doktorska disertacija
Mirjam Cvelbar (Author), Marko Hočevar (Mentor), Iztok Takač (Thesis defence commission member)

Abstract

Uvod: Germinalna mutacija (patogena ali verjetno patogena različica) v enem od dveh tumor-supresorskih genov BRCA1 ali BRCA2 pomeni dedno predispozicijo za določene vrste raka, kar pri ženskah pomeni visoko ogroženost za raka dojk in za raka jajčnikov. Kadar se pri isti osebi pojavita oba raka, in sicer sinhrono ali metahrono, govorimo o dvojnem primarnem raku jajčnikov in dojk (DPRJD). Verjetnost BRCA1/2 mutacije je takrat pričakovano bistveno večja kot pri enojnem raku. DPRJD velja zato za indikacijo za genetsko onkološko svetovanje in testiranje, ki je po ASCO priporočilih indicirano vedno, kadar je verjetnost za prisotnost mutacije večja od 10%. Začetni matematični izračuni (Berry 1997) in izsledki prvih, majhnih raziskav so kazali, da pri bolnicah z DPRJD frekvenca BRCA1/2 mutacij znaša 87-100%. Tudi že sam pojav epitelnega raka jajčnika (ERJ), in to ne glede na družinsko anamnezo, po podatkih novejših raziskav predstavlja večjo verjetnost germinalne BRCA1/2 mutacije, kot je veljalo doslej, in sicer do 17%. ERJ pri mlajši ženski, pred 50. letom starosti, pa po podatkih iz novejše mednarodne literature kaže na še večjo verjetnost germinalne BRCA1/2 mutacije, in sicer do 23%. Kljub temu ob začetku naše raziskave sam ERJ v Sloveniji še ni bil vključen med indikacije za genetsko svetovanje. Nekateri avtorji so ob tem že tudi opozarjali, da lahko zgodnja ugotovitev BRCA1/2 statusa pri bolnicah z ERJ pomeni drugačen način zdravljenja, glede na različno kemosenzitivnost in glede na takrat že potekajoče klinične raziskave s PARP inhibitorji. Ali gre pri bolnicah z DPRJD in tistih s solitarnim ERJ pred 45. letom ter prisotno/odsotno BRCA1/2 mutacijo za isto bolezen, še ne vemo, saj razlike v kliničnih in patoloških značilnostih pri BRCA1/2 pozitivnih in pri BRCA1/2 negativnih bolnicah doslej v mednarodni literaturi še niso bile v celoti analizirane. Namen: Naš namen je bil ugotoviti frekvenco germinalnih mutacij v BRCA1/2 genih pri bolnicah, ki so zbolele za (I) DPRJD oz. za (II) ERJ pred 45. letom, ter primerjati klinično-patološke značilnosti skupine bolnic z germinalno BRCA1/2 mutacijo in skupine bolnic brez germinalne BRCA1/2 mutacije . Hipoteze: 1. DPRJD je največkrat posledica germinalne BRCA1/2 mutacije. 2. BRCA1/2 pozitivna in BRCA1/2 negativna podskupina bolnic z DPRJD se razlikujeta glede družinske anamneze in glede klinično-patoloških značilnosti. 3. Frekvenca germinalnih BRCA1/2 mutacij pri bolnicah z ERJ pred 45. letom starosti v Sloveniji je nad 10 %. 4. BRCA1/2 pozitivna in BRCA1/2 negativna skupina bolnic z ERJ pred 45. oz. 50. letom starosti se med seboj razlikujeta glede klinično-patoloških značilnosti. Bolnice in metode: Ad I. Raziskava o BRCA1/2 statusu in klinično-patoloških značilnostih pri bolnicah z DPRJD je bila retrospektivna analiza genetskih in klinično-patoloških podatkov bolnic z DPRJD, obravnavanih v Ambulanti za genetsko onkološko svetovanje na Onkološkem inštitutu Ljubljana v letih 2002-2008. Te rezultate smo primerjali z analizo klinično-patoloških podatkov večje skupine netestiranih bolnic z DPRJD. Genetsko obravnavanih in testiranih bolnic je bilo 20 (ostalih 32 še živečih se na vabilo ni odzvalo); netestiranih bolnic z dostopnimi kliničnimi podatki, vključenih v kontrolno skupino, pa je bilo 51. Ad II. Raziskava o genetskem testiranju, BRCA1/2 statusu in klinično-patoloških značilnostih pri bolnicah z ERJ pred 45. (50). letom starosti je bila prospektivna raziskava, prijavljena in izvedena na Onkološkem inštitutu Ljubljana v letih 2012-2015. V Ambulanto za genetsko onkološko svetovanje smo povabili še žive, opravilno sposobne bolnice, ki so bile v letih 1999-2008 terapevtsko obravnavane na Onkološkem inštitutu Ljubljana zaradi primarnega ERJ. Genetskega svetovanja in tudi testiranja in sodelovanja v raziskavi z informiranim soglasjem se je udeležilo 22 bolnic od 51 povabljenih. Skupno s 5 predhodno testiranimi bolnicami je skupina preiskovank štela 27 bolnic. Mutacijsko presejanje preiskovank je zajemalo popolno analizo vseh eksonov BRCA1 in BRCA2 gena. Dodatno smo nato v raziskavo retrospektivno vključili še podatke bolnic z ERJ v starosti 45 do 49 let, ki so zbolele v letih 1999-2010, bile zdravljene na Onkološkem inštitutu in so bile genetsko testirane. Rezultati: Ad I: Ugotovili smo, da je bilo 60% (12 od 20) testiranih bolnic z DPRJD BRCA1/2 pozitivnih, od teh 75% (9) BRCA1 in 25% (3) BRCA2. Glede družinske anamneze smo našli trend večjega deleža raka dojk v I. kolenu pri pozitivni skupini. Glede starosti ob diagnozi prvega raka, glede stadija raka jajčnikov in glede histološkega tipa raka jajčnikov nismo našli značilnih razlik. Glede gradusa raka jajčnikov je bil pri BRCA1/2 pozitivnih značilno višji delež visokega gradusa raka jajčnikov. Glede raka dojk je bil pri BRCA1/2 pozitivnih značilno višji delež dvojnega primarnega raka dojk. Glede preživetja ni bilo značilne razlike med BRCA1/2 pozitivnimi in negativnimi; bila pa je značilna razlika med testiranimi in netestiranimi, in sicer so testirane bolnice imele daljše preživetje. Ad II: Delež sodelujočih glede na povabljene bolnice z ERJ je bil 43,1%. V skupini 27 povabljenih in testiranih bolnic z ERJ pred 45. letom je bilo najdenih 5 mutacij. Delež BRCA1/2 pozitivnih bolnic je bil 18,5%. Ugotovljene so bile 4 BRCA1 mutacije in 1 BRCA2 mutacija. V razširjeni skupini 42 testiranih bolnic z ERJ pred 50. letom je bilo najdenih 14 BRCA1/2 mutacij. Delež BRCA1/2 pozitivnih bolnic v tej razširjeni, delno selekcionirani skupini, je bil 33,3%. Ugotovljenih je bilo 11 BRCA1 mutacij in 3 BRCA2 mutacije. Prisoten je bil značilno večji delež pozitivne družinske anamneze raka jajčnikov v prvem kolenu pri BRCA1/2 pozitivnih bolnicah. Povprečna starost ob diagnozi ERJ je bila pri BRCA1/2 pozitivnih bolnicah značilno višja. Kljub temu pa je bila ugotovljena BRCA1/2 mutacija pri bolnici, stari komaj 24 let. Delež ERJ kot drugega primarnega raka je bil v skupini BRCA1/2 pozitivnih bolnic značilno višji. Ugotovljen je bil mejno značilno večji delež prvega stadija ERJ v skupini BRCA1/2 negativnih bolnic (60,7% vs. 26,7% pri pozitivnih; p=0,055). Glede histološkega tipa ERJ ni bilo statistično značilnih razlik med skupinama in delež seroznega tipa je bil skoraj enak (40% pri BRCA1/2 pozitivnih vs. 46% pri negativnih). Glede gradusa (stopnje diferenciacije) je bil ugotovljen značilno večji delež visoko-gradusnih (G2 in G3) ERJ v BRCA1/2 pozitivni skupini (66,7 % vs. 21,4% v negativni skupini; p=0,008). Ugotovljen pa je bil tudi primer mejno-malignega epitelnega tumorja jajčnika v BRCA1/2 pozitivni skupini. Zaključki: Ad I: Bolnice z DPRJD imajo v 60% prisotno germinalno BRCA1/2 mutacijo. BRCA1/2 pozitivna podskupina ima značilno višji gradus raka jajčnikov in značilno večji delež multiplega primarnega raka dojk. Ad II: Bolnice z ERJ pred 45. letom imajo v 18,5% germinalno BRCA1/2 mutacijo in zato izpolnjujejo kriterij za prediktivno genetsko testiranje. Skupaj z neposredno terapevtsko koristjo testiranja, zaradi možne uvedbe PARP inhibitorjev za BRCA1/2 pozitivne bolnice, obstaja zdaj dvojni razlog za genetsko testiranje (in ne le svetovanje) za vse bolnice z ERJ pred 50. letom starosti. BRCA1/2 pozitivne bolnice z ERJ pred 50. letom starosti imajo ERJ višjega gradusa in višjega stadija. Pri skoraj polovici BRCA1/2 pozitivnih bolnic z ERJ pred 50. letom starosti je bil ERJ histološko opredeljen kot endometrioidni tip ERJ. Pri klinični obravnavi bolnic z ERJ je pomembno upoštevati, kdaj je bila histološka diagnoza postavljena, ker je visoko-gradusni endometrioidni tip ERJ vse pogosteje preklasificiran v visoko-gradusni serozni tip, to pa spremeni terapevtske možnosti glede uporabe PARP inhibitorjev. Možni so tudi drugi tipi ERJ. Zato moramo za BRCA1/2 testiranje upoštevati vse bolnice z ERJ pred 50. letom in ne samo tistih z visoko-gradusnim seroznim ERJ.

Keywords

dvojni primarni rak jajčnikov in dojk;epitelni rak jajčnikov;dedna predispozicija;antionkogeni;gen BRCA1;gen BRCA2;mutacije;Genetsko svetovanje;

Data

Language: Slovenian
Year of publishing:
Typology: 2.08 - Doctoral Dissertation
Organization: UL MF - Faculty of Medicine
Publisher: [M. Cvelbar]
UDC: 577.21:618.11-006(043.3)
COBISS: 298155264 Link will open in a new window
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Secondary language: English
Secondary title: BRCA1/2 STATUS AND CLINICO-PATHOLOGIC CHARACTERISTICS OF PATIENTS WITH DOUBLE PRIMARY BREAST AND OVARIAN CANCERAND OF PATIENTS WITH EPITHELIAL OVARIAN CANCER
Secondary abstract: Introduction: Germinal mutation (patogenic or likely patogenic variant) in one of the tumor-supressor gens BRCA1 or BRCA2 confers hereditary predisposition for certain cancers, which in women means high risk of breast and/or ovarian cancer. When both cancers appear in the same person, in a synchronous or metachronous way, such a situation is called double primary breast and ovarian cancer (DPBOC). In such a case, the probability of BRCA1/2 mutation is much higher. Therefore DPBOC is an indication for genetic counselling and testing, which is according to ASCO guidelines indicated when the probability of mutation exceeds 10%. Initial calculations (Berry 1997) and results of the first, small studies were indicating that the frequency of BRCA1/2 mutations among DPBOC patients is as high as 87-100%. Even solitary development of epithelial ovarian cancer (EOC), with negative family history, has a probability of BRCA1/2 germinal mutation of up to 17%, according to the most recently published studies. When EOC develops before the age of 50 years, the probability of germinal BRCA1/2 mutation is as high as 23%. Nonetheless, at the beginning of our study solitary EOC was not an indication for genetic counselling in Slovenia. Some of the authors at that time have already been putting attention also to therapeutic benefit of early-known BRCA1/2 status in patients with EOC, because of different chemosensitivity of tumors and because of promising results of PARP inhibitors clinical trials. Whether patients with DPBOC and with solitary EOC before 45 (50) years of age have the same disease when BRCA1/2 mutation is present or absent, is not resolved yet, because the differences in clinico-pathologic characteristics have not been completely analysed yet. Aims: The aims of our study were to determine the frequency of germinal BRCA1/2 mutations in patients (I) with DPBOC (II) with EOC before 45 years of age, and to compare clinico-pathologic characteristics of the groups of patients with BRCA1/2 mutation and without BRCA1/2 mutation. Hypotheses: 1. DPBOC is frequently caused by germinal BRCA1/2 mutation. 2. BRCA1/2 positive and BRCA1/2 negative subgroup of patients with DPBOC differ regarding family history and regarding clinico-pathologic characteristics. 3. Frequency of germinal BRCA1/2 mutations in patients with EOC before 45 years of age in Slovenia is higher than 10 %. 4. BRCA1/2 positive and BRCA1/2 negative groups of the patients with EOC before 45 years of age differ regarding clinico-pathologic characteristics. Patients and methods: Ad I. The study of BRCA1/2 status and clinico-pathologic characteristics of patients with DPBOC was a retrospective analysis of genetic and clinico-pathologic data of patients with DPBOC, tested at Cancer Genetic Clinic, Institute of Oncology Ljubljana, during the period 2002-2008. These results were compared to analysis of clinico-pathologic data of a larger group of untested patients with DPBOC. Twenty patients with DPBOC responded to the invitation of Cancer Genetic Clinic and were included in the study (additional 32 patients did not respond). The control group consisted of 51 patients with DPBOC who were not tested for BRCA1/2 mutation. Ad II: The study of genetic testing, BRCA1/2 status and clinico-pathologic characteristics of patients with EOC before 45 (50) years of age was a prospective study, registrated and performed at the Institute of Oncology Ljubljana during the years 2012-2015. We invited to Cancer Genetic Clinic all eligible alive patients who had been diagnosed with EOC before 45 years of age during the period 1999-2008 and had been treated at the Institute of Oncology Ljubljana. Out of 51 invited patients, 22 patients responded in a positive way and participated in the study. Together with additional 5 patients who were eligible and were found to have been already tested, there were 27 patients included in the study group. Mutation screening included complete analysis of all exons of BRCA1 and BRCA2 genes. Additionally, patients with EOC at the age of 45-49 years, diagnosed in the period 1999-2010 and treated at the Institute of Oncology Ljubljana and counselled and tested at Cancer Genetic Clinic we also included. Results: Ad I: There was 60% rate of germinal BRCA1/2 mutations in tested patients with DPBOC (12/20). Among positive patients, 75% (9) were BRCA1 positive and 25% (3) were BRCA2 positive. A trend of higher rate of family history of breast cancer in first degree relatives was found in BRCA1/2 positive group. No significant differences were found regarding the age at the diagnosis of the first cancer, the stage of EOC and the histotype of EOC. Higher rate of high-grade EOC was found in BRCA1/2 positive group. Higher rate of multiple primary breast cancer was found in BRCA1/2 positive group. There was no significant difference in survival between BRCA1/2 positive and BRCA1/2 negative group of DPBOC patients. Tested group had a significantly longer survival than untested group of patients with DPBOC . Ad II: Compliance rate of patients with EOC invited to Cancer Genetic Clinics was 43,1%. BRCA1/2 mutations were found in 18,5% of tested patients with EOC before 45 years of age (5/27). There were 4 BRCA1 mutations and 1 BRCA2 mutation. In the extended group of 42 tested patients with EOC before 50 years age, 14 BRCA1/2 mutations were found (33,3% mutation rate). There were 11 BRCA1 mutations and 3 BRCA2 mutations. Higher rate of positive family history of ovarian cancer in first degree relatives was found in BRCA1/2 positive group. Age at the diagnosis of EOC was significantly higher in BRCA1/2 positive patients. Nevertheless, BRCA1/2 mutation was found in EOC patient aged only 24 years. Rate of EOC as a second primary cancer was higher in BRCA1/2 positive group of EOC patients. There was a marginally significant higher rate of stage I EOC in BRCA1/2 negative group (60,7% vs. 26,7%; p=0,055). Regarding histotype of EOC no significant differences between groups were found. Serous-type EOC rate was nearly equal in both groups (40% in BRCA1/2 positive vs. 46% in negative group). There was a higher rate of high-grade (G2 and G3) EOC in BRCA1/2 positive group (66,7 % vs. 21,4%; p=0,008). Nevertheless, a case of borderline or LMP (low-malignant-potential) epithelial ovarian tumor was found in BRCA1/2 positive group. Conclusions: Ad I. Patients with DPBOC carry germinal BRCA1/2 mutation in 60%. BRCA1/2 positive DPBOC group had a higher grade EOC and a higher rate of multiple primary breast cancer. AD II. Patients with EOC before 45 years age carry germinal BRCA1/2 mutation in 18,5% and therefore they fulfill criteria for predictive genetic testing. Together with direct therapeuthic benefit of testing because of possible application of PARP inhibitors to BRCA1/2 positive EOC patients, there exists a double reason for genetic testing (and not only counselling) for all patients with EOC before 50 years age. BRCA1/2 positive patients with EOC before 50 years age had EOC of higher grade and of higher stage. Almost half of BRCA1/2 positive patients with EOC before 50 years age had endometrioid histotype diagnosed. It's important to consider the year of diagnose, because high-grade endometrioid type EOC, on the basis of recent molecular analyses, more and more often is reclassified in high-grade serous type, and this may change therapeutic possibilities regarding treatment with PARP inhibitors. There are also other EOC hystotypes possible. Therefore all patients with EOC before 50 years age, and not only those with HGSC, should have access to BRCA1/2 genetic testing.
Secondary keywords: Dojke;Disertacije;Rak (medicina);Genetika;Jajčnik;Genes, BRCA1;Genetics;Genes, BRCA2;Mutation rate;Neoplasms, multiple primary;Breast neoplasms;Ovarian neoplasms;Genetic testing;Genetic counseling;Geni BRCA 1;Geni BRCA 2;Frekvenca mutacij;Večkratne primarne novotvorbe;Novotvorbe dojk;Novotvorbe jajčnikov;Genetsko testiranje;
Type (COBISS): Dissertation
Study programme: 0
Embargo end date (OpenAIRE): 1970-01-01
Thesis comment: Univ. v Ljubljani, Medicinska fak.
Pages: 81, [15] f.
ID: 10994479