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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 '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 for preventing ways in health carriers and tailoring treatments in cancer patients.The prevalence of BRCA1 and BRCA2 data varies Ma luna o nā ʻohana Sicilian, nele nā haʻawina e pili ana i ka heluna kanaka ma Sicily hikina. ʻO ka pahuhopu o kā mākou noiʻi ʻana e noiʻi i ka hanana a me ka hāʻawi ʻana o BRCA pathogenic germline hoʻololi i loko o kahi pūʻulu o nā maʻi BC mai Sicily hikina a e loiloi i kā lākou hui ʻana me nā ʻano BC kikoʻī me ka hoʻohana ʻana i ka hanauna hou aku. 35 mau maʻi (9%) he BRCA pathogenic ʻano like ʻole, 17 (49%) ma BRCA1 a me 18 (51%) ma BRCA2.BRCA1 hoʻololi i laha i loko o triple-negative BC maʻi, oiai BRCA2 mutations mea maʻamau i luminal BC maʻi. ʻO ka nānā ʻana i ke kūlana mutational BRCA i nā maʻi BC mai Sicily hikina a hōʻoia i ke kuleana o ka nānā ʻana o NGS i ka ʻike ʻana i nā maʻi me ka BC hoʻoilina.
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 ʻO nā hiʻohiʻona ola e hoʻoholo ai i ka prognosis BC a me ka hana lapaʻau ua aʻo nui ʻia a wehewehe ʻia i ka manawa. amplification, proliferation index Ki-67 and tumor grade (G).2 ʻO ka hui pū ʻana o kēia mau ʻano hoʻololi i ʻike i nā ʻano BC penei: 1) Luminal tumors, e hōʻike ana i ka ER a me / a i ʻole PgR hōʻike, helu ʻia no 75% o BC. i mua o ka hoʻonui ʻana o HER2, 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 CHK2, PALB2, RAD51C, a me RAD51D) ke kuleana nui no ka BC hoʻoilina. pancreatic, colorectal, a me melanoma. 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 hele ʻana o BRCA1 a i ʻole BRCA2 PV ua pili pū me nā hiʻohiʻona biological a me clinicopathological like ʻole.16,17 BRCA1-pili BCs maʻamau i ka maʻi hōʻeha, maikaʻi ʻole ka ʻokoʻa, a me ka hoʻonui nui. proliferative indices.ʻO kēia mau maʻi koko ka mea maʻamau i loko o ka lumen B a maʻamau i nā poʻeʻelemakule.16-18 No ka mea, hoʻonui ka hoʻololiʻana i BRCA1 a me BRCA2 i ka noʻonoʻo i nā lāʻau kūikawā, e like me nā paʻakai platinum a me nā lāʻau lapaʻau e like me poly(ADP-ribose) polymerase inhibitors (PARPi).19,20
I nā makahiki i hala iho nei, ua hiki i ka hoʻokō ʻana i ka hoʻokō ʻana o ka hanauna hou (NGS) i ka hoʻomaʻamaʻa lapaʻau i hiki ai i ka nui o nā maʻi BC ke hana i ka hoʻāʻo molecular no nā syndromes susceptibility maʻi maʻi, me BRCA1/2.21 I ka manawa like, nā wehewehe e pili ana i ka moʻolelo o ka ʻohana, demographic, a me clinicopathological hiʻohiʻona e ʻike maikaʻi ai i nā hōʻike kūpono i kēia BRCA1/2. ʻO ka nānā ʻana o BRCA1 / 2 i nā heluna kikoʻī, e hōʻike ana i nā ʻokoʻa ma waena o nā ʻāpana ʻāina.24–27 ʻOiai aia nā hōʻike e pili ana i ka cohort BC ma ke komohana ʻo Sicily, ʻoi aku ka liʻiliʻi o nā ʻikepili i loaʻa ma BRCA1 / 2 screening ma ka hikina Sicily population.28,29
Hōʻike mākou ma aneʻi i nā hopena o ka nānā ʻana i ka germline BRCA1/2 i nā mea 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 / 2 genetic hoʻokolohua i alakaʻi ʻia i kā mākou BRCA / 2 genetic hoʻokolohua. o Helsinki, a ua hāʻawi nā mea komo a pau i ka ʻae ʻike i kākau ʻia ma mua o ka ʻike molecular.
Ua helu ʻia nā hiʻohiʻona mōʻaukala a me ke ola kino (ER, PgR, HER2 kūlana, Ki-67, a me ka papa) o BC ma ka biopsy kumu a i ʻole nā mea hoʻoheheʻe ʻana, me ka noʻonoʻo ʻana i nā ʻāpana tumo koʻikoʻi wale nō. Ki-67≥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 ka Italian Society of Medical Oncology (AIOM) guidelines and local Sicilian recommendations.30,31 Aia kēia mau pae hoʻohālikelike: (i) ka moʻolelo o kaʻohana 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) non-mucinous a me ka palena palena ʻole OC 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 kahi o 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 ʻo Genomic DNA mai 0.7 mL mau hōʻailona 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® 3.0. MA, USA) Hana i ka helu helu. 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 kuhikuhi a ka mea hana. Genes.Piki, 15 µL o kēlā me kēia DNA sample diluted (10 ng) i hoʻohui ʻia i nā papa barcoded no ka hoʻomākaukau ʻana i ka hale waihona puke a ua hoʻouka ʻia nā reagents a pau a me nā mea hoʻohana ma ka mea Ion Chef™. ʻO Scientific, Waltham, MA, USA) e like me nā kuhikuhi a ka mea hana. ʻO ka hope, ua hui ʻia nā hale waihona puke i nā ratio equimolar i loko o Ion Chef™ library sample tubes (barcoded tubes) a hoʻouka ʻia ma ka mea hana Ion Chef™. (Thermo Fisher Scientific). Ua hana ʻia ka ʻikepili e Amplicon Suite (SmartSeq 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). ARUP, BRCAEXCHANGE , ClinVar, IARC_LOVD, a me UMD. Aia i loko o ka papa helu ʻelima mau ʻano pilikia ʻē aʻe: maikaʻi (māhele I), maikaʻi paha (māhele II), ʻano like ʻole o ka manaʻo maopopo ʻole (VUS, ʻāpana III), pathogenic (māhele IV), a me ka pathogenic (ka helu V). 30 waihona.32
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-GVGD (http://agvgd.hci.utah.edu/agvgd_input.php). Ua manaʻo ʻia nā ʻano like ʻole ma ke ʻano he papa 1 a me 2.
Ua hōʻoia ʻo Sanger sequencing i ka hele ʻana o kēlā me kēia ʻano pathogenic. ʻO ka pōkole, ua hoʻolālā ʻia kahi pālua o nā primers kikoʻī no kēlā me kēia ʻano ʻike ʻia ma o ka hoʻohana ʻana i ka BRCA1 a me BRCA2 gene reference sequences (NG_005905.2, NM_007294.3 a me NG_012772.3, NM_000059.3). ke kaʻina ʻana.
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 hele ʻana o nā genomic rearrangements nui (LGR). ʻO nā huahana hoʻonui lōʻihi.Probe, i loaʻa i kahi pūʻulu kūʻokoʻa o nā amplicons PCR, a laila ua kālailai ʻia e ka electrophoresis capillary a me nā 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 ʻana o Sicilian (http://www.gurs.regione.sicilia.it/Indicep1.hìna.it/Indicep1.hìna. 2020), ʻo 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 mea maʻi e like me ke ʻano o ka maʻi maʻi a me nā hopena hōʻike i ka Figure 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%) i loaʻa i ka 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, ʻoiai ʻo BRCA18% a me 17. BRCA2 (Nā Kiʻi 1 a me 2). ʻAʻole i loaʻa ʻo LGR i ka loiloi MLPA.
Kiʻi 2. Ka nānā ʻana i nā hoʻololi ʻana o 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 (uliuli) i nā maʻi maʻi maʻi umauma 389; (B) 389 mau maʻi maʻi maʻi maʻi maʻi umauma He kanakolukumamālima (9%) i loaʻa nā 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 BC molecular 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 BRTNBC1-posit. luminal B BC, 2 (11.8%) i HER2 + maʻi, a me 10 (58.8%) i TNBC. ʻO nā puʻupuʻu me ka 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, HER2 16.7%. ʻO TNBC a me 2 (11.1%) he luminal A (Figure 3). ʻAʻole i loaʻa nā maʻi HER2 + i loko o kēia hui. No laila, nui 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 mai, ua loiloi mākou i ke ʻano a me ka gene localization o BRCA1 a me BRCA2 PV. Ma BRCA1 PV, ua ʻike mākou i 7 mau ʻano nucleotide hoʻokahi (SNVs), 6 holoi ʻana, 3 hana hou a me 1 hoʻokomo. c.5035_5039delCTAAT. ʻO kēia hoʻololi e pili ana i ka holoi ʻia ʻana o ʻelima nucleotides (CTAAT) ma BRCA1 exon 15, ka hopena i ka hoʻololi ʻana o ka amino acid leucine e tyrosine ma codon 1679, a ma muli o ka hoʻololi ʻana i ka frameshift me ka wānana koho ʻē aʻe e hoʻololi i ka codon. ʻO nā PV i hōʻike ʻia aia ma ka ʻāpana consensus site splice (c.4357+1G>T) (Papa 1).
E pili ana i ka BRCA2 PV, ua ʻike mākou i 6 holoi ʻia, 6 SNV a me 2 hoʻololi. e hana hou i ka C ma ka exon 5 o BRCA2, i wanana e hoʻopili i kahi pūmua i ʻoki ʻia, ʻaʻole hana. ma muli o ka holoi ʻia ʻana o 4-nucleotide mai nā kūlana nucleotide 5851 a i 5854 i ka coding exon 10 o ka BRCA2 gene a me nā hopena i ka unuhi ʻana me kahi codon hoʻomaha ʻē aʻe i wānana ʻia (p.S1951WfsTer). hoʻomanawanui.34 ʻO ka mutation mua e pili ana i ka hoʻololi ʻana o adenosine (A) i BRCA2 exon 7 me kahi 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. Pili kēia hoʻololi i ka maʻamau mRNA splicing. ka hoʻololi ʻana ma mua o ka exon 13 o ka gene encoding BRCA2. Hiki i ka hoʻololi c.7008-2A>T ke hana i nā transcripts he nui o nā lōʻihi like ʻole.
A laila mākou i palapala i ka BRCA1 / 2 deleterious mutations i loko o ka functional domains a me ka protein-binding regions (Fig. 4). I ka BRCA1 gene, 50% o PVs i loaʻa i loko o ka umauma maʻi 'aʻai'āina cluster (BCCR), aʻo 22% o ka mutations aia ma ka ovarian cancer cluster region (OCCR) (Fig. 4A). ʻO 42.8% o nā hoʻololi i loaʻa i ka OCCR (Fig. 4B). A laila, ua loiloi mākou i ka wahi o PV i loko o ka BRCA1 a me BRCA2 protein domains. Ua ʻike ʻia nā hoʻololi intronic a me 3 exonic i 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. domain (RING) a me ka nuclear localization sequence (NLS), he coiled-coil domain, SQ/TQ cluster domain (SCD), a me BRCA1 C-terminal domain (BRCT). (B) Aia ka BRCA2 protein i ewalu BRC repeats, he DNA-binding domain with a helical domain (Helical), ekolu oligonucleotide/oligosaccharide domain (toB) NLS ma ka ʻaoʻao C. Hōʻike ʻia nā ʻāpana i kapa ʻia ʻo Breast Cancer Cluster Region (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-nā maʻi maikaʻi ʻole (nā mea lawe ʻole) a me nā mea lawe āpau (n = 35).
Ua helu mākou i ka hāʻawi ʻana o Ki-67 ma muli o ka median o kā mākou cohort (25%, ākea <10-90%). ʻO nā kumuhana me Ki-67 <25% ua wehewehe ʻia ʻo "Ki-67 haʻahaʻa", ʻoiai ʻo nā kānaka me nā waiwai ≥ 25% i manaʻo ʻia ʻo "Ki-67 kiʻekiʻe". Nā mea lawe PV (Fig. 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 ka BRCA2 PVs a me ka ʻole o BRCA1 a me BRCA2. nā pūʻulu papa histological (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 hoʻopaʻa ʻana i kahi hoʻohālikelike nui ma waena o ka papa tumora a me ka mutation BRCA1, me kahi kiʻekiʻe o nā maʻi maʻi G3
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, 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 mea hoihoi, 3% (13/389) o kā mākou cohort he kāne. ʻAʻole naʻe, ʻaʻohe o kēia mau kāne i hoʻomohala i kahi BRCA1/2 PV, no laila, he mau moho lākou no ka hoʻāʻo ʻana i ka molekala hou e hoʻoholo ai 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 PV i kā mākou cohort - e laʻa me c.181T>G, c.514del, c.3253dupA a me c.5266dupC - i ʻike ʻia ma kēia mau ʻano ʻelua BRCA1, ʻelua. (c.181T>G a me c.5266dupC) loaʻa maʻamau ma Ashkenazi nā Iudaio o ka Hikina a me Central Europe (Poland, Czech), Slovenian, Austrian, Hungarian, Belarusian and German ), 44,45 a, ma ʻAmelika Hui Pū ʻIa a me Argentina, ua wehewehe koke ʻia he "variant germline recurrent" i nā maʻi Italia me 4del a me OC. nā maʻi mai ka ʻĀkau Sicily ma Palermo a me Messina. ʻO ka mea hoihoi, ʻo Incorvaia et al. loaʻa ka c.3253dupA ʻokoʻa i loko o kekahi mau ʻohana ma Catania.28 ʻO ka BRCA2 PVs i hōʻike nui ʻia he c.428dup, c.5851_5854delAGTT a me ka ʻokoʻa intronic c.8487+1G>A, i hōʻike ʻia i nā kikoʻī hou aku 28 i ka mea maʻi ma Palermo me c.4258dup1, AG.858dup. ʻike ʻia ma nā ʻohana ma ke komohana ʻākau o Sicily, ʻo ka hapa nui ma nā ʻāina ʻo Trapani a me Palermo, ʻoiai c.5851_5854delAGTT PV i ʻike ʻia ma nā hale ma ke komohana komohana ʻo Sicily. i wehewehe mua ʻia i ka c.5851_5854delAGTT hoʻololi i Colombia.37 ʻO kekahi BRCA2 PV, c.631+1G>A, ua loaʻa i nā maʻi BC a me OC mai Sicily (Agrigento, Siracusa a me Ragusa). i loko o ka mea maʻi hoʻokahi, a mākou i manaʻo e hoʻokaʻawale ʻia ma ke ʻano cis, e like me ka mea i hōʻike mua ʻia e like me that.34,46 ʻO kēia mau BRCA2 uble mutations i ʻike pinepine ʻia ma ka ʻāina ʻItalia a ua ʻike ʻia e hoʻolauna i nā codons hoʻomaha premature, e pili ana i ka ʻelele RNA splicing a me ka hoʻopau ʻana 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 ʻāpana protein a me nā genes. Ua wehewehe ʻia kēia mau ʻāina e Rebbeck et al. ʻO nā wahi pilikia no ka hoʻomohala ʻana i ka maʻi kanesa a me ka umauma.49 Eia naʻe, ʻo nā hōʻike e pili ana i ka hui ʻana ma waena o ka wahi o nā ʻano germline a me ka umauma a i ʻole ka maʻi kanesa ovarian e mau nō ka controversial. a me nā māhele BCCR a me nā hiʻohiʻona BC. ʻO kēia paha ma muli o ka palena palena o nā maʻi me BRCA1 / 2 hoʻololi.
ʻO ka mea hope loa, ua hoʻopili mākou i nā hiʻohiʻona clinicopathological BC me BRCA1 / 2 PV. Ma muli o ka helu palena o nā maʻi i hoʻokomo ʻia, ua ʻike wale mākou i kahi pilina koʻikoʻi ma waena o Ki-67 a me ka papa tumora. ʻO Ki-67 ka 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 o nā kiʻekiʻe Ki-67 kiʻekiʻe e hiki ke wehewehe ʻia e ka prevalence i kā mākou luminal B a me TNBC cohorts, kahi liʻiliʻi luminal A maʻi maʻi i loaʻa. stratify maʻi e like me kā lākou prognosis.53,54 Mai nā hopena o kā mākou hōʻuluʻulu ʻana, ʻaʻole he mea kupanaha ka correlation koʻikoʻi. E hana ʻia ma waena o Ki-67 kiʻekiʻe a me nā māka a me ka hele ʻana o BRCA1 PV. ʻOiaʻiʻo, ʻo nā maʻi maʻi e pili ana i ka BRCA1 he ʻano maʻamau o TNBC a hōʻike i nā hiʻohiʻona koʻikoʻi.16,17
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 mau ʻike me nā hōʻike preexisting, ma ke ʻano o ka prevalence mutation a me nā hiʻohiʻona clinicopathological i BC. ʻokoʻa a emi iki ma mua o BRCA1 / 2. ʻO kēia ka mea e ʻae ai i ka ʻike a me ka hoʻokele pono ʻana i ka piʻi nui ʻana o nā kumuhana i ka piʻi ʻana o ka maʻi kanesa ma muli o nā hoʻololi genetic.
Ua hōʻoia mākou ua kau inoa nā mea maʻi i ka ʻae ʻike e hoʻokuʻu i kā lākou mau maʻi tumora me ka inoa ʻole no ka noiʻi noiʻi. ʻae i ka hoʻohana ʻana i kā lākou ʻikepili no nā kumu noiʻi.
Mahalo mākou iā Prof. Paolo Vigneri no kāna kōkua ʻana i ka mālama ʻana i nā maʻi maʻi maʻi umauma e like me ke noi ʻana e ke Kōmike Kūʻai.
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.
Ka manawa hoʻouna: Apr-15-2022
