I-Li-Fraumeni syndrome, noma i-LFS, isimo sezakhi zofuzo esenza abantu babe nezifo ezahlukene zegazi. Abantu abane-LFS bavame ukuthuthukisa le kansela empilweni empilweni kunalokho okujwayelekile emphakathini jikelele. Kungase kube nomngcipheko omkhulu wegciwane lesandulela ngculazi noma elilandelayo ku-LFS.
I-syndrome yabonakala kuqala emindenini eminingana eyayihlakulela izinhlobo ezihlukahlukene ze-cancer, ikakhulukazi ama-sarcomas, ekuqaleni kokuphila.
Ukwengeza, amalungu omndeni avele abe namathuba amaningi okuthuthukisa amakhemikhali amaningi, amasha kanye ahlukene phakathi nenkathi yokuphila. UFrederick Li noJoseph Fraumeni, Jr, babengabadokotela abaqala ukubika ngalokhu okutholwe ngo-1969, futhi yilokho uLFS enalo igama layo.
Kungani Ingozi Ephakeme Kakhulu?
Abantu abane-Li-Fraumeni syndrome banengozi enkulu yomdlavuza ngenxa yokuthi bazuze lokho okuyaziwa ngokuthi ukuguqulwa kwamagciwane ku-gene ebizwa ngokuthi i-TP53.
Ukuguqulwa kwamagciwane kuyishintsho sezakhi zofuzo ezenzeke emgodini wabazali bomuntu ngamunye othintekayo-okungukuthi, ukuguqulwa kokuqala kuvela emaqenjini ama-ovari noma ama-testes abangela iqanda nesidoda. Izinguquko kulezi zingqamuzana kuphela izinhlobo zokuguqulwa komzimba ezingadluliselwa ngqo enzalweni ngesikhathi sokukhulelwa lapho iqanda nesidoda behlangana ukudala i-zygote. Ngakho-ke, ukuguquguquka kwamagciwane kuzothinta yonke iseli emzimbeni wenzalo entsha; Ngokuphambene nalokho, ukuguquguquka kwe-somatic kwakha endaweni ethile komunye umuntu ngesikhathi esithile ngemuva kokukhulelwa, noma okuningi, kamuva, futhi kuthinta inombolo eguquguqukayo yamaseli emzimbeni.
Ukuguqulwa kwamagciwane okuyisisekelo emindenini ene-LFS yilabo abathinta umsebenzi wegciwane le-TP53. Ezweni lokucwaninga komdlavuza, isakhi se-TP53 sibi kakhulu kangangokuthi sekubizwa ngokuthi "umgcini we-genome."
I-TP53 isisindo se-tumor-suppressor-okungukuthi, isisindo esivikela iseli kusuka kwesinyathelo esisodwa endleleni eya emdlalweni.
Uma lesi sakhi sishintsha kangako ukuthi asisebenzi njengoba kuhloswe, noma ukuthi umsebenzi wayo unciphise kakhulu, iseli lingathuthuka emdlalweni, ngokuvamile lihambisana nezinye izinguquko zofuzo. Ukuhlolwa kwe- TP53 ukuguqulwa kwamagciwane kwaqala ukuqala ngo-1990 lapho ukuxhumana phakathi kwe-p53 ne-LFS kuqinisekiswa. Kusukela ngaleso sikhathi, ukuguqulwa okungaba ngu-250 kulo lonke i- TP53 gene kutholakale.
Ukuguqulwa kwesinye isakhi, hCHK2, futhi kuhlotshaniswa ne-LFS, noma kunjalo, ukubaluleka kwayo akucacile. I-hCHK2 yegciwane iyisisindo sokucindezela i-tumor esisetshenziselwa ukuphendula umonakalo we-DNA. Inombolo encane yemindeni ithwala lolu shintsho, futhi labo abathintekayo banamanye amabizo afanayo njengalawo aguquguquka kwe-TP53.
Iphakeme Kangakanani Le Risk?
Kulinganiselwa ukuthi, jikelele, umuntu one-LFS unethuba elingamaphesenti angama-50 lokuba nomdlavuza oneminyaka engama-40 futhi okungenani amaphesenti angama-90 eneminyaka engama-60. Uma une-LFS, ingozi yakho ngayinye ixhomeke ingxenye kungakhathaliseki ukuthi ungowesilisa noma wesifazane, abesifazane ngokuvamile banengozi enkulu kunamadoda.
Uma ubheka ingozi yokuphila komdlavuza emadodeni nakwabesifazane abane-LFS eneminyaka engama-50, ingozi yokuba nomdlavuza ihlehla kanje: amaphesenti angu-93 kwabesifazane namaphesenti angu-68 amadoda.
Uma behlakulela umdlavuza, abesifazane nabo bathambekele ekuhlakuleleni umdlavuza ngesikhathi esingaphansi kweminyaka engama-29, ngokwesilinganiso, eminyakeni engama-40 ubudala emadodeni.
Ingozi ephakeme kwabesifazane ibangelwa umdlavuza webele webele, ngokusho kocwaningo lwamaMi nozakwethu. Laba baphandi baphinde bathola ukuthi, phakathi kwabesifazane abavivinya amathuba okuguqulwa kwe-TP53, umdlavuza webele wawungumonakalo ovame kakhulu. Isibalo somdlavuza webele wesisindo samabele sasingamaphesenti angaba ngu-85 eneminyaka engama-60. Esikhathini esifundweni esifanayo, ingozi yomdlavuza webele isanda kakhulu phakathi nama-20s wesifazane, eqinisekisa ukuthi ukuhlolwa komdlavuza webele kusukela ekuqaleni kweminyaka engu-20 kuyindlela enhle kwabesifazane abane-LFS.
Lelizinga leengozi yezinguquko ze-TP53 lifaniswa nalokho okwenziwe kwabesifazane abanokushintshashintsha kwegciwane e-BRCA1 ne-BRCA2-lezi zakhi zofuzo zaphakama nokubika okuthandwayo mayelana nokuhlolwa kwezakhi zofuzo lwe-BRCA1 / 2 kanye nezindlela zokuzivikela zokuvimbela (ngabamhlonishwa njengo-Angelina Jolie).
Yiziphi Amanqamu Asemdlavuza Asebenzayo?
Noma imuphi umdlavuza ungathuthuka kunoma yimuphi umuntu nganoma yisiphi isikhathi. Kodwa-ke, abantu abane-LFS bayaziwa ukuthi banomdlavuza wokuqala kanye nomngcipheko wokuphila okuphezulu wezinhlobo ezimbalwa ze-"core" zomdlavuza, kufaka phakathi okulandelayo:
- I-osteosarcoma -uhlobo oluvame kakhulu lomdlavuza oqala emathanjeni
- Ama-sarcomas ashukela -uhlobo lomdlavuza ovela ezicukheni ezithile, njengamafutha, imisipha, izinzwa, izicubu ezinamafutha, izitsha zegazi, noma izicubu ezinzulu zesikhumba
- Umdlavuza webele wekusasa
- Izicubu zesibindi
- I-leukemia -umdlavuza wezingqamuzana ezenza igazi
- I-adrenal cortic carcinoma -umdlavuza we-correx e-adrenal, okuyinto ungqimba lwangaphandle lwezinhlayiya ze-adrenal. Izigulane ezinama-adrenal ziphezu kwezinso futhi zidlala indima ebalulekile emisebenzini ehlukahlukene ye-hormonal.
Ngocwaningo luka-1997 olwenziwa yi-Kleihues, i-sarcoma eyaziwa kakhulu e-LFS yi-osteosarcoma, ehambisana namaphesenti angu-12,6 wamacala, alandelwa izicubu zobuchopho (amaphesenti angu-12) kanye nama-sarcomas angu-soft (11.6%). Ezingxenyeni ezithambile zezicubu, i-rhabdomyosarcomas (i-RMS) yiyona ehlonishwa kakhulu. Amanye ama-sarcomas ajwayelekile angabika ahlanganisa i-fibrosarcomas (engasabhekwa njengenhlangano yangempela), ama-fibroxanthomas atypical, i-leiomyosarcomas, ama-liposarcomas ama-orbital, ama-sarcomas e-spindle, kanye nama-sarcomas angenayo i-pleomorphic. Izifo ze-hematological, noma i-blood cancers (njenge-acute lymphoblastic leukemia ne-Hodgkin's lymphoma) kanye ne-carcinomas e-adrenocortical yenzeke ngezinga le-4.2 ne-3.6%, ngokulandelana.
Njengoba imindeni eminingi enezakhi zofuzo ezifana ne-LFS ikhonjisiwe, kunezifo eziningi ze-cancer eziye zathinteka.
I-spectrum yomdlavuza we-LFS uye wanda ukuze ihlanganise i-melanoma, imaphaphu, isisu somzimba, i-thyroid, i-ovarian, nezinye izifo zomdlavuza.
Ngokusekelwe ekuhloleni kwendabuko, ingozi yokuthuthukisa i-sarcoma ye-soft-tissu kanye nomdlavuza womqondo kubonakala sengathi inkulu kakhulu ebuntwaneni, kuyilapho ingozi ye-osteosarcoma ingaba yilapho iphakeme kakhulu ngesikhathi sobusha, futhi ingozi yesifo somdlavuza wesifazane yanda kakhulu eminyakeni engama-20 futhi iyaqhubeka ibe yidala umuntu omdala. Lezi zibalo ziyakushintsha, noma kunjalo, ngoba imikhuba yokuhlola i-gene-predisposition genes iguqukile.
Li-Fraumeni Syndrome Ichazwe Kanjani?
Kunezinqubo ezahlukene nezincazelo zalesi sifo. Ezinye zihlanganisa kakhulu kunezinye. I-Classic LFS iyincazelo engavinjelwe kakhulu, njengoba idinga ukuxilongwa kwe-sarcoma ngaphambi kweminyaka engu-45, kanti izincazelo ezalandela ezifana nezindlela ze-Chompret zizama ukufaka ulwazi lokusakaza ulwazi lwesayensi mayelana nezinhlobo zezintuthwane kanye neminyaka ephathelene nokuxilongwa.
I-Classic LFS criteria:
- Uthola ukuthi une-sarcoma (uhlobo lomdlavuza oluhlanganisa amangqamuzana e-muscle / amahlumela / amajoyina / umsuka wamafutha) ngaphambi kweminyaka engu-45 futhi
- Isihlobo esithile sokuqala (umzali, umntakwethu noma ingane) nganoma yimuphi umdlavuza otholakala ngaphambi kweminyaka engu-45 futhi
- Esinye isihlobo sokuqala noma sesibili (sibandakanya okakazi, omalume, nokuningi) nganoma yimuphi umdlavuza otholakala ngaphambi kweminyaka engu-45 noma i-sarcoma etholakalayo nganoma yisiphi isikhathi.
Imithetho ye-Li-Fraumeni-like (LFL):
- Izindlela ze-LFL zenza inetha elibanzi ukuze lihlanganise nezinye izinhlobo zomdlavuza futhi zihlanganise ezinye izihlobo ezixilongwe ngemuva kweminyaka engu-45, futhi kunezincazelo ezimbili ezihlukene ezisetshenziswayo:
- Incazelo ye-Birch: Uthola ukuthi unomdlavuza wezingane noma i-sarcoma, i-tumor ebuchosheni, noma i-carcinoma engakaze itholwe ngaphambi kweminyaka engu-45 nesilinganiso sesibili noma sesibili ngesifo somdlavuza we-Li-Fraumeni (i-sarcoma, umdlavuza webele, isisu sobuchopho, i-adrenocortical i-carcinoma, noma i-leukemia) nganoma yisiphi isikhathi futhi isihlobo sokuqala noma sesibili-degree nanoma imuphi umdlavuza ngaphambi kweminyaka engama-60.
- I-Eels ichaza: Unesihlobo sesibili sokuqala noma sesibili esiphathelene nezifo ezihlobene ne-Li-Fraumeni (i-sarcoma, umdlavuza webele, isifo sobuchopho, i-leukemia, isifo socansi, i-melanoma, umdlavuza wesifo sofuba, umdlavuza we-pancreatic) kunoma yisiphi isikhathi.
I-criteria ye-Chompret:
- Unesifo somzimba we-Li-Fraumeni isifo somzimba (i-soft-tissu sarcoma, i-osteosarcoma, umdlavuza webele we-premenopausal, i-brain tumor, i-carcinoma ye-adrenocortical, i-leukemia, noma umdlavuza wamaphaphu we-bronchoalveolar) ngaphambi kweminyaka engu-46 futhi okungenani owodwa wokuqala noma wesibili- i-degree ehlobene nesifo se-Li-Fraumeni (ngaphandle komdlavuza webele, uma unomdlavuza webele) ngaphambi kweminyaka engu-56 noma enezicubu eziningi noma
- Unezicubu eziningi (ngaphandle kwezicubu eziningi zesifuba), oku-2 zazo ezingezansi kwe-tumor ye-Li-Fraumeni kanye neyokuqala eyenzeka ngaphambi kweminyaka engu-46 noma
- Uthola ukuthi une-carcinoma e-adrenocortical noma i-choroid plexus tumor, kungakhathaliseki ukuthi umlando womndeni.
Ngokusho kokubuyekezwa kwe-LFS nguSchneider kanye nozakwabo, okungenani amaphesenti angu-70 abantu abatholakale behlolwe ngokomzimba (okungukuthi, ukusebenzisa izincazelo ezinjengalezi ezingenhla) banomthelela omubi wokuguquka kwamagciwane ku-TP53 ukucindezela izakhi zofuzo.
Ukuphathwa kwamaKhansela
Uma umuntu one-LFS eba nomdlavuza, ukwelashwa okujwayelekile komdlavuza kunconywa, ngaphandle kwemdlavuza webele, lapho kutholakala khona i-mastectomy, kunokuba i-lumpectomy, ukunciphisa izingozi zomdlavuza wesibeletho wesibili kanye nokugwema ukwelashwa kwemisebe.
Labo abane-LFS bayelulekwa ukuba bagweme ukwelashwa kwe-radiation noma kunini lapho kungenzeka ukuze kunciphise ingozi yezilonda ezibangelwa ukushisa imisebe yesibili. Kodwa-ke, uma imisebe ibhekwa njengokwelashwa ukuze kuthuthukiswe ithuba lokusinda ebubini obunikwe, ingasetshenziswa ekuqapheleni kwodokotela nesiguli.
Ukuhlola nokuhlola
Kube khona ucingo olwandayo lwabachwepheshe ukuba bavumelane ngokuthi imindeni ene-FLS kufanele ihlolwe kanjani futhi inakekelwe. Ngeshwa, ngenkathi isayensi ishintsha ngokushesha, akukho ukuvumelana okunjalo okwamanje kuzo zonke izindawo.
Imvamisa yezinguquko ze- TP53 eziyingozi emphakathini jikelele aziwa, futhi imvamisa yeqiniso ye-FLS ayifakazi. Ukulinganiswa kuyahluka phakathi kokungu-1 ku-5,000 no-1 ku-20,000. Njengoba imindeni eminingi ihlolwa nge-TP53, ukusakazeka kwangempela kwe-LFS kungase kuvele kucace.
Ukubhekana neengozi yomdlavuza webele
E-United States, imihlahlandlela ye-National Comprehensive Cancer Network (NCCN) ikhuthaza i-MRI yamabele minyaka yonke iminyaka engama-20-29 no-MRI waminyaka yonke kanye ne-mammography kusukela eminyakeni engu-30 kuya ku-75. E-Australia, imihlahlandlela kazwelonke iphakamisa ukuthi kufanele kwenziwe i-mastectomy ephakathi kwamanye amazwe, kungenjalo ngonyaka we-MRI webele wezinyosi unconywa kusukela eminyakeni engu-20 kuya kweyengu-50. U-Schon kanye nozakwethu batusa ukuthi ukhetho lokunciphisa ingozi lokunciphisa amathuba emzimbeni noma ukuhlolwa kwebele kufanele kubhekwe kwabesifazane abangenayo umdlavuza onguquko kulesigqi se- TP53 .
Izincomo ze-NCCN
Ngokususelwa ekutholeni ukuthi ingozi yomdlavuza webele isanda kakhulu emva kweminyaka eyishumi, izincomo zifake ukuthi ukuhlaselwa kwe-mastectomy kokubili kufanele kubhekwe kusukela eminyakeni engama-20. Ingozi yomdlavuza wonyaka waminyaka yonke ineminyaka engama-40-45 ubudala bese iyancipha, njengokuthi i-mastectomy yezizwe ezimbili amathuba okuzuzisa abesifazane abangaphezu kweminyaka engama-60.
- Ukuqwashisa ngebele, kusukela ekuqaleni kweminyaka engu-18, ngezikhathi ezithile, ezibelethweni zokuzivocavoca.
- Ukuhlolwa kwebele emtholampilo, njalo ezinyangeni ezingu-6-12, kusukela ekuqaleni kweminyaka engama-20
- Iminyaka engu-20-29 ubudala, ukuhlolwa kwe-MRI yamabele yonyaka ngokuphambene
- Iminyaka engu-30-75 yobudala, ukuhlolwa kwe-MRI yamabele yonyaka ngokuphambene nokuxilongwa kwe-mammogram ngokucubungula i-Tomosynthesis
- Ubudala> iminyaka engu-75, ukuphathwa kufanele kubhekwe njengomuntu ngamunye.
- Kulabo besifazane abanokuguqulwa kwe-TP53 abaphathwa ngomdlavuza wesifuba, futhi abangenayo i-mastectomy ye-bilateral, ukuhlolwa nge-breast MRI yaminyaka yonke kanye ne-mammogram kufanele iqhubeke njengoba kuchaziwe ngenhla.
- Uma kuxoxwa ngakho okukhethwa kukho kokunciphisa amathuba okunciphisa ingozi, kuzomele kube neseluleko mayelana namazinga okuvikelwa, izinga lokungena komdlavuza osemdala, izinketho zokuvuselela, kanye nezingozi zokuncintisana kwamanye amagciwane. Izici zengqondo, ezenhlalakahle kanye nezemfanelo zokuphila ezibhekene nokunciphisa amathuba okunciphisa ingozi kufanele zifakwe ezinkulumweni ezinjalo.
Ukubhekisela Kweminye Ingozi Yomdlavuza
Izincomo ze-NCCN
- Ukuhlolwa okuphelele ngokomzimba kubandakanya ukuhlolwa kwe-neurologic nge-index ephezulu yokusola ngamanqamu angavamile kanye nokulimala okwesibini kumalondolozo omdlavuza njalo ezinyangeni ezingu-6-12.
- I-colonoscopy ne-endoscopy engenayo yonke iminyaka engu-2-5 kusukela ekuqaleni kweminyaka engu-25 noma eminyakeni emihlanu ngaphambi komdlavuza wokuqala we-colon emndenini (noma yikuphi okuza kuqala).
- Ucwaningo lwe-dermatologic wonyaka kusukela eminyakeni engu-18.
- Umzimba wonke wonyaka we-MRI
- U-MRI wengqondo yonyaka ingenziwa njengengxenye yomzimba wonke we-MRI noma njengokuhlolwa okuhlukile.
Amanye amafomu okuhlola nokuhlola
Kwakukhona isilingo sokuhlolwa kwe-positron emission tomography (FDG-PET) / CT izikrini kubantu abadala abane-LFS abathola izicubu kubantu abathathu kwabangu-15. Lezi zilinganiso ze-PET-CT, nakuba zikhulu ekutholeni izicubu ezithile, futhi zandisa ukuvezwa kwemisebe isikhathi ngasinye lapho seziqedile, ngakho-ke le ndlela yokuskena isimisiwe futhi ishintshele ku-MRI umzimba wonke kubantu abadala nge- TP53 ezihlukahlukene ezilimazayo.
Amaqembu amaningi okucwaninga aseqalile ukusebenzisa uhlelo olujulile lokuhlola uhlelo olufaka phakathi i-MRI ephelele yomzimba, ubuchopho be-MRI, ukuhlolwa kwesisu kwe-abdominal, kanye nokuhlolwa kobuchwepheshe bokusebenza komzimba we-cortic. Lolu hlobo lwenqubo yokuqapha lungathuthukisa ukusinda kwabantu abane-LFS ngokuthola izicubu ngaphambi kokuba zikhona izimpawu, kodwa kunezifundo ezingaphezulu ezidingekayo ukubonisa ukuthi lolu hlobo lohulumeni lusebenza kubantu abadala nabantwana abane-LFS.
Abantu abane-LFS babuziwe mayelana nesimo sengqondo sabo ngokubhekwa komdlavuza, futhi abaningi babonakala bakholelwa ukubaluleka kokubhekwa ukuze bathole izicubu ekuqaleni. Babuye babika umuzwa wokulawula nokuvikeleka okuhlobene nokuhlanganyela ohlelweni lokuhlola okujwayelekile
Ukuhlola Izingane ze-TP53 Izinguquko
Kungenzeka ukuhlola izingane kanye nentsha ngokushintshashintsha okuphawulekayo kwe-LFS, kodwa ukukhathazeka kuye kwaphakanyiswa mayelana nezingozi, izinzuzo, nokulinganiselwa okungenzeka kube khona, kubandakanya ukungabi namasu okuhlola okuqinisekisiwe noma ukuvimbela, nokukhathazeka mayelana nokucwaswa nokucwaswa.
Kunconywe ukuthi ukuhlola abantu abancane abaneminyaka engaphansi kweyi-18 yokushintshashintsha kwe- TP53 kwe- pathogenic ngaphakathi kohlelo olunikeza kokubili ulwazi lokuhlolwa kwangaphambi kokuhlolwa nokuhlolwa kokuthunyelwa kanye nokululekwa.
> Imithombo:
> Ballinger ML, Best A, Mai PL, et al. Ukuqapha okuyisisekelo ku-Li-Fraumeni syndrome besebenzisa izithombe zomzimba wonke womhlaba wonke: i-meta-analysis [eshicilelwe ku-Agasti 3, 2017]. I-JAMA i-Oncol.
> Correa H. Li-Fraumeni Syndrome. J Pediatr Genet. 2016; 5 (2): 84-88.
> Katherine Schon noMarc Tischkowitz. Imithelela emitholampilo yokushintshashintsha kwegciwane lomdlavuza webele: TP53. Ukwelashwa Kwesifo Sebele Isisu. 2018; 167 (2): 417-423.
> PL Pl, Best AF, Peters JA, et al. Izingozi zamanqamu okuqala kanye alandelayo phakathi kwe- TP53 abaguquli bezakhi zohlobo lwe-NCI LFS. I-Cancer . 2016; 122 (23): 3673-3681.
> Imihlahlandlela ye-NCCN yokwelashwa kwe-clinical in oncology 1.2018 - Okthoba 3, 2017: Ukuhlolwa kwesifo sofuzo / emndenini: ibele ne-ovarian. Izinkombandlela Zokuziphatha Zomtholampilo ze-NCCN: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.
> Tinat J, Bougeard G, Baert-Desurmont S, et al. I-2009 inguqulo ye-Chompret ye-Li Fraumeni syndrome . J Clin Oncol. 2009; 27 (26): e108-9.