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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, 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 ʻo Catperi, 7 Livia ʻo Catania, 7 ʻO ke Keʻena Lapaʻau ʻo Cat. ania, 95123, Italia;2 Center for Experimental Oncology and Hematology, AOU Policlinico "G.Rodolico - San Marco", Catania , 95123, Italia;3 Kauka 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 'Oihana o Biomedical a me Biotechnology Sciences, University of Catania, Medical Genetics, Catania, Italia, 95123;7Oasi Research Institute-IRCCS, Troina, 94018, Italia Nā Kūkākūkā: Stefania Stella, tel +39 095 378 1946, leka uila [email protected];[email protected] Ke kumu: Germline mutations in BRCA1 and BRCA2 and found breast cancer (BC), ovary (OC) and other related with a life risk of cancer.Tsting for the BRCA gene is key to assessing individual risk, as well as no preventing ways in health carriers and tailoring treatments in cancer patients.The prevalence of BRCA1 and BRCA2 a broadcast ʻO nā ʻohana lian, nā haʻawina e kuhikuhi pono ana i ka poʻe ma ka hikina Sicily. ic variant, 17 (49%) ma BRCA1 a me 18 (51%) ma BRCA2.BRCA1 hoʻololi i laha i ka triple-negative BC maʻi, akā, BRCA2 mutations mea maʻamau i luminal BC maʻi. cily a hōʻoia i ke kuleana o ka nānā ʻana o NGS i ka ʻike ʻana i nā maʻi me ka BC hoʻoilina. ʻO ka holoʻokoʻa, ua kūlike kēia mau ʻikepili me nā hōʻike mua e kākoʻo ana i ka screening BRCA no ka pale pono ʻana a me ka mālama ʻana i ka maʻi kanesa i nā mea lawe mutation.
ʻO ka maʻi kanesa o ka umauma (BC) ka maʻi maʻi maʻamau a puni ka honua a ʻo ka maʻi maʻi make loa i nā wahine.1 Ua aʻo nui ʻia nā hiʻohiʻona ola e hoʻoholo ai i ka prognosis BC a me nā ʻano hana lapaʻau a wehewehe ʻia i ka manawa. ration index Ki-67 and tumor grade (G) .2 ʻO ka hui pū ʻana o kēia mau mea hoʻololi i ʻike i nā ʻano BC penei: 1) Luminal tumors, e hōʻike ana i ka ER a / a i ʻole PgR expression, helu ʻia no 75% o BCs. me ka nānā ʻole i ka index proliferation;2) HER2+ maʻi ʻo ER a me PgR maikaʻi ʻole akā hōʻike i ka hoʻonui HER2. ʻO kēia pūʻulu he 10% o nā maʻi umauma umauma;3) Triple-negative breast cancer (TNBC), ʻaʻole i hōʻike i ka ER a me PgR expression a me ka hoʻonui ʻana o HER2, e pili ana i ka 15% o nā maʻi maʻi umauma.2-4
Ma waena o kēia mau BC subtypes, tumor grade and proliferation index e hōʻike ana i nā biomarkers cross-sectional i pili pololei a kūʻokoʻa me ka aggressiveness tumor a me ka prognosis.5,6
Ma waho aʻe o nā hiʻohiʻona olaola i ʻōlelo ʻia ma mua, ua lilo ka hana o nā hoʻololi genetic hoʻoilina e alakaʻi ana i ka hoʻomohala ʻana o BC i nā makahiki i hala. ʻO LB2, RAD51C, a me RAD51D) ke kuleana nui no ka hoʻoilina BC. Ma waena o kēia mau genes, BRCA1 a me BRCA2 (ma hope i kapa ʻia ʻo BRCA1/2) i hōʻike i ka pilina ikaika loa me ka ulu ʻana o nā maʻi maʻi umauma. Mai ka makahiki 13 a hiki i ka 80 makahiki, he 72% ka huina o BC i na wahine me ka BRCA1 pathogenic variant (PV) a me 69% i na wahine me BRCA2 PV.14
ʻOiaʻiʻo, ua hōʻike ʻia kahi paʻi hou e pili ana ka pilikia BC i ke ʻano o ka PV. ʻOiaʻiʻo, ke hoʻohālikelike ʻia me nā ʻano ʻoki ʻoki pathogenic, pili nā ʻano like ʻole o ka missense, ʻoi aku hoʻi i ka gene BRCA1, me ka hōʻemi o ka pilikia o BC, ʻoi aku i nā wahine kahiko.
ʻO ka hiki ʻana o BRCA1 a i ʻole BRCA2 PV ua pili pū me nā hiʻohiʻona biological a me clinicopathological like ʻole.16,17 BRCA1-pili BC maʻa mau i ka hoʻoikaika kino, maikaʻi ʻole ka ʻokoʻa, a me ka hoʻonui nui. ʻoi aku ka maʻamau o nā maʻi maʻi i loko o ka lumen B a loaʻa pinepine i nā poʻe ʻelemakule.16-18 ʻO ka mea nui, hoʻonui ʻia ka ʻike ʻana o BRCA1 a me BRCA2 i nā lāʻau lapaʻau kūikawā, me nā paʻakai platinum a me nā lāʻau lapaʻau e like me ka poly (ADP-ribose) polymerase inhibitors (PARPi).19,20
I loko o nā makahiki i hala iho nei, ua hiki i ka hoʻokō ʻana i ka hoʻokō ʻana o ka hanauna hou (NGS) i ka hoʻomaʻamaʻa hoʻomaʻamaʻa ua hiki i ka heluna nui o nā maʻi BC e hana i ka hoʻāʻo molecular no nā syndromes susceptibility maʻi kanesa, me BRCA1/2.21 Concurrently, wehewehe e pili ana i nā koina kikoʻī e pili ana i ka mōʻaukala ʻohana, demographic, a me clinicopathological hiʻohiʻona e ʻike maikaʻi ai i ka poʻe pono no BRCA1/2 hōʻike. i nā heluna kanaka kūikawā, e hōʻike ana i nā ʻokoʻa ma nā ʻāpana ʻāina.24–27 ʻOiai aia nā hōʻike e pili ana i ka cohort BC ma ke komohana o Sicily, ʻoi aku ka liʻiliʻi o nā ʻikepili i loaʻa ma BRCA1 / 2 screening i ka heluna hikina Sicily.28,29
Hōʻike mākou ma aneʻi i nā hopena o ka germline BRCA1/2 screening i nā maʻi BC mai Sicily hikina, e hoʻopili hou i ka hiki ʻana o BRCA1 a i ʻole BRCA2 mutations me nā hiʻohiʻona clinicopathological nui o kēia mau ʻōpū.
Ua hana ʻia kahi noiʻi retrospective ma ka "Center for Experimental Oncology and Hematology" ma ka Halemai Policlinico.Rodolico - San Marco ma Catania.Mai Ianuali 2017 a Malaki 2021, he 455 mau mea maʻi me ka umauma a me ka ovarian, melanoma, pancreatic a i ʻole prostate cancer i alakaʻi ʻia no kā mākou BRCA / kiʻi hoʻonaʻauao genetic hoʻokolohua i alakaʻi ʻia i kā mākou BRCA/sinki genetic hoʻokolohua. , a ua hāʻawi nā mea komo a pau i ka ʻae ʻike i kākau ʻia ma mua o ka hoʻāʻo ʻana i ka molekala.
ʻO nā hiʻohiʻona o ka mōʻaukala a me ke ola kino (ER, PgR, HER2 kūlana, Ki-67, a me ka papa) o BC ua loiloi ʻia ma ka biopsy kumu a i ʻole nā ​​​​mea hoʻokalakupua, me ka noʻonoʻo ʻana i nā mea maʻi maʻi ʻino wale nō. ≥20%), luminal B-HER2+ (ER a/a i ʻole PgR+, HER2+), HER2+ (ER a me PgR-, HER2+) a i ʻole ʻekolu ʻino (ER a me PgR-, HER2-).
Ma mua o ka loiloi ʻana i ke kūlana mutation BRCA1 a me BRCA2, ua alakaʻi kahi hui multidisciplinary me ka oncologist, geneticist, a me ka psychologist i kahi kūkākūkā genetics tumor no kēlā me kēia maʻi e hoʻoholo ai i ka loaʻa ʻana o BRCA1 a/a i ʻole BRCA1.aiʻole nā ​​kānaka me ka pilikia nui o ka PV ma ka BRCA2 gene. Ua hanaʻia ka koho maʻi e like me nā alakaʻi alakaʻi o ka Italian Society of Medical Oncology (AIOM) a me nā'ōlelo aʻo Sicilian kūloko.30,31 Aia kēia mau pae hoʻohālikelike: (i) ka moʻoleloʻohana o nāʻano pathogenic iʻikeʻia i nā genes susceptibility (eg, BRCA1, BRCA2, TP53, PTEN);(ii) nā kāne me BC;(iii) ka poe me BC a me OC;(iv) wahine me BC <36 makahiki, TNBC <60 makahiki, a i ole bilateral BC <50 makahiki;(v) ka moʻolelo olakino pilikino o BC <50 makahiki a ma kahi o hoʻokahi pili degere mua: (a) BC < 50 makahiki;(b) OC non-mucinous a me ka palena ʻole o kēlā me kēia makahiki;(c) bilateral BC;(d) kāne BC;(e) ka ma'i 'a'ai pancreatic;(f) ka maʻi maʻi prostate;(vi) ʻelua a ʻoi aʻe ka moʻolelo pilikino o BC > 50 makahiki a me ka moʻolelo ʻohana o BC, OC, a i ʻole ka maʻi maʻi pancreatic no nā ʻohana i pili i ka pae mua o kekahi i kekahi (me nā ʻohana me ia he ʻohana degere mua);(vii) Ka moʻolelo pilikino o OC a ma ka liʻiliʻi hoʻokahi pili degere mua: (a) BC <50 makahiki;(b) NOC;(c) bilateral BC;(d) kāne BC;(vii) wahine me ka OC serous kiʻekiʻe.
Ua loaʻa ka 20 mL o ke koko peripheral mai kēlā me kēia maʻi a hōʻiliʻili ʻia i loko o nā paipu EDTA (BD Biosciences). Ua hoʻokaʻawale ʻia ka DNA Genomic mai 0.7 mL mau hōʻike koko holoʻokoʻa me ka hoʻohana ʻana i ka QIAsymphony DSP DNA Midi kit Isolation Kit (QIAGEN, Hilden, Italia) e like me nā ʻōlelo a ka mea hana a hele i loko o kahi Qubitor ® 3. ka helu ana.Hana ʻia ka hoʻonui ʻana a me ka hoʻomākaukau hale 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 hale waihona puke e like me nā ʻōlelo a ka mea hana. , 15 µL o kēlā me kēia DNA hāpana i hoʻoheheʻe ʻia (10 ng) i hoʻohui ʻia i nā papa barcoded no ka hoʻomākaukau ʻana i ka waihona a ua hoʻouka ʻia nā reagents a pau a me nā mea hoʻohana ma ka mea Ion Chef™. ʻO nā ʻōlelo aʻoaʻo a ka mea hana. ʻO ka hope, ua hui ʻia nā hale waihona puke i nā ratio equimolar ma Ion Chef™ hale waihona puke sample tubes (barcoded tubes) a hoʻouka ʻia ma luna o ka mea hana Ion Chef™. Ua hana ʻia ka Sequencing me ka hoʻohana ʻana i kahi mea hana Ion Torrent S5 (Thermo Fisher Scientific) (Thermo Fisher Scientific) me ka hoʻohana ʻana i ka Ion 510 (Thermo Fisher Scientific). Seq srl) a me Ion Reporter Software.
Ua hahai nā ʻano inoa ʻokoʻa a pau i nā alakaʻi o kēia manawa o ka Human Genome Variation Consortium, i loaʻa ma ka pūnaewele (HGVS, http://www.hgvs.org/mutnomen). HANGE , ClinVar, IARC_LOVD, a me UMD. Aia i loko o ka ho'oka'awale 'ana i 'elima mau 'ano pilikia: benign (kekahi I), he maikai paha (ka helu II), 'ano like 'ole o ka mana'o maopopo 'ole (VUS, wae'ano III), pathogenic paha (ka helu IV), a me ka pathogenic (ka helu V).
No ka hāʻawi ʻana i ke koʻikoʻi koʻikoʻi i kēlā me kēia VUS, ua hoʻohana ʻia nā algorithm wānana protein computational penei: MUTATION TASTER, 33 PROVEAN-SIFT (http://provean.jcvi.org/index.php), POLYPHEN-2 (http:// /genetics.bwh.harvard.edu/pph2/) a me Align-aghvgd. ʻO nā ariants i hoʻokaʻawale ʻia ma ka papa 1 a me 2 ua manaʻo ʻia he ʻano hihiu.
Ua hōʻoia ʻo Sanger sequencing i ka loaʻa ʻana o kēlā me kēia ʻano pathogenic. ʻO ka pōkole, ua hoʻolālā ʻia kahi pālua o nā primers kikoʻī no kēlā me kēia ʻano i ʻike ʻia ma o ka hoʻohana ʻana i ka BRCA1 a me ka BRCA2 gene reference sequences (NG_005905.2, NM_007294.3 a me NG_012772.3, NM_000059.3.
ʻO nā maʻi i hoʻāʻo maikaʻi ʻole no ka BRCA1/2 gene ua hoʻāʻo ʻia e ka multiplex ligation-dependent probe amplification (MLPA) e like me nā ʻōlelo a ka mea hana e loiloi i ka hiki ʻana o nā hoʻonohonoho hou genomic nui (LGR). ʻO ka pōkole, ua denatured nā hōʻailona DNA a hiki i ka 60 BRCA1 a me BRCA2 gene-specific amplide probes i hoʻohana ʻia i nā kikoʻī kikoʻī kikoʻī kikoʻī o ka DNA 6. ʻO nā huahana, kahi pūʻulu kūikawā o nā amplicons PCR, a laila nānā ʻia e ka electrophoresis capillary a me ka polokalamu Cofalyser.Net i hui pū me nā papa Cofalyser kikoʻī kūpono (www.mrcholland.com).
ʻO nā ʻano koho clinicopathological i koho ʻia (ka helu histological a me ka Ki-67% proliferation index) i pili me ka loaʻa ʻana o BRCA1/2 PV, i helu ʻia me ka polokalamu Prism v. 8.4 me ka hoʻohana ʻana i ka hoʻāʻo pololei a Fisher e manaʻo ana he mea nui ka p-value <0.05.
Ma waena o Ianuali 2017 a me Malaki 2021, ua nānā ʻia nā mea maʻi 455 no nā mutations germline BRCA1/2. Ua hana ʻia ka hoʻāʻo ʻana ma ka Halemai Policlinico Center for Experimental Oncology and Hematology. E like me ke alakaʻi Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.hìna02. ), ka Rodolico o Catania - San Marco" holoʻokoʻa, 389 nā mea maʻi He maʻi maʻi umauma, 37 ovarian cancer, 16 pancreatic cancer, 8 prostate cancer a me 5 melanoma.Hōʻike ʻia ka māhele ʻana o nā maʻi e like me ke ʻano maʻi maʻi a me nā hopena o ka nānā ʻana ma ke Kiʻi 1.
Hōʻike ka Figure 1 i kahi pakuhi kahe e hōʻike ana i kahi hiʻohiʻona o ke aʻo ʻana. Ua hoʻāʻo ʻia nā maʻi me ka umauma, melanoma, pancreatic, prostate, a i ʻole ovarian tumors no ka hoʻololi ʻana i nā genes BRCA1 a me BRCA2.
Nā pōkole: PVs, pathogenic variant;VUS, ʻokoʻa o ka manaʻo maopopo ʻole;WT, ʻano ʻāhiu BRCA1/2 kaʻina.
Ua koho mākou i kā mākou noiʻi ʻana i nā cohorts maʻi maʻi umauma. Ua loaʻa i ka poʻe maʻi he makahiki waena o 49 mau makahiki (pae 23-89) a he wahine ka nui (n=376, a i ʻole 97%).
ʻO kēia mau kumuhana, 64 (17%) he BRCA1 / 2 mutations a he wahine a pau. He kanakolukumamālima (9%) i PV a me 29 (7.5%) i VUS. He ʻumikūmāhiku (48.6%) o nā ʻano pathogenic 35 i loaʻa i BRCA1 a me 18 (51.4%) i BRCA2, aʻo BRCA12% i loaʻa i ka BRCA2 (8%) a me BRCA12 (12%). kumu 1 a me 2). ʻAʻole i loaʻa ʻo LGR i ka loiloi MLPA.
Kiʻi 2. Ka nānā ʻana i nā hoʻololi BRCA1 a me BRCA2 i nā maʻi maʻi maʻi umauma 389. (A) Ka mahele ʻana o nā ʻano pathogenic (PV) (ʻulaʻula), nā ʻano like ʻole o ka manaʻo maopopo ʻole (VUS) (ʻalani), a me WT (blue) i nā maʻi maʻi maʻi umauma 389;(B) 389 maʻi maʻi maʻi maʻi umauma He kanakolukumamālima (9%) i loaʻa iā BRCA1 / 2 pathogenic variants (PVs). Ma waena o lākou, 17 (48.6%) nā mea lawe BRCA1 PV (ʻulaʻulaʻeleʻele) a me 18 (51.4%) nā mea lawe BRCA2 (ulaula māmā);(C) 29 (7.5%) o nā kumuhana 389 i lawe i ka VUS, 5 (17.2%) BRCA1 genes (ʻalani ʻeleʻele) a me 24 (82.8%) BRCA2 genes (ʻalani māmā).
Nā pōkole: PVs, pathogenic variant;VUS, ʻokoʻa o ka manaʻo maopopo ʻole;WT, ʻano ʻāhiu BRCA1/2 kaʻina.
Ua noiʻi hou mākou i ka nui o nā subtypes mole BC i nā poʻe maʻi me BRCA1 / 2 PV. ʻO ka hāʻawi ʻana i ka 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%) i nā maʻi BRTNBC 19. , 2 (11.8%) i loaʻa i ka maʻi HER2 +, a me 10 (58.8%) i loaʻa iā TNBC. ʻO nā puʻupuʻu me ka ʻole o BRCA1 nā hoʻololi ʻana he luminal A a i ʻole luminal B-HER2 + (Figure 3). I loko o ka BRCA2-positive subgroup, 10 (55.6%) nā maʻi maʻi he luminal B, 3 (16.7%) a me luminal B, 3 (16.7%) a me 16.7% TN (16.7%). %) he luminal A (Figure 3). ʻAʻohe maʻi maʻi HER2 + i loko o kēia hui. No laila, ʻoi aku ka nui o ka hoʻololi ʻana o BRCA1 i nā maʻi TNBC, akā ʻo ka hoʻololi ʻana o BRCA2 ka mea nui i nā lumen B poʻe.
Kiʻi 3 Ka laha ʻana o nā subtypes o ka umauma maʻi maʻi i nā maʻi me nā ʻano pathogenic i BRCA1 a me BRCA2. Nā hiʻohiʻona e hōʻike ana i ka puʻunaue ʻana o BRCA1- (ʻulaʻula ʻulaʻula) a me BRCA2- (ʻulaʻula ʻulaʻula) ma waena o nā ʻano subtypes o nā maʻi maʻi maʻi umauma. ʻO nā helu i hōʻike ʻia i loko o kēlā me kēia pahu e hōʻike ana i ka pakeneka o nā maʻi me BRCA1 a me BRCA2 PV subtype no kēlā me kēia maʻi maʻi kanesa umauma.
Nā pōkole: PVs, pathogenic variant;HER2+, kanaka epidermal growth factor receptor 2 maikaʻi;TNBC, triple-negative breast cancer.
Ma hope iho, ua loiloi mākou i ke ʻano a me ka gene localization 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. .Keia hoololi e pili ana i ka holoiʻia o elima nucleotides (CTAAT) ma BRCA1 exon 15, ka hopena i ka hoololi ana o ka amino acid leucine e tyrosine ma codon 1679, a ma muli o ka unuhi frameshift me ka wanana 'ē aʻe pani codon alakai i premature protein truncation.All 'ē aʻe hoʻololi i ikeia ma ka wahi splic wale nō. .4357+1G>T) (Papa 1).
E pili ana i ka BRCA2 PV, ua ʻike mākou i 6 holoi ʻia, 6 SNV a me 2 mau hoʻololi. ma ka 5 o BRCA2, wanana e hoʻopaʻa i ka pūmua i ʻoki ʻia, ʻaʻole hana. ʻO ka c.8487+1G>A hoʻololi ʻia i loko o ka ʻāpana intronic o BRCA2 intron 19 (± 1,2) a hoʻopili i ke kaʻina consensus splicing, ka hopena i ka hoʻololi ʻana i ka splicing e hopena i ka abnormal a i ʻole ka ʻano protein4del-AG585. deletion from nucleotide positions 5851 to 5854 in the coding exon 10 of the BRCA2 gene and results in a translational frameshift with a alternative stop codon (p.S1951WfsTer) Notaly, as previously reported, both holterations c.631G>A and c.7008-2A. (A) ma BRCA2 exon 7 me ka guanine (G) i loko o ka nucleotide e hopena i ka hoʻololi ʻana o valine i isoleucine ma codon 211, isoleucine Amino acid he amino acid me nā waiwai like loa. Hoʻopili kēia hoʻololi i ka splicing mRNA maʻamau. Aia ka lua o ka ʻano i loko o kahi intronic māhele a loaʻa i kahi pālua A i ka thymine BR120 ex. 8-2A> Hiki i ka hoʻololi T ke hoʻohua i nā kope 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 hoʻopaʻa mākou i ka BRCA1 / 2 deleterious mutations i loko o nā kikowaena hana a me nā ʻāpana hoʻopaʻa protein (Fig. 4). Ma ka BRCA1 gene, 50% o nā PV i loaʻa i loko o ka ʻāpana o ka maʻi kanesa o ka umauma (BCCR), ʻoiai ʻo 22% o nā mutations aia ma ka ovarian cancer cluster region (OCCR) (Fig. 4A). Loaʻa ka % o nā hoʻololi i ka OCCR (Fig. 4B). Ma hope, ua loiloi mākou i kahi o PV i loko o ka BRCA1 a me BRCA2 protein domains. i loko o ka oligo/oligosaccharide-binding (OB) a me ka hale kiaʻi (T) domains (Figure 4B).
Hōʻike 4 Schematic representation of BRCA1 and BRCA2 proteins and localization of pathogenic variants. This figure show the distribution of BRCA1 (A) and BRCA2 (B) pathogenic variants in breast cancer patient. he nuclear localization sequence (NLS), he coiled-coil domain, he SQ/TQ cluster domain (SCD), a he BRCA1 C-terminal domain (BRCT). (B) Aia ka BRCA2 protein i ewalu BRC hou ana, he DNA-binding domain me ka helical domain (Helical), ekolu oligonucleotide/oligosaccharide-binding (AOligosaccharide-binding) domains (AOligosaccharide-binding), a me ka CLS. hōʻike ʻia ka ʻāpana ʻĀpana ʻĀpana maʻi maʻi umauma (BCCR) a me Ovarian Cancer Cluster Region (OCCR) ma lalo.
A laila ua noiʻi mākou i nā hiʻohiʻona clinicopathological BC e pili ana me ka loaʻa ʻana o BRCA1 / 2 PV. Loaʻa nā moʻolelo lapaʻau piha no 181 BRCA1 / 2-negative maʻi (nā mea lawe ʻole) a me nā mea lawe āpau (n = 35). Aia kahi pilina ma waena o ka piʻi ʻana o ka maʻi tumora a me ka papa.
Ua helu mākou i ka hāʻawi ʻana o Ki-67 ma muli o ka median o kā mākou cohort (25%, range <10-90%). ʻO nā kumuhana me Ki-67 < 25% ua wehewehe ʻia ʻo "Ki-67 haʻahaʻa", aʻo nā poʻe me nā waiwai ≥ 25% i manaʻo ʻia ʻo "Ki-67 kiʻekiʻe". g. 5A).
Kiʻi 5 Ka hoʻopili ʻana o Ki-67 me ka hāʻawi ʻana i ka papa i nā wahine maʻi maʻi umauma me ka BRCA1 a me BRCA2 PVs a me ka ʻole. G2 a me G3) e like me ke kūlana mutation BRCA1 a me BRCA2 (nā kumuhana WT, nā mea lawe PV BRCA1 a me BRCA2).
Pēlā nō, ua nānā mākou inā pili ka papa tumora me ka loaʻa ʻana o BRCA1 / 2 PV. Mai ka hele ʻole ʻana o G1 BC i ko 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 ʻia ka loiloi i ka hoʻohālikelike nui ʻana ma waena o ka papa tumora a me ka mutation BRCA1, me ka hapa kiʻekiʻe o nā maʻi maʻi ʻole G3 i hoʻohālikelike ʻia me nā maʻi maʻi ʻole G3 (P50gurer ma BRCA50). B ).
ʻO nā holomua i ka ʻenehana hoʻokaʻina DNA ua hiki i ka holomua mua ʻole i ka BRCA1/2 genetic hoʻokolohua, me nā hopena koʻikoʻi no nā poʻe maʻi me ka mōʻaukala ʻohana o ka maʻi kanesa. ʻO Italia, ka helu o BRCA1 / 2 PVs mai ka 8% a hiki i ka 37%, e hōʻike ana i ka variability intra-country ākea.38,39 Me ka heluna kanaka kokoke i 5 miliona, ʻo Sicily ka ʻelima o ka ʻāina nui loa ma Italia ma ke ʻano o ka heluna o nā kānaka.
ʻO kā mākou noiʻi kekahi o nā hōʻike mua e pili ana i ka loaʻa ʻana o BRCA1 / 2 PV i nā maʻi BC ma Sicily hikina.28 Ua kālele mākou i kā mākou loiloi ma BC, ʻoiai ʻo kēia ka maʻi maʻamau i kā mākou cohort.
I ka ho'āʻoʻana i nā maʻi 389 BC, 9% lawe BRCA1 / 2 PVs, i puunaue like ma waena o BRCA1 a me BRCA2. Ua kūlike kēia mau hualoaʻa me nā mea i hōʻike muaʻia ma ka Italian population.28 ʻO ka hoihoi, 3% (13/389) o kā mākou cohort he kāne. ʻOi aku ka kiʻekiʻe o kēia helu ma mua o ka mea i manaʻo ʻia no ka maʻi maʻi maʻi kāne kāne (1% o ka nui o ka BRCA hoʻi i koho ʻia i ka 40 o nā BCs a pau i koho ʻia). Ua hoʻomohala kekahi o kēia mau kāne i kahi BRCA1/2 PV, no laila ua lilo lākou i mau moho no ka hoʻoponopono molekala hou e kāpae i ka hiki ʻana mai o nā hoʻololi like ʻole e like me PALB2, RAD51C a me D, a me nā mea ʻē aʻe.
I ko makou anaana i ka mahele ana o BC molecular subtypes ma BRCA1 / 2 mutant wahine, ua hooiaio makou i na hui i ikeia 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 ka luminal A a me ka HER2 + maʻi maʻi i BRCA1 a me BRCA2 PV nā mea lawe palapala 16.
A laila nānā mākou i ke ʻano a me kahi o ka BRCA1/2 PV. Ma kā mākou hui, ʻo ka BRCA1 PV maʻamau ʻo c.5035_5039delCTAAT. ʻOiai ʻo Incorvaia et al.ʻAʻole i wehewehe i kēia ʻano ʻokoʻa i kā lākou cohort Sicilian, ua hōʻike nā mea kākau ʻē aʻe ma ke ʻano he germline BRCA1 PV.34 Ua loaʻa kekahi mau BRCA1 PVs i loko o kā mākou cohort - e laʻa c.181T>G, c.514del, c.3253dupA a me c.5266dupC - i ʻike ʻia ma kēia mau ʻano ʻelua o ka BRCA1, ʻelua. .5266dupC) loaʻa maʻamau ma Ashkenazi Iudaio o ka Hikina a me Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian a me Kelemānia ), 44,45 a, i loko o ʻAmelika Hui Pū ʻIa a me Argentina, ua wehewehe koke ʻia ʻo ia he "recurrent germline variant" i nā maʻi Italia me BC a me OC.The 34c. ʻoi aku ka maikaʻi, ʻo Incorvaia et al.ua loaʻa ka c.3253dupA ʻokoʻa i kekahi mau ʻohana ma Catania.28 ʻO ka BRCA2 PVs i hōʻike ʻia he c.428dup, c.5851_5854delAGTT a me ka ʻokoʻa intronic c.8487+1G>A, i hōʻike ʻia ma nā kikoʻī hou aku 28 i kahi mea maʻi ma Palermo me c.5858dup PV, c.5858dup. ma ke komohana ʻākau o Sicily, ma ka ʻāina ʻo Trapani a me Palermo, ʻoiai c.5851_5854delAGTT PV i ʻike ʻia ma nā hale ma ke komohana ʻākau o Sicily.i wehewehe mua ʻia i ka c.5851_5854delAGTT hoʻololi i Colombia.37 ʻO kekahi BRCA2 PV, c.631+1G>A, ua loaʻa ma BC a me OC maʻi mai Sicily (Agrigento, Siracusa a me Ragusa). 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 Ke nānā pinepine ʻia kēia mau hoʻololi BRCA2 uble ma ka ʻāina ʻItalia a ua ʻike ʻia e hoʻolauna i nā codons hoʻomaha mua, e hoʻopili ana i ka ʻelele RNA splicing a hoʻopau i ka protein BRCA2.47,48
Hoʻopili pū mākou i nā BRCA1 a me BRCA2 PVs i nā wahi o OCCR a me BCCR o nā kikowaena protein a me nā genes. Ua wehewehe ʻia kēia mau ʻāina e Rebbeck et al.he mau wahi pilikia no ka hooulu ana i ka ovarian a me ka ma'i ma'i ma'i ma'i.49 Eia na'e, ua ho'opa'apa'a ka 'ike e pili ana i ka pilina ma waena o ka wahi o ka germline a me ka umauma a i 'ole ka ma'i 'a'ai. s a me nā hiʻohiʻona BC. No ka palena palena o nā maʻi me nā hoʻololi BRCA1 / 2. Mai kahi hiʻohiʻona domain protein, ua puʻunaue ʻia nā BRCA1 PV ma ka protein holoʻokoʻa, a ʻike ʻia nā hoʻololi BRCA2 ma ka BRC repeat domain.
ʻO ka hope, ua hoʻopili mākou i nā hiʻohiʻona clinicopathological BC me BRCA1 / 2 PV. Ma muli o ka helu palena o nā maʻi i hoʻokomo ʻia, ʻike wale mākou i kahi pilina koʻikoʻi ma waena o Ki-67 a me ka papa tumora. 20%. Akā naʻe, ʻaʻole pili kēia paepae i kā mākou BRCA1 / 2 mutation maʻi heluna kanaka, nona ka median Ki-67 waiwai o 25%. ʻO kēia ʻano i nā kiʻekiʻe Ki-67 kiʻekiʻe hiki ke wehewehe ʻia e ka prevalence i kā mākou luminal B a me TNBC cohorts, kahi liʻiliʻi luminal A maʻi maʻi i loaʻa. 53,54 Mai nā hualoaʻa o kā mākou hōʻuluʻuluʻana,ʻaʻole he mea kupanaha ka hoʻopiliʻana.
I ka hopena, hāʻawi kēia haʻawina i kahi hōʻike e pili ana i ke kūlana mutational o BRCA1 / 2 i kahi cohort BC mai Sicily hikina. ʻO ka holoʻokoʻa, ua kūlike kā mākou ʻike me nā hōʻike preexisting, ʻelua ma ke ʻano o ka prevalence mutation a me nā hiʻohiʻona clinicopathological i BC. nt ma mua o BRCA1 / 2. E ʻae kēia i ka ʻike a me ka hoʻokele pono ʻana i ka piʻi ʻana o ka helu o nā kumuhana i ka piʻi nui ʻana o ka maʻi kanesa ma muli o nā hoʻololi genetic.
Ua hōʻoia mākou ua kau inoa nā poʻe maʻi i ka ʻae ʻike e hoʻokuʻu i kā lākou mau maʻi tumora me ka inoa ʻole no ka noiʻi noiʻi. kā lākou ʻikepili no ka noiʻi ʻana.
Mahalo mākou iā Prof. Paolo Vigneri no kāna kōkua ʻana i ka mālama ʻana i nā poʻe maʻi maʻi maʻi maʻi e like me ke noi ʻana e ke Komite Ethics.
Hōʻike ʻo Federica Martorana i ka hanohano mai Istituto Gentili, Eli Lilly, Novartis, Pfizer. ʻO nā mea kākau ʻē aʻe e hōʻike nei ʻaʻohe paio o ka hoihoi i kēia hana.
1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: Hoʻohālikelike ʻo GLOBOCAN i ka ulu a me ka make o 36 mau maʻi maʻi maʻi ma 185 mau ʻāina a puni ka honua.