5c [19]--- 1768A>TAsn590TyrExon150[2]1[2] 0.3[4] --noinfluenceonmembranelocalizationin transfectedcells[20] 1858G>AAsp620AsnExon16-0.5c [19]--noinfluenceonmembranelocalizationortransport intransfectedcells[8,20] c Population93%Caucasian.

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ABCG2 p.Val508Leu 18464048:290:3489

status: VERIFIED

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95 Histone deacetylase inhibitors rescue newly synthesized transporter proteins and prevent aggresome targeting by disturbing TableÊf;1ߒߙMajor non-synonymous single-nucleotide polymorphisms found in the ABCG2 coding region Allele frequencies presented in this table do not reflect interethnic differences Mutation Position in BCRP Cellular effects of SNP Allele frequency % References 34G>A, V12M (rs2231137) N-terminus Lower expression, no impact on function 0-29.8 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 151G>T, G51C N-terminus Slightly overexpressed, decreased transport activity 0.1 Tamura et al. (2006), Yoshioka et al. (2007) 376C>T, Q126X (rs7255271) NBD No expression, no activity 0-1.7 Tamura et al. (2006), Mizuarai et al. (2004), Itoda et al. (2003), Imai et al. (2002), Kobayashi et al. (2005), Kondo et al. (2004) 421C>A, Q141K (rs2231142) NBD Lower expression, decreased transport activity, substrate specificity altered 0-35.7 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 458C>T, T153 M NBD Slightly lower expression, no impact on function 3.3 Tamura et al. (2006), Mizuarai et al. (2004) 479G>A, R160Q NBD Not determined 0.5 Bosch et al. (2005), Tamura et al. (2006) 496C>G, Q166E (rs1061017) NBD Slightly lower expression, no impact on function 0-1.1 Tamura et al. (2006), Kondo et al. (2004), Yoshioka et al. (2007) 616A>C, I206L (rs12721643) NBD Well expressed, decreased transport activity 0-10.0 Tamura et al. (2006), Zamber et al. (2003), Vethanayagam et al. (2005), Ieiri (2012a) 623T>C, F208 (rs1061018) NBD No expression, no transport activity 0.9-3.9 Tamura et al. (2006) 742T>C, S248P (rs3116448) NBD Well expressed, no transport activity 0.5 Tamura et al. (2006), Yoshioka et al. (2007) 1000G>T, E334X (rs3201997) NBD No expression, no transport activity Not determined Tamura et al. (2006), Ishikawa et al. (2005) 1291T>C F431L ECL1 Lower expression, substrate specificity altered 0.6-0.8 Tamura et al. (2006), Itoda et al. (2003), Yoshioka et al. (2007) 1322G>A, S441 N ECL1 Slightly lower expression, no transport activity 0.5 Tamura et al. (2006), Kobayashi et al. (2005), Kondo et al. (2004) 1465T>C, F489L TM3 Slightly lower expression, no transport activity 0.5-0.8 Tamura et al. (2006), Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F506S TM4 Not determined 0.5 Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F507L 1515delC, V508L 1515delC, M509X 1711T>A, F571I (rs9282571) TM5 Well expressed, substrate specificity altered 0.5 Tamura et al. (2006) 1723C>T, R575X TM5 Not determined 0.5 Tamura et al. (2006) 1768A>T, N590Y (rs34264773) ECL3 Slightly overexpressed, substrate specificity altered 0-9.7 Tamura et al. (2006), Mizuarai et al. (2004), Zamber et al. (2003), Vethanayagam et al. (2005) 1858G>A, D620 N (rs34783571) ECL3 Slightly overexpressed, substrate specificity altered 0-11.1 Tamura et al. (2006), Bosch et al. (2005), Honjo et al. (2002), Vethanayagam et al. (2005) the trafficking along microtubules (Basseville et al. 2012).

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ABCG2 p.Val508Leu 24777822:95:2665

status: NEW

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