Behold BRCA2!

editorial • © 1996 Nature Publishing Group http://www.nature.com/naturegenetics Behold BRCA2 ! Last December, the race to unearth the second hereditary breast and ovarian cancer gene, BRCA2, was concluded. Michael Stratton and colleagues reported that they had identified part of the massive BRCA2 gene on chromosome 13 and identified six mutations in families with breast and ovarian cancer, including some cases of male breast cancer (Nature 378, 789-781; 1995). Not to be outdone, however, scientists at Myriad Genetics, who had isolated BRCAJ in 1994, rushed to submit a patent application for BRCA2 coinciding with the publication of the Nature paper. In remarkably little time, the group and its collaborators had managed - with the help of the 900 kilobases of publicly available genomic DNA sequence - to assemble the complete gene sequence (GenBank accession number U43746). MPIGSKERPTFFEI FKTRCNKADLGPISLNWFEELSSEAPPYNSEPAEESEHKNNNYEPN 60 The fruits of that endeavour are presented by Tavtigian 120 LFKTPQRKPS YNQLASTPI IFKEQGLTLPLYQSPVKELDKFKLDLGRNVPNSRHKSLRTV 180 KTKMDQADDVSCPLLNSCLSESPVVLQCTHVTPQRDKSWCGSLFHTPKFVKGRQTPKHI et al. on page 333, together with the first results of a 24 0 SESLGAEVDPDMSWSSSLATPPTLSSTVLIVRNEEASETVFPHDTTANVKSYFSNHDESL 300 KKNDRFIASVTDSENTNQREAASHGFGKTSGNS FKVNSCKDHIGKSMPNVLEDEVYETVV mutational analysis for the entire coding region. DTSEEDSFSLCFSKCRTKNLQKVRTSKTRKKIFHEANADECEKSKNQVKEKYSFVSEVEP 360 If BRCAJ was a large gene, then BRCA2 is gargantuan. 420 NDTDPLDSNVAHQKPFESGSDKISKEVVPSLACEWSQLTLSGLNGAQMEKIPLLHISSCD QNISEKDLLDTENKRKKDFLTSENSLPRISSLPKSEKPLNEETVVNKRDEEQHLES HTDC 480 The gene encodes a protein of 3,418 amino acids (Strat540 ILAVKQAISGTSPVASSFQGI KKSIFRIRESPKETFNASFSGHMTDPNFKKETEASESGL 600 EIHTVCSQKEDSLCPNLIDNGSWPATTTQNSVALKNAGLISTLKKKTNKFIYAIHDETFY ton et al. presented about 68% of the coding sequence 660 KGKKIPKDQKSELINCSAQFEANAFEAPLTFANADSGLLHSSVKRSCSQNDSEEPTLSLT 720 SSFGTILRKCSRNETCSNN'IVISQDLDYKEAKCNKEKLQLFITPEADSLSCLQEGQCEND in their paper). And while BRCA2 certainly contains 780 PKSKKVSDIKEEVLAAACHPVQHSKVEYSIJTDFQSQKSLLYDHENASTLILTPTSKDVLS 840 NLVMISRGKESYKMSDKLKGNNYESDVELTKNIPMEKNQDVCALNENYKNVELLPPEKYM general similarities to BRCAJ, Tavtigian et al. some 900 RVASPSRKVQFNQNTNLRVIQKNQEETTSI SKITVNPDSEELFSDNENNFVFQVANERNN LALGNTKELHETDLTCVNEPIFKNSTMVLYGDTGDKQATQVS I KKDLVYVLAEENKNSVK 960 report that BRCA2 shows no significant homologies 1020 QHIKMTLGQDLKSDISLNIDKIPEKNNDYMNKWAGLLGPISNHSFGGSFRTASNKEIKLS with BRCAJ or anything else in the database for that 1080 EHNIKKSKMFFKDIEEQYPTSLACVEIVNTLALDNQKKLSKPQSINTVSAHLQSSVWSD 1140 CKNSHITPQMLFSKQDFNSNHNLTPSQKAEITELSTILEESGSQFEFTQFRKPSYILQKS matter. However, results presented on page 298 of this 1200 TFEVPENQMTILKTTSEECRDADLHVIMNAPSIGQVDSSKQFEGTVEIKRKFAGLLKNDC 1260 NKSASGYLTDENEVGFRGFYSAHGTKLNVSTEALQKAVKLFSDIENI S EETSAEVHP I SL issue by the teams of Jeffrey Holt and Roy Jensen at Van1320 SSSKCHDSWSMFKIENHNDKTVSEKNNKCQLILQNNIEMTTGTFVEEITENYKRNTENE 1380 DNKYTAASRNSHNLEFDGSDSSKNDTVCIHKDETDLLFTDQHNICLKLSGQFMKEGNTQI University, and Mary-Claire King at the Univerderbilt 144 0 KEDLSDLTFLEVAKAQEACHGNTSNKEQLTATKTEQNI KDFETSIJTFFQTASGKNISVAK 1500 ESFNKIVNFFDQKPEELHNFSLNSELHSDIRKNKMDILS YEETDIVKHKILKESVPVGTG sity of Washington in Seattle, suggest that there may be NQLVTFQGQPERDEKIKEPTLLGFHTASGKKVKIAKESLDKVKNLFDEKEQGTSEITSFS 1560 1620 HQWAKTLKYREACKDLELACETIEITAAPKCKEMQNSLNNDKNLVSIETVVPPKLLSDNL a significant motif in both BRCA l and BRCA2. The 1680 CRQTENLKTSKSIFLKVKVHENVEKETAKSPATCYTNQSPYSVIENSALAFYTSCS RKTS sequence in question is the granin consensus site (see 174 0 VSQTSLLEAKK\'ILREGIFDGQPERINTADYVGNYLYENNSNSTIAENDKNHLSEKQDTYL 1800 SNSSMSNSYSYHSDEVYNDSGYLSKNKLDSGIEPVLKNVEDQKNTSFSKVISNVKDANAY News & Views on page 223), which is located in the 1860 PQTVNEDICVEELVTSSSPCKNKNAAIKLS I SNSNNFEVGPPAFRIASGKIVCVSHETIK 1920 KVKDIITDSFS KVIKENNENKSKICQTKIMAGCYEALDDSEDILHNS LDNDECSTHSHKV middle ofBRCAl but in the more orthodox C-terminal 1980 FADIQSEEILQHNQNMSGLEKVSKISPCDVSLETSDICKCSIGKLHKSVSSANTCGIFST 2040 ASGKSVQVSDASLQNARQVFSEIEDSTKQVFSKVLFKSNEHSDQLTREENTAIRTPEHLI region of BRCA2. It should be stressed that no func2100 SQKGFSYNVVNSSAFSGFSTASGKQVSILESSLHKVKGVLEEFDLI RTEHSLHYS PTSRQ 2160 NVS KI LPRVDKRNPEHCVNS EMEKTCSKEFKLSNNLNVEGGSSENNHS I KVS PYLSQFQQ tional studies have yet been performed on BRCA2, and 2 220 DKQQLVLGTKVSLVENIHVLGKEQASPKNVKMEI GKTETF SDVPVKTNIEVCSTYSKDSE 2280 indeed the evidence for BRCAl acting as a granin is NYFETEAVEIAKAFMEDDELTDSKLPSHATHSLITCPENEEMVLSNSRIGKRRGE PLILV 2 340 GEPSIKRNLLNEFDR I IENQEKSLKASKSTPDGTIKDRRLFMHHVSLEPITCVPFRTTKE largely circumstantial at this stage. 2400 RQEIQNPNFTAPGQEFLSKSHLYEHLTLEKSSSNLAVSGHPFYQVSATRNEKMRHLI TTG 2460 RPTKVFVPPFKTKSHFHRVEQCVRNINLEENRQKQNIDGHGS DDSKNKINDNEIHQFNKN The Myriad group has also uncovered nine separate 2 52 0 NSNQAAAVTFTKCEEEPLDLITSLQNARDIQDMRIKKKQRQRVFPQPGSLYLAKTST LPR 2580 I SLKAAVGGQVPSACSHKQLYTYGVSKHCI KINSKNAES FQFHTEDYFGKESLWTGKGIQ in different families, out of a total of 18 tested mutations 2640 LADGGWLIPSNDGKAGKEEFYRALCDTPGVDPKLI S R f WVYNHYRWIIWKLAAMECAFPK 2700 EfANRCLSPERVLLQLKYRYDTEIDRSRRSAIKKIMERDDTAAKTLVLCVSDIISLSANI thought likely to be attributable to a flaw in were which 2760 SETSSNKTSSADTQKVAIIELTDGWYAVKAQLDPPLLAVLKNGRLTVGQKIILHGAELVG 2820 S PDACTPLEAPESLMLKI SANSTRPARWYTKLGFFPDPRPFPLPLSSLFSDGGNVGCVDV BRCA2. The results are both good and bad from the per2 880 IIQRAYPIQWMEKTSSGLYIFRNEREEEKEAAKYVEAQQKRLEALFTKIQEEFEEHEENT spective of genetic testing. The bad news is that each of 2 940 TKPYLPSRALTRQQVRALQDGAELYEAVKNAADPAYLEGYFSEEQLRALNNHRQMLNDKK 3000 QAQIQLEIRKAMESAEQKEQGLSRDVTTVWKLRIVSYSKKEKDSVILSIWRPSSDLYS LL the 15 mutations published so far are distinct, apparently 3060 TEGKRYR IYHLATSKSKSKSERANI QLAATKKTQYQQLPVSDEILFQI YQPREPLHFSKF 3120 LDPDFQPSCSEVDLIGFVVSVVKKTGLAPFVYLS DECYNLLAI KFWIDLNEDI I KPHMLI thwarting those who had hoped that genetic predisposi3180 AAS NLQWRPESKSGLLTLFAGDFS VFSAS PKEGHFQE'TFNKMKNTVENIDILCNEAENKL 3240 MHI LHANDPKWSTPTKDCTSGPYTAQIIPGTGNKLLMSS PNCEIYYQSPLS LCMAKRKSV tion at this locus might be confined to a small number of 3300 STPVSAQMTSKSCKGEKEIDDQKNCKKRRALDFLSRLPLPPPVS PICTFVSPAAQKAFQP 3360 PRSCGTKYETPIKKKELNSPQMTPFKKFNEI SLLESNS IADEELALINTQALLSGSTGEK However, virtually all of the mutations witnessed defects. 3418 QFISVSESTRTAPTSSEDYLRLKRRCTTSLIKEQESSQ!\STEECEKNKQDTITTKKYI so far are nonsense or frameshift mutations, which might simplify the task of genetic testing. Who will reap The BRCA2 protein: the putative granin sequence is underlined. The weak region of homology between BRCA1 and BRCA2 noted by Stratton et al. begins the rewards from such tests is another question entirely. at lysine 2064 and extends for 80 residues. Two rival patent applications have been submitted in the United Kingdom and United States. Each group obviously feels it has a case: the E.uropean group was the first to publish evidence that BRCA2 had been cloned, by virtue of _ documenting a handful of mutations in affe (...truncated)