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作者 Stella S, Vitale SR, Martorana F, Massimino M, Pavone G, Lanzafame K, Bianca S, Barone C, Gorgone C, Fichera M, Manzella L
ʻO Stefania Stella, 1,2 Silvia Rita Vitale, 1,2 Federica Martorana, 1,2 Michele Massimino, 1,2 Giuliana Pavone, 3 Katia Lanzafame, 3 Sebastiano Bianca, 4 Chiara Barone, 5 Cristina Gorgone, 6 Marco Fichera, 6, 7 o ke Keʻena Lapaʻau o Manperi, 7 Livia. Catania, Catania, 95123, Italia;2 Center for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania , 95123, Italia; 3 Medical Oncology, AOU Policlinico "G. Rodolico - San Marco", Catania, 95123, Italia; 4 Medical Genetics, ARNAS Garibaldi, Catania, 95123, Italia; 5 Medicine Genetics, ASP, Syracuse, 96100, Italia; 6 Keʻena o nā ʻEpekema Biomedical a me Biotechnology, Ke Kulanui o Catania, Medical Genetics, Catania, Italia, 95123; 7Oasi Research Institute-IRCCS, Troina, 94018, Italia Nā Kamaʻilio: Stefania Stella, kelepona +39 095 378 1946, leka uila [email protected]; [email protected] Pahuhopu: Nā hoʻololi Germline ma BRCA1 a me BRCA2 a me ka maʻi ʻaʻai umauma i hoʻokumu ʻia (BC), ovary (OC) a me nā mea ʻē aʻe e pili ana me ka pilikia o ke ola o ka maʻi ʻaʻai. ʻO ka hoʻāʻo ʻana no ka gene BRCA he kī ia i ka loiloi ʻana i ka pilikia pilikino, a no ka loaʻa ʻana o nā ʻano pale i nā mea lawe olakino a me nā lāʻau lapaʻau i nā maʻi maʻi kanesa. ʻOkoʻa ka nui o nā hoʻololi BRCA1 a me BRCA2 ma nā wahi ʻāina, a ʻoiai aia ka ʻikepili ma nā ʻano pathogenic BRCA i nā ʻohana Sicilian, nele nā ​​​​haʻawina e kuhikuhi pono ana i nā heluna kanaka ma ka hikina o Sicily. ʻO ka pahuhopu o kā mākou noiʻi ʻana, ʻo ia ke noiʻi i ka hanana a me ka hoʻolaha ʻana o nā hoʻololi germline pathogenic BRCA i loko o kahi hui o nā maʻi BC mai ka hikina o Sicily a e loiloi i kā lākou pilina me nā ʻano BC kikoʻī me ka hoʻohana ʻana i ka hoʻonohonoho hanauna hou. ʻO ke alo o nā hoʻololi e pili ana me ka pae tumor a me ka helu proliferation. NĀ HUALOAʻA: Ma keʻano holoʻokoʻa, he 35 mau maʻi (9%) i loaʻa kahi ʻano pathogenic BRCA, 17 (49%) ma BRCA1 a me 18 (51%) ma BRCA2. Loaʻa nā hoʻololi BRCA1 i nā maʻi BC triple-negative, ʻoiai ʻoi aku ka maʻamau o nā hoʻololi BRCA2 i nā maʻi luminal BC. Hoʻohālikelike ʻia me ʻo nā mea lawe ʻole, ʻo nā kumuhana me nā ʻano like ʻole BRCA1 he kiʻekiʻe loa ka pae tumor a me ka helu proliferative. Nā hopena: Hāʻawi kā mākou mau ʻike i kahi ʻike o ke kūlana mutational BRCA i nā poʻe maʻi BC mai ka hikina o Sicily a hōʻoia i ke kuleana o ka loiloi NGS i ka ʻike ʻana i nā poʻe maʻi me ka BC hoʻoilina. Ma keʻano holoʻokoʻa, kūlike kēia mau ʻikepili me nā hōʻike mua e kākoʻo ana i ka nānā ʻana o BRCA no ka pale pono ʻana a me ka mālama ʻana i ka maʻi kanesa i nā mea lawe mutation.
ʻO ke kanesa umauma (BC) ka maʻi ʻino maʻamau ma ka honua holoʻokoʻa a ʻo ia ka maʻi kanesa make loa i nā wahine.1 Ua aʻo nui ʻia nā hiʻohiʻona olaola e hoʻoholo ai i ka prognosis BC a me ke ʻano lapaʻau a ua wehewehe hapa ʻia i ka hala ʻana o ka manawa. ʻO ka ʻoiaʻiʻo, ua hoʻohana ʻia kekahi mau māka pani e hoʻokaʻawale iā BC i nā ʻano molekala like ʻole. ʻO lākou ka estrogen (ER) a/a i ʻole ka progesterone receptor (PgR), ka hoʻonui ʻana o ka human epidermal growth factor receptor 2 (HER2), ka proliferation index Ki-67 a me ka tumor grade (G).2 ʻO ka hui pū ʻana o kēia mau loli i ʻike i nā ʻano BC penei: 1) ʻO nā tumors Luminal, e hōʻike ana i ka hōʻike ʻana o ER a/a i ʻole PgR, i helu ʻia no 75% o BCs. Ua māhele hou ʻia kēia mau tumors i Luminal A, i ka wā i emi ai ʻo Ki-67 ma lalo o 20% a ʻaʻole maikaʻi ʻo HER2, a me Luminal B, i ka wā i like ai ʻo Ki-67 me a ʻoi aku paha ma mua o 20% a i ke alo o ka hoʻonui ʻana o HER2, me ka nānā ʻole i ka proliferation index; 2) ʻO nā tumors HER2+ he ER a me PgR maikaʻi ʻole akā hōʻike i ka hoʻonui ʻana o HER2. ʻO kēia hui he 10% o nā tumors umauma āpau; 3) ʻO ka maʻi ʻaʻai umauma Triple-negative (TNBC), ʻaʻole ia e hōʻike i ka hōʻike ʻana o ER a me PgR a me ka hoʻonui ʻana o HER2, e hōʻike ana ma kahi o 15% o nā maʻi ʻaʻai umauma.2-4
Ma waena o kēia mau ʻano BC, hōʻike ka pae tumor a me ka proliferation index i nā biomarkers cross-sectional e pili pono ana a kūʻokoʻa me ka hoʻouka kaua tumor a me ka prognosis.5,6
Ma waho aʻe o nā hiʻohiʻona olaola i ʻōlelo ʻia ma luna, ua lilo ke kuleana o nā hoʻololi genetic i hoʻoilina ʻia e alakaʻi ana i ka hoʻomohala ʻana o BC i mea nui i nā makahiki i hala iho nei.7 Ma kahi o 1 i loko o 10 mau puʻupuʻu umauma i hoʻoilina ʻia ma muli o nā hoʻololi germline i nā genes kikoʻī.8 ʻElua mau haʻawina epidemiological nui e pili ana i nā wahine he 180,000 i ʻike koke nei i kahi hui o ʻewalu mau genes (ʻo ia hoʻi, ATM, BARD1, BRCA1, BRCA2, CHK2, PALB2, RAD51C, a me RAD51D) ke kuleana nui no ka BC hoʻoilina. Ma waena o kēia mau genes, ʻo BRCA1 a me BRCA2 (i kapa ʻia ma hope aku ʻo BRCA1/2) i hōʻike i ka pilina ikaika loa me ka hoʻomohala ʻana o nā puʻupuʻu umauma.9-12 ʻO ka ʻoiaʻiʻo, ʻo nā mutations germline BRCA1/2 e hoʻonui nui i ka pilikia o ke ola o BC a me nā maʻi ʻino ʻē aʻe, me ka ovarian, prostate, pancreatic, colorectal, a me melanoma. Mai ka makahiki 13 a 80 mau makahiki, ʻo ka nui o ka BC he 72% i nā wahine me kahi ʻano pathogenic BRCA1 (PV) a me 69% i nā wahine me kahi BRCA2. PV.14
ʻO ka mea nui, ua hōʻike ʻia kahi puke hou e pili ana ka pilikia o BC i ke ʻano o PV. ʻO ka ʻoiaʻiʻo, i hoʻohālikelike ʻia me nā ʻano truncating pathogenic, ʻo nā ʻano missense glaring, ʻoi aku hoʻi i ka gene BRCA1, e pili ana me ka emi ʻana o ka pilikia o BC, ʻoi aku hoʻi i nā wahine ʻelemakule.15
ʻO ke alo o BRCA1 a i ʻole BRCA2 PV ua pili pū me nā hiʻohiʻona olaola a me nā clinicopathological like ʻole.16,17 ʻO nā BC e pili ana iā BRCA1 e hōʻeuʻeu pinepine i ka maʻi, hoʻokaʻawale maikaʻi ʻole ʻia, a hoʻonui nui ʻia. ʻO kēia mau puʻupuʻu he triple negative a he ʻōpiopio ko lākou makahiki. ʻO nā puʻupuʻu e kū mai ana i nā maʻi BRCA2-mutated e hōʻike pinepine ana i nā māka waena a maikaʻi ke ʻano a me nā ʻōkuhi proliferative loli. ʻOi aku ka maʻamau o kēia mau puʻupuʻu i ka lumen B a loaʻa pinepine i nā pākeke.16-18 ʻO ka mea nui, ʻo nā mutations ma BRCA1 a me BRCA2 e hoʻonui i ka ʻike i nā lāʻau lapaʻau kikoʻī, me nā paʻakai platinum a me nā lāʻau lapaʻau i kuhikuhi ʻia e like me nā poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
I nā makahiki i hala iho nei, ʻo ka hoʻokō ʻana o ka hoʻonohonoho hanauna hou (NGS) i ka hana lapaʻau ua hiki ai i ka nui o nā maʻi BC ke hana i ka hoʻāʻo molekala no nā syndromes susceptibility cancer, me BRCA1/2.21 I ka manawa like, nā wehewehe ʻana e pili ana i nā pae kikoʻī e pili ana i ka mōʻaukala ʻohana, demographic, a me nā ʻano clinicopathological e ʻike maikaʻi i nā poʻe kūpono i ka hoʻāʻo ʻana o BRCA1/2.22,23 Ma kēia ʻano, ke hōʻiliʻili nei nā hōʻike ma ka nānā ʻana o BRCA1/2 i nā heluna kanaka kikoʻī, e hōʻike ana i nā ʻokoʻa ma waena o nā wahi ʻāina.24-27 ʻOiai aia nā hōʻike e pili ana i ka cohort BC ma ke komohana o Sicily, ʻoi aku ka liʻiliʻi o ka ʻikepili i loaʻa ma ka nānā ʻana o BRCA1/2 ma ka heluna kanaka hikina o Sicily.28,29
Ke wehewehe nei mākou ma aneʻi i nā hopena o ka nānā ʻana o ka germline BRCA1/2 i nā poʻe maʻi BC mai ka hikina o Sicily, e hoʻopili hou ana i ke alo o nā mutations BRCA1 a i ʻole BRCA2 me nā hiʻohiʻona clinicopathological nui o kēia mau tumors.
Ua mālama ʻia kahi noiʻi retrospective ma ke "Center for Experimental Oncology and Hematology" ma ka Halemai Policlinico. Rodolico - San Marco ma Catania. Mai Ianuali 2017 a Malaki 2021, ua kuhikuhi ʻia he 455 mau maʻi me ka umauma a me ka ovarian, melanoma, pancreatic a i ʻole prostate cancer i kā mākou keʻena hoʻokolohua diagnostic molecular no ka hoʻāʻo ʻana i ka genetic BRCA/2. Ua mālama ʻia kēia noiʻi e like me ka Hōʻike o Helsinki, a ua hāʻawi nā mea komo āpau i ka ʻae ʻia ma ke kākau ʻana ma mua o ka nānā ʻana i ka molecular.
Ua loiloi ʻia nā ʻano histological a me nā ʻano olaola (ER, PgR, ke kūlana HER2, Ki-67, a me ka papa) o BC ma ka biopsy koʻikoʻi a i ʻole nā ​​​​​​laʻana ʻoki kino, me ka noʻonoʻo ʻana i nā ʻāpana puʻupuʻu ikaika wale nō. Ma muli o kēia mau ʻano, ua hoʻokaʻawale ʻia nā BC penei: luminal A (ER+ a/a i ʻole PgR+, HER2-, Ki-67<20%), luminal B (ER+ a/a i ʻole PgR+, HER2-, Ki-67≥20%), luminal B-HER2+ (ER a/a i ʻole PgR+, HER2+), HER2+ (ER a me PgR-, HER2+) a i ʻole triple negative (ER a me PgR-, HER2-).
Ma mua o ka loiloi ʻana i ke kūlana mutation BRCA1 a me BRCA2, ua hana kahi hui multidisciplinary e komo pū ana me kahi oncologist, kahi geneticist, a me kahi psychologist i kahi kūkākūkā genetics tumor no kēlā me kēia mea maʻi e hoʻoholo ai i ke alo o BRCA1 a/a i ʻole BRCA1. a i ʻole nā ​​​​kānaka me ka pilikia kiʻekiʻe o PV i loko o ka gene BRCA2. Ua hana ʻia ke koho ʻana o ka mea maʻi e like me nā alakaʻi o ka Italian Society of Medical Oncology (AIOM) a me nā ʻōlelo paipai kūloko a Sicilian.30,31 ʻO kēia mau pae hoʻohālikelike: (i) mōʻaukala ʻohana o nā ʻano pathogenic i ʻike ʻia i nā genes susceptibility (e.g., BRCA1, BRCA2, TP53, PTEN); (ii) nā kāne me BC; (iii) ka poʻe me BC a me OC; (iv) nā wahine me BC <36 mau makahiki, TNBC <60 mau makahiki, a i ʻole bilateral BC <50 mau makahiki; (v) mōʻaukala lapaʻau pilikino o BC <50 mau makahiki a ma ka liʻiliʻi hoʻokahi hoahānau mua: (a) BC <50 mau makahiki; (b) non-mucinous a me non-borderline OC o kēlā me kēia makahiki; (c) bilateral BC; (d) kāne BC; (e) maʻi ʻaʻai pancreatic; (f) ka maʻi ʻaʻai prostate; (vi) ʻelua a ʻoi aku paha Moʻolelo pilikino o BC > 50 mau makahiki a me ka moʻolelo ʻohana o BC, OC, a i ʻole ka maʻi ʻaʻai pancreatic no nā hoahānau he hoahānau mua kekahi i kekahi (me nā hoahānau nona nā hoahānau mua); (vii) Moʻolelo pilikino o OC a me ka liʻiliʻi hoʻokahi hoahānau mua: (a) BC <50 mau makahiki; (b) NOC; (c) bilateral BC; (d) kāne BC; (vii) wahine me ka serous OC kiʻekiʻe.
Ua loaʻa kahi hāpana koko peripheral 20 mL mai kēlā me kēia mea maʻi a hōʻiliʻili ʻia i loko o nā ʻōmole EDTA (BD Biosciences). Ua hoʻokaʻawale ʻia ka DNA genomic mai nā hāpana koko holoʻokoʻa 0.7 mL me ka hoʻohana ʻana i ka QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italia) e like me nā kuhikuhi a ka mea hana a ua hoʻouna ʻia ma o kahi Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). Hana i ka helu ʻana. Hana ʻia ka hoʻonui ʻana i ka pahuhopu a me ka hoʻomākaukau ʻana i ka waihona puke e ka Oncomine™ BRCA Research Assay Chef, mākaukau e hoʻouka ʻia i loko o ka Ion AmpliSeq™ Chef Reagents DL8 Kit no ka hoʻomākaukau ʻana i ka waihona puke automated e like me nā kuhikuhi a ka mea hana. Aia ka pahu i ʻelua mau waihona primer PCR multiplex hiki ke hoʻohana ʻia e aʻo i nā genes BRCA1 (NM_007300.3) a me BRCA2 (NM_000059.3) āpau. I ka pōkole, ua hoʻohui ʻia he 15 µL o kēlā me kēia DNA laʻana i hoʻoheheʻe ʻia (10 ng) i nā papa barcoded no ka hoʻomākaukau ʻana i ka waihona puke a ua hoʻouka ʻia nā reagents a me nā mea hoʻopau āpau ma ka mea hana Ion Chef™. A laila ua hana ʻia ka hoʻomākaukau ʻana i ka waihona puke automated a me ka barcoded sample library pooling ma ka mea hana Ion Chef™. A laila ua loiloi ʻia ka helu o nā waihona puke i hoʻomākaukau ʻia e kahi Qubit® 3.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA) e like me nā kuhikuhi a ka mea hana. ʻO ka hope, ua hui pū ʻia nā waihona puke ma nā lakio equimolar i loko o nā paipu laʻana waihona puke Ion Chef™ (nā paipu barcoded). a ua hoʻouka ʻia ma luna o ka mea hana Ion Chef™. Ua hana ʻia ke kaʻina hana me ka hoʻohana ʻana i kahi mea hana Ion Torrent S5 (Thermo Fisher Scientific) (Thermo Fisher Scientific) me ka hoʻohana ʻana i kahi Ion 510 Chip (Thermo Fisher Scientific). Ua hana ʻia ka loiloi ʻikepili e Amplicon Suite (SmartSeq srl) a me Ion Reporter Software.
Ua hahai nā nomenclature variant āpau i nā alakaʻi o kēia manawa o ka Human Genome Variation Consortium, i loaʻa ma ka pūnaewele (HGVS, http://www.hgvs.org/mutnomen). Ua wehewehe ʻia ke koʻikoʻi lapaʻau o nā ʻano BRCA1/2 me ka hoʻohana ʻana i ka hoʻokaʻawale ʻana o ka International Consortium ENIGMA (Evidence-Based Network for Interpreting Germline Mutant Alleles, https://enigmaconsortium.org/) a me ka nīnau ʻana i nā waihona ʻikepili like ʻole e like me ARUP, BRCAEXCHANGE, ClinVar, IARC_LOVD, a me UMD. Aia i loko o ka hoʻokaʻawale ʻana ʻelima mau ʻano pilikia like ʻole: benign (māhele I), likely benign (māhele II), variant of uncertain significance (VUS, māhele III), likely pathogenic (māhele IV), a me pathogenic (māhele V). Ua kālailai pū ʻo VarSome i ka hopena o nā mutations ma ke ʻano a me ka hana o ka protein, kahi mea hana ʻike me ke komo ʻana i 30 mau waihona ʻikepili.32
No ka hāʻawi ʻana i ke koʻikoʻi lapaʻau hiki i kēlā me kēia VUS, ua hoʻohana ʻia nā algorithms wānana protein computational: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:///genetics.bwh.harvard.edu/pph2/) a me Align-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Ua manaʻo ʻia nā ʻano like ʻole i hoʻokaʻawale ʻia he papa 1 a me 2 he ʻano hihiu.
Ua hōʻoia ka hoʻonohonoho ʻana o Sanger i ke alo o kēlā me kēia ʻano pathogenic. I ka pōkole, ua hoʻolālā ʻia kahi pālua o nā primers kikoʻī no kēlā me kēia ʻano i ʻike ʻia ma ka hoʻohana ʻana i nā kaʻina kuhikuhi gene BRCA1 a me BRCA2 (NG_005905.2, NM_007294.3 a me NG_012772.3, NM_000059.3, kēlā me kēia). No laila, ua hana ʻia ka PCR i kuhikuhi ʻia a ukali ʻia e ka hoʻonohonoho ʻana o Sanger.
Ua hoʻāʻo ʻia nā maʻi i hoʻāʻo maikaʻi ʻole no ka gene BRCA1/2 e ka multiplex ligation-dependent probe amplification (MLPA) e like me nā kuhikuhi a ka mea hana e loiloi i ke alo o nā hoʻonohonoho genomic nui (LGR). I ka pōkole, ua denatured nā laʻana DNA a hiki i ka 60 mau probes BRCA1 a me BRCA2 gene-specific i hoʻohana ʻia, e ʻike ana kēlā me kēia i kahi moʻo DNA kikoʻī ma kahi o 60 mau nucleotides ka lōʻihi. A laila ua kālailai ʻia nā huahana hoʻonui Probe, i haku ʻia me kahi hoʻonohonoho kū hoʻokahi o nā amplicons PCR, e ka electrophoresis capillary a me ka polokalamu Cofalyser.Net me ka hui pū ʻana me nā papa Cofalyser batch-specific kūpono (www.mrcholland.com).
Ua pili nā loli clinicopathological i koho ʻia (histological grade a me Ki-67% proliferation index) me ke alo o BRCA1/2 PV, i helu ʻia me ka hoʻohana ʻana i ka polokalamu Prism v. 8.4 me ka hoʻohana ʻana i ka hoʻāʻo pololei a Fisher me ka manaʻo he koʻikoʻi ka p-value <0.05.
Ma waena o Ianuali 2017 a me Malaki 2021, ua nānā ʻia he 455 mau maʻi no nā hoʻololi germline BRCA1/2. Ua hana ʻia ka hoʻāʻo ʻana i ka hoʻololi ʻana ma ke kikowaena o ka Halemai Policlinico no ka Oncology Experimental a me ka Hematology. Wahi a ke alakaʻi Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.htm, N. 02-Venerdì 10 Ianuali 2020), ʻo Rodolico o Catania - San Marco ”ma ke ʻano holoʻokoʻa, 389 mau maʻi. He maʻi ʻaʻai umauma, 37 maʻi ʻaʻai ovarian, 16 maʻi ʻaʻai pancreatic, 8 maʻi ʻaʻai prostate a me 5 melanoma. Hōʻike ʻia ka hoʻokaʻawale ʻana o nā maʻi e like me ke ʻano o ka maʻi ʻaʻai a me nā hopena loiloi ma ke Kiʻi 1.
Hōʻike ka Kiʻi 1 i kahi pakuhi kahe e hōʻike ana i kahi ʻike holoʻokoʻa o ke aʻo ʻana. Ua hoʻāʻo ʻia nā maʻi me nā ʻōpū umauma, melanoma, pancreatic, prostate, a i ʻole ovarian no nā mutations i loko o nā genes BRCA1 a me BRCA2.
Nā pōkole: PVs, ʻano pathogenic; VUS, ʻano o ke koʻikoʻi maopopo ʻole; WT, kaʻina BRCA1/2 ʻano hihiu.
Ua kālele koho mākou i kā mākou mau haʻawina ma nā hui maʻi ʻaʻai umauma. ʻO ka makahiki waena o nā maʻi he 49 mau makahiki (pae 23-89) a he wahine ka hapa nui (n = 376, a i ʻole 97%).
No kēia mau kumuhana, he 64 (17%) i loaʻa nā hoʻololi BRCA1/2 a he wahine lākou a pau. He kanakolukumamālima (9%) i loaʻa ka PV a he 29 (7.5%) i loaʻa ka VUS. He ʻumikumamāhiku (48.6%) o nā ʻano pathogenic 35 i loaʻa i ka BRCA1 a me 18 (51.4%) ma BRCA2, ʻoiai he 5 VUS i loaʻa i ka BRCA1 (17.2%) a me 24 (82.8%) ma BRCA2 (Nā Kiʻi 1 a me 2). ʻAʻole i loaʻa ka LGR ma ka loiloi MLPA.
Kiʻi 2. Ka nānā ʻana i nā hoʻololi ʻana o BRCA1 a me BRCA2 i loko o 389 mau maʻi maʻi ʻaʻai umauma. (A) Ka hoʻolaha ʻana o nā ʻano pathogenic (PV) (ʻulaʻula), nā ʻano o ke koʻikoʻi maopopo ʻole (VUS) (ʻalani), a me WT (polū) i loko o 389 mau maʻi maʻi ʻaʻai umauma; (B) 389 mau maʻi maʻi ʻaʻai umauma He kanakolukūmālima (9%) i loaʻa nā ʻano pathogenic BRCA1/2 (PV). I waena o lākou, he 17 (48.6%) nā mea lawe BRCA1 PV (ʻulaʻula ʻeleʻele) a he 18 (51.4%) nā mea lawe BRCA2 (ʻulaʻula māmā); (C) 29 (7.5%) o 389 mau kumuhana i lawe iā VUS, 5 (17.2%) nā genes BRCA1 (ʻalani ʻeleʻele) a me 24 (82.8%) nā genes BRCA2 (ʻalani māmā).
Nā pōkole: PVs, ʻano pathogenic; VUS, ʻano o ke koʻikoʻi maopopo ʻole; WT, kaʻina BRCA1/2 ʻano hihiu.
Ua noiʻi hou mākou i ka laha ʻana o nā ʻano molekala BC i nā poʻe maʻi me BRCA1/2 PV. ʻO ka hoʻolaha ʻana ua komo pū me 2 (5.7%) luminal A, 15 (42.9%) luminal B, 3 (8.6%) luminal B-HER2+, 2 (5.7%) HER2+ a me 13 (37.1%) mau maʻi TNBC. Ma waena o nā maʻi BRCA1-positive, 5 (29.4%) i loaʻa iā luminal B BC, 2 (11.8%) i loaʻa i ka maʻi HER2+, a he 10 (58.8%) i loaʻa iā TNBC. ʻO nā puʻupuʻu me ka ʻole o nā hoʻololi BRCA1 he luminal A a i ʻole luminal B-HER2+ (Kiʻi 3). I loko o ka hui liʻiliʻi BRCA2-positive, 10 (55.6%) nā puʻupuʻu he luminal B, 3 (16.7%) he luminal B-HER2+, 3 (16.7%) TNBC a me 2 (11.1%) he luminal A (Kiʻi 3). ʻAʻohe puʻupuʻu HER2+. aia i loko o kēia hui. No laila, ʻike nui ʻia nā hoʻololi ʻana o BRCA1 i nā poʻe maʻi TNBC, ʻoiai ʻo nā hoʻololi ʻana o BRCA2 ka mea nui i nā poʻe lumen B.
Kiʻi 3 Ka laha ʻana o nā ʻano maʻi ʻaʻai umauma i nā poʻe maʻi me nā ʻano pathogenic ma BRCA1 a me BRCA2. Hōʻike nā histograms i ka hoʻolaha ʻana o nā BRCA1- (ʻulaʻula ʻeleʻele) a me BRCA2- (ʻulaʻula māmā) PV ma waena o nā ʻano molekala o nā poʻe maʻi ʻaʻai umauma. Hōʻike nā helu i hōʻike ʻia i loko o kēlā me kēia pahu i ka pakeneka o nā poʻe maʻi me BRCA1 a me BRCA2 PV no kēlā me kēia ʻano maʻi ʻaʻai umauma.
Nā pōkole: PVs, ʻano pathogenic; HER2+, human epidermal growth factor receptor 2 positive; TNBC, maʻi ʻaʻai umauma triple-negative.
Ma hope mai, ua loiloi mākou i ke ʻano a me ka localization gene o BRCA1 a me BRCA2 PVs. Ma BRCA1 PV, ua ʻike mākou i 7 mau ʻano nucleotide hoʻokahi (SNVs), 6 holoi ʻana, 3 duplications a me 1 hoʻokomo. Hoʻokahi wale nō mutation (c.5522delG) e hōʻike ana i kahi ʻike hou. ʻO ka BRCA1 PV maʻamau i ʻike ʻia i nā kumuhana ʻelua ʻo c.5035_5039delCTAAT. Pili kēia hoʻololi i ka holoi ʻana o ʻelima mau nucleotides (CTAAT) ma BRCA1 exon 15, e hopena ana i ka pani ʻana o ka amino acid leucine e tyrosine ma codon 1679, a ma muli o kahi translation frameshift me kahi codon stop ʻē aʻe i wānana ʻia e alakaʻi i ka truncation protein premature. ʻIke ʻia nā hoʻololi ʻē aʻe a pau i hoʻokahi hihia wale nō. ʻIke ʻia, aia kekahi o nā PV i hōʻike ʻia ma ka ʻāpana splice site consensus (c.4357+1G>T) (Papa 1).
E pili ana i ka BRCA2 PV, ua ʻike mākou i 6 mau holoi ʻana, 6 SNV a me 2 mau hana pālua. ʻAʻohe o nā loli i loaʻa he mea hou. ʻEkolu mau mutations i hana hou ʻia i loko o kā mākou heluna kanaka, ʻo c.428dup a me c.8487+1G>A i ʻike ʻia i 3 mau kumuhana, a ukali ʻia e c.5851_5854delAGTT i loaʻa i ʻelua mau hihia. ʻO ka hoʻololi ʻana o c.428dup e pili ana i ka hana hou ʻana o C ma ka exon 5 o BRCA2, i wānana ʻia e hoʻopili i kahi protein truncated, non-functional. ʻO ka mutation c.8487+1G>A e hana ʻia ma ka ʻāpana intronic o BRCA2 intron 19 (± 1,2) a hoʻopilikia i ka ʻaelike splicing consensus, e hopena ana i ka splicing i hoʻololi ʻia e hopena ana i ka protein maʻamau a ʻaʻohe paha. ʻO ka c.5851_5854delAGTT pathogenic variant ma muli o ka holoi ʻana o 4-nucleotide mai nā kūlana nucleotide 5851 a i 5854 i ka coding exon 10 o ka gene BRCA2 a hopena i he frameshift translational me kahi codon hoʻōki ʻē aʻe i wānana ʻia (p.S1951WfsTer). ʻIke ʻia, e like me ka mea i hōʻike mua ʻia, ua ʻike ʻia nā hoʻololi ʻelua c.631G>A a me c.7008-2A>T i ka mea maʻi like.34 ʻO ka mutation mua e pili ana i ka hoʻololi ʻana o adenosine (A) ma BRCA2 exon 7 me kahi guanine (G) i loaʻa ka nucleotide e hopena ana i ka hoʻololi ʻana o valine i isoleucine ma codon 211, isoleucine ʻO ka waikawa Amino kahi waikawa amino me nā waiwai like loa. Hoʻopilikia kēia hoʻololi i ka splicing mRNA maʻamau. Aia ka lua o ka variant ma kahi ʻāpana intronic a hopena i kahi pani pālua A i thymine (T) ma mua o ka exon 13 o ka gene encoding BRCA2. ʻO ka hoʻololi c.7008-2A>T hiki ke hoʻopuka i nā transcripts he nui o nā lōʻihi like ʻole. Eia kekahi, ma ka hui o BRCA2 PVs, 4 o 18 mau hoʻololi (22.2%) he intronic.
A laila ua palapala mākou i nā hoʻololi ʻino o BRCA1/2 i nā kikowaena hana a me nā wahi e hoʻopaʻa ai i ka protein (Kiʻi 4). I loko o ka gene BRCA1, aia ka 50% o nā PV ma ka ʻāpana hui kanesa umauma (BCCR), ʻoiai he 22% o nā hoʻololi i loaʻa ma ka ʻāpana hui kanesa ovarian (OCCR) (Kiʻi 4A). I ​​loko o ka BRCA2 PV, aia ka 35.7% o nā ʻano like ʻole ma ka ʻāpana BCCR a he 42.8% o nā hoʻololi i loaʻa ma ka OCCR (Kiʻi 4B). Ma hope, ua loiloi mākou i kahi o PV i loko o nā kikowaena protein BRCA1 a me BRCA2. No ka protein BRCA1, ua loaʻa iā mākou ʻekolu PV i loko o nā kikowaena loop a me coiled coil, a me ʻelua mau hoʻololi ma ka kikowaena BRCT (Kiʻi 4A). No ka protein BRCA2, ua palapala ʻia nā PV 4 i ka ʻāpana hana hou BRC, ʻoiai ua ʻike ʻia nā loli intronic 3 a me 3 exonic i nā kikowaena oligo/oligosaccharide-binding (OB) a me tower (T) (Kiʻi 4B).
Kiʻi 4 Hōʻike kiʻi o nā protein BRCA1 a me BRCA2 a me ka localization o nā ʻano pathogenic. Hōʻike kēia kiʻi i ka hoʻolaha ʻana o nā ʻano pathogenic BRCA1 (A) a me BRCA2 (B) i nā maʻi maʻi ʻaʻai umauma. Hōʻike ʻia nā mutations Exonic i ka uliuli, ʻoiai ua hōʻike ʻia nā ʻano intronic i ka ʻalani. Hōʻike ke kiʻekiʻe o ka pā i ka helu o nā hihia. Hōʻike ʻia nā protein BRCA1 a me BRCA2 a me kā lākou mau kikowaena hana. (A) Loaʻa i ka protein BRCA1 kahi loop domain (RING) a me kahi nuclear localization sequence (NLS), kahi coiled-coil domain, kahi SQ/TQ cluster domain (SCD), a me kahi BRCA1 C-terminal domain (BRCT). (B) Loaʻa i ka protein BRCA2 ʻewalu mau hana hou BRC, kahi DNA-binding domain me kahi helical domain (Helical), ʻekolu oligonucleotide/oligosaccharide-binding (OB) folds, kahi hale kiaʻi (T), a me An NLS ma ka ʻaoʻao C. Hōʻike ʻia nā wahi i kapa ʻia ʻo Breast Cancer Cluster Region (BCCR) a me Ovarian Cancer Cluster Region (OCCR) ma lalo. *Hōʻike i nā mutations e hoʻoholo ai i ka hoʻōki nā codon
A laila ua noiʻi mākou i nā hiʻohiʻona clinicopathological BC e pili paha me ke alo o BRCA1/2 PV. Loaʻa nā moʻolelo lapaʻau piha no 181 mau maʻi BRCA1/2-maikaʻi ʻole (nā mea lawe ʻole) a me nā mea lawe āpau (n = 35). Aia kahi pilina ma waena o ka nui o ka hoʻonui ʻana o ka maʻi puʻupuʻu a me ke ʻano.
Ua helu mākou i ka hoʻolaha ʻana o Ki-67 ma muli o ka median o kā mākou cohort (25%, pae <10-90%). Ua wehewehe ʻia nā kumuhana me Ki-67 < 25% he "Ki-67 haʻahaʻa", ʻoiai ʻo nā kānaka me nā waiwai ≥ 25% i manaʻo ʻia he "Ki-67 kiʻekiʻe". Ua loaʻa nā ʻokoʻa Ki-67 koʻikoʻi (p<0.01) ma waena o nā mea lawe ʻole a me nā mea lawe BRCA1 PV (Kiʻi 5A).
Kiʻi 5 Pilina o Ki-67 me ka hoʻokaʻawale ʻana o ka papa i nā wahine maʻi ʻaʻai umauma me a me ka ʻole o BRCA1 a me BRCA2 PVs.(A) Boxplot e hōʻike ana i nā waiwai waena Ki-67 i loko o 181 mau maʻi BC ʻaʻole lawe ʻia e kūʻē i nā maʻi BRCA1 (18) a i ʻole BRCA2 (17) PV. Ua manaʻo ʻia he koʻikoʻi nā waiwai P ma lalo o 0.5.(B) ʻO ka Histogram e hōʻike ana i ka hoʻokaʻawale ʻana o nā maʻi maʻi ʻaʻai BC i nā hui papa histological (G2 a me G3) e like me ke kūlana mutation BRCA1 a me BRCA2 (nā kumuhana WT, nā mea lawe BRCA1 a me BRCA2 PVs).
Pēlā nō, ua nānā mākou inā pili ka pae tumor me ke alo o BRCA1/2 PV. ʻOiai ʻaʻohe G1 BC i loko o kā mākou heluna kanaka, ua māhele mākou i nā maʻi i ʻelua mau pūʻulu (G2 a i ʻole G3). E like me nā hopena Ki-67, ua hōʻike ka loiloi i kahi pilina koʻikoʻi ma waena o ka pae tumor a me ka mutation BRCA1, me kahi hapa kiʻekiʻe o nā tumors G3 i nā mea lawe BRCA1 i hoʻohālikelike ʻia me nā mea lawe ʻole (p <0.005) (Kiʻi 5B).
Ua hiki i nā holomua i ka ʻenehana hoʻonohonoho DNA ke hiki i nā holomua i manaʻo ʻole ʻia ma ka hoʻāʻo ʻana i ka genetic BRCA1/2, me nā hopena koʻikoʻi no nā poʻe maʻi me ka mōʻaukala ʻohana o ka maʻi kanesa. A hiki i kēia lā, ua ʻike ʻia a hoʻokaʻawale ʻia ma kahi o 20.000 mau ʻano BRCA1/2 e like me ka American Society of Medical Genetics 35 a me ka ʻōnaehana ENIGMA.35,36 Ua ʻike maopopo ʻia he ʻokoʻa loa ka spectrum mutational BRCA1/2 ma nā wahi ʻāina.37 I loko o Italia, ʻo ka helu o BRCA1/2 PVs mai 8% a 37%, e hōʻike ana i ka loli ākea o loko o ka ʻāina.38,39 Me ka heluna kanaka kokoke i 5 miliona, ʻo Sicily ka ʻāina ʻelima nui loa ma Italia e pili ana i ka nui o ka poʻe noho. ʻOiai aia ka ʻikepili ma ka hoʻolaha ʻana o BRCA1/2 ma ke komohana o Sicily, ʻaʻohe hōʻike nui ma ka ʻaoʻao hikina o ka mokupuni.
ʻO kā mākou noiʻi kekahi o nā hōʻike mua e pili ana i ka hanana o BRCA1/2 PV i nā poʻe maʻi BC ma ka hikina o Sicily.28 Ua kālele mākou i kā mākou loiloi ma BC, ʻoiai ʻo ia ka maʻi maʻamau loa i kā mākou cohort.
I ka hoʻāʻo ʻana i nā maʻi 389 BC, ua lawe ʻia he 9% o BRCA1/2 PVs, i hoʻokaʻawale like ʻia ma waena o BRCA1 a me BRCA2. Ua kūlike kēia mau hopena me nā mea i hōʻike mua ʻia ma ka heluna kanaka Italia.28 ʻO ka mea hoihoi, he 3% (13/389) o kā mākou cohort he kāne. ʻOi aku ke kiʻekiʻe o kēia helu ma mua o ka mea i manaʻo ʻia no ka maʻi ʻaʻai umauma kāne (1% o nā BC āpau),40 e hōʻike ana i kā mākou koho ʻana o nā heluna kanaka ma muli o ka pilikia mutation BRCA1/2. Eia naʻe, ʻaʻohe o kēia mau kāne i hoʻomohala i kahi BRCA1/2 PV, no laila he mau moho lākou no ka loiloi molekala hou aʻe e kāpae i ke alo o nā mutations maʻamau ʻole e like me PALB2, RAD51C a me D, a me nā mea ʻē aʻe. Ua kiʻi ʻia nā ʻano like ʻole o ke koʻikoʻi maopopo ʻole i loko o 7% o nā kumuhana i ʻike ʻia ai ʻo BRCA2 VUS. ʻOiai kēia hopena e kūlike me nā hōʻike mua.28,41,42
I ko mākou kālailai ʻana i ka hoʻolaha ʻana o nā ʻano molekala BC i nā wahine mutant BRCA1/2, ua hōʻoia mākou i nā pilina i ʻike ʻia ma waena o TNBC a me BRCA1 PV (58.8%) a ma waena o luminal B BC a me BRCA2 PV (55.6%).16,43 ʻO nā puʻupuʻu luminal A a me HER2+ i nā mea lawe BRCA1 a me BRCA2 PV e kūlike me ka ʻikepili palapala e kū nei.16,43
A laila e kālele ana mākou i ke ʻano a me kahi o ka BRCA1/2 PV. I loko o kā mākou cohort, ʻo ka BRCA1 PV maʻamau ʻo c.5035_5039delCTAAT. ʻOiai ʻo Incorvaia et al. ʻaʻole i wehewehe i kēia ʻano like ʻole i kā lākou cohort Sicilian, ua hōʻike nā mea kākau ʻē aʻe he germline BRCA1 PV.34 Ua loaʻa kekahi mau BRCA1 PV i kā mākou cohort - eg c.181T>G, c.514del, c.3253dupA a me c.5266dupC - i ʻike ʻia ma Sicily.28 No kēia mau mea, ʻelua mau mutations hoʻokumu BRCA1 (c.181T>G a me c.5266dupC) i loaʻa pinepine ʻia i nā Iudaio Ashkenazi o Eastern a me Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian a me German), 44,45 a, ma ʻAmelika Hui Pū ʻIa a me Argentina, ua wehewehe hou ʻia ʻo ia he "recurrent germline variant" i nā maʻi Italia me BC a me OC. Ua ʻike mua ʻia ka variant 34c.514del i 8 mau maʻi maʻi umauma mai ka ʻākau o Sicily ma Palermo a me Messina. ʻO ka mea hoihoi, ʻoiai ʻo Incorvaia et al. ua loaʻa ka ʻano c.3253dupA i kekahi mau ʻohana ma Catania.28 ʻO nā BRCA2 PVs i hōʻike nui ʻia ʻo c.428dup, c.5851_5854delAGTT a me ka ʻano intronic c.8487+1G>A, i hōʻike ʻia ma nā kikoʻī hou aku 28 i kahi maʻi ma Palermo me c.428dup, c.5851_5854delAGTT PV i ʻike ʻia ma nā hale ma ke komohana ʻākau o Sicily, ʻo ia hoʻi ma nā wahi ʻo Trapani a me Palermo, ʻoiai ʻo c.5851_5854delAGTT PV i ʻike ʻia ma nā hale ma ke komohana ʻākau o Sicily. ʻOi aku ka maʻamau o ka ʻano 8487+1G>A i nā kumuhana mai Messina, Palermo, a me Caltanissetta.28 Rebbeck et al. ua wehewehe mua ʻia ka hoʻololi ʻana o c.5851_5854delAGTT ma Colombia.37 Ua loaʻa kekahi BRCA2 PV ʻē aʻe, c.631+1G>A, i nā maʻi BC a me OC mai Sicily (Agrigento, Siracusa lāua ʻo Ragusa).28 ʻO ka mea nui, ua ʻike mākou i ka noho pū ʻana o ʻelua mau ʻano BRCA2 (BRCA2 c.631G>A a me c.7008-2A>T) i loko o ka maʻi hoʻokahi, a mākou i manaʻo ai ua hoʻokaʻawale ʻia ma ke ʻano cis, e like me ka mea i hōʻike mua ʻia e like me kēlā.34,46 ʻIke pinepine ʻia kēia mau hoʻololi BRCA2 ma ka ʻāina Italia a ua ʻike ʻia e hoʻolauna i nā codons hoʻōki mua, e hoʻopilikia ana i ka splicing RNA ʻelele a ke kumu o ka hāʻule ʻana o ka protein BRCA2.47,48
Ua hoʻopaʻa pū mākou i nā BRCA1 a me BRCA2 PVs ma nā ʻāpana OCCR a me BCCR i manaʻo ʻia o nā kikowaena protein a me nā genes. Ua wehewehe ʻia kēia mau ʻāpana e Rebbeck et al. ma ke ʻano he mau wahi pilikia no ka hoʻomohala ʻana i ka maʻi ʻaʻai ovarian a me ka umauma.49 Eia nō naʻe, ke hoʻopaʻapaʻa nei nā hōʻike e pili ana i ka pilina ma waena o kahi o nā ʻano germline a me ka pilikia o ka maʻi ʻaʻai umauma a ovarian paha.28,50-52 I loko o ko mākou heluna kanaka, aia ka nui o nā BRCA1 PVs ma ka ʻāpana BCCR, ʻoiai ʻo BRCA2 PVs i loaʻa nui ma ka ʻāpana OCCR. Eia naʻe, ʻaʻole hiki iā mākou ke loaʻa i kekahi pilina ma waena o nā ʻāpana OCCR a me BCCR i manaʻo ʻia a me nā hiʻohiʻona BC. Hiki paha kēia ma muli o ka palena o ka nui o nā maʻi me nā hoʻololi BRCA1/2. Mai kahi hiʻohiʻona kikowaena protein, ua hoʻolaha ʻia nā BRCA1 PVs ma ka protein holoʻokoʻa, a ʻoi aku ka makemake o nā hoʻololi BRCA2 ma ka ʻāpana hana hou BRC.
ʻO ka mea hope loa, ua hoʻopili mākou i nā hiʻohiʻona clinicopathological BC me BRCA1/2 PV. Ma muli o ka palena o nā maʻi i hoʻokomo ʻia, ua loaʻa iā mākou kahi pilina koʻikoʻi ma waena o Ki-67 a me ka pae tumor. ʻOiai ke hoʻopaʻapaʻa nei ka loiloi a me ka wehewehe ʻana o Ki-67, he ʻoiaʻiʻo nō e pili ana nā helu proliferative kiʻekiʻe me ka hoʻonui ʻia o ka pilikia o ka hoʻi hou ʻana o ka maʻi a me ka emi ʻana o ke ola. I kēia lā, ʻo ka palena no ka hoʻokaʻawale ʻana ma waena o "kiʻekiʻe" a me "haʻahaʻa" Ki-67 he 20%. Eia naʻe, ʻaʻole pili kēia paepae i kā mākou heluna kanaka maʻi mutation BRCA1/2, nona ka waiwai waena Ki-67 o 25%. Hiki ke wehewehe ʻia kēia ʻano i nā helu Ki-67 kiʻekiʻe e ka laha ʻana i kā mākou luminal B a me TNBC cohorts, kahi i loaʻa ai nā tumors luminal A liʻiliʻi. Eia nō naʻe, ke hōʻike nei kekahi mau hōʻike e hiki i kahi cutoff Ki-67 kiʻekiʻe (25-30%) ke hoʻokaʻawale maikaʻi i nā maʻi e like me kā lākou prognosis.53,54 Mai nā hopena o kā mākou loiloi, ʻaʻole ia he mea kupanaha kahi pilina koʻikoʻi. Hana ʻia ma waena o ke kiʻekiʻe Ki-67 a me nā pae a me ke alo o ʻO BRCA1 PV. ʻO ka ʻoiaʻiʻo, ʻo nā puʻupuʻu e pili ana iā BRCA1 he ʻano maʻamau o TNBC a hōʻike i nā hiʻohiʻona ʻoi aku ka ikaika.16,17
I ka hopena, hāʻawi kēia haʻawina i kahi hōʻike e pili ana i ke kūlana mutational o BRCA1/2 i loko o kahi cohort BC mai ka hikina o Sicily. Ma keʻano holoʻokoʻa, kūlike kā mākou mau ʻike me nā hōʻike mua, ma ke ʻano o ka prevalence mutation a me nā hiʻohiʻona clinicopathological ma BC. Pono nā haʻawina hou aʻe i nā heluna nui o nā maʻi BRCA1/2-mutant BC, e like me ka hoʻohana ʻana i ka multigenome expanded mutational analysis, e loiloi i ke alo o nā PV i ʻokoʻa a emi pinepine ʻole ma mua o BRCA1/2. E ʻae kēia i ka ʻike a me ka hoʻokele kūpono o ka nui o nā kumuhana i hoʻonui ʻia ka pilikia o ka maʻi kanesa ma muli o nā mutations genetic.
Ua hōʻoia mākou ua kau inoa nā mea maʻi i ka ʻae ʻia e hoʻokuʻu i kā lākou mau laʻana puʻupuʻu me ka ʻike ʻole ʻia no nā kumu noiʻi. Ua kau inoa nā mea maʻi a pau i ka ʻae ʻia i kākau ʻia e like me ka Hōʻike ʻo Helsinki. Wahi a ke kulekele o AOU Policlinico "G.Rodolico - S.Marco", ua hoʻokuʻu ʻia kēia haʻawina mai ka loiloi pono no ka mea ua hana ʻia ka loiloi BRCA1/2 e like me ka hana lapaʻau a ua hāʻawi nā mea maʻi a pau i ka ʻae ʻia i kākau ʻia. Ua ʻae pū nā mea maʻi i ka hoʻohana ʻana i kā lākou ʻikepili no nā kumu noiʻi.
Mahalo mākou iā Polopeka Paolo Vigneri no kāna kōkua ʻana i ka mālama ʻana i nā maʻi maʻi ʻaʻai umauma e like me ke noi a ke Kōmike Hoʻopono.
Hōʻike ʻo Federica Martorana i nā hanohano mai Istituto Gentili, Eli Lilly, Novartis, Pfizer. Ke hōʻike nei nā mea kākau ʻē aʻe ʻaʻohe hakakā o ka hoihoi i kēia hana.
1. Sung H, Ferlay J, Siegel RL, et al. Nā Heluhelu Kanesa Honua 2020: Kuhi ʻo GLOBOCAN i ka nui a me ka make ʻana o 36 mau maʻi kanesa ma 185 mau ʻāina a puni ka honua. CA Cancer J Clin.2021;71(3):209-249.doi: 10.3322/caac.21660