Klinično-patološke značilnosti nosilcev zarodnih patogenih različic v genih ATM in PALB2

Mesarič, Vita Andreja (avtor), Krajc, Mateja (mentor), Drusany Starič, Kristina (komentor)

Uvod. Sindrom dednega raka dojk in/ali jajčnikov (HBOC) je prisoten pri 5–10 % bolnic z rakom dojk in pri približno 20–30 % bolnic z epitelnim rakom jajčnikov. Poleg genov BRCA1 in BRCA2, ki sta najbolj raziskana, poznamo še številne druge gene, ki v primeru prisotnosti zarodne patogene/verjetno patogene različice (PR/VPR) prav tako občutno povečajo ogroženost za razvoj raka, kot na primer geni ATM, PALB2 in CHEK2. S pričujočo raziskavo smo želeli analizirati prevalenco in spekter zarodnih PR/VPR v genih ATM in PALB2 ter ugotoviti pojavnost različnih vrst raka pri nosilcih zarodnih PR/VPR v slovenski populaciji in raziskati histopatološke značilnosti tumorjev, saj ti podatki še niso na voljo. Metode. V retrospektivno kohortno raziskavo smo vključili nosilce zarodnih PR/VPR v genih ATM in PALB2, ki smo jih na Onkološkem inštitutu Ljubljana diagnosticirali med testiranjem za HBOC med leti 2015 in 2022. Posameznike smo testirali s panelom 19 genov, povezanih s povečano ogroženostjo za raka dojk in/ali jajčnikov. Sorodnikom nosilcev zarodnih PR/VPR v enem izmed HBOC genov smo ponudili kaskadno testiranje. S pomočjo deskriptivne statistične analize smo opredelili klinične in genetske lastnosti nosilcev zarodnih PR/VPR v genih ATM in PALB2 ter patološke značilnosti tumorjev pri bolnih. Incidenco raka jajčnikov smo za vsako kohorto posebej primerjali z incidenco raka jajčnikov v Sloveniji. Presežno zbolevnost nosilk zarodnih PR/VPR v genih ATM in PALB2 smo izračunali z metodo indirektne standardizacije. Rezultati. Med prvim januarjem 2015 in 31. januarjem 2022 je bilo s panelom za HBOC testiranih 5099 posameznikov iz 4610 družin. V 19,1 % družinah je bila dokazana zarodna PR/VPR v enem izmed pregledovanih genov. Najpogosteje, v 8,1 % (386/4610), smo odkrili zarodno PR/VPR v genu BRCA1, sledile pa so zarodne PR/VPR v genih BRCA2 (224/4610; 4,9 %), CHEK2 (83/4610; 1,8 %), ATM (69/4610; 1,5 %) in PALB2 (40/4610; 0,9 %). Dokazali smo 23 različnih zarodnih PR/VPR v genu ATM in 13 v genu PALB2. Trojno negativni rak dojk (TNRD) je bil v kohorti ATM diagnosticiran v 9,1 %, v kohorti PALB2 pa v 41,2 %. Razlika v pojavnosti novega primarnega raka dojk med skupinama ATM-pozitivnih bolnic, ki so bile zdravljene z radioterapijo in tistimi, ki niso bile, ni bila statistično značilna (p=0,43). Pri 19,4 % PALB2-pozitivnih bolnic je bil diagnosticiran nov primarni rak dojk. Statistične razlike v pojavnosti novega raka dojk med bolnicami s tumorji, ki so izražali estrogenske receptorje (ER) in tistimi, ki jih niso, ni bilo (p=0,88). V obeh preiskovanih kohortah je bila incidenca raka jajčnikov večja kot v splošni populaciji. Mediana starost ob diagnozi raka jajčnikov je bila v kohorti ATM 61 let (razpon 51–78) in v kohorti PALB2 57 let (razpon 48–68). Zaključki. V naši raziskavi smo prvič opisali pojavnost, spekter in značilnosti zarodnih PR/VPR v genih ATM in PALB2 ter analizirali klinične značilnosti ATM- in PALB2-pozitivnih bolnikov z rakom v Sloveniji. Ugotovili smo, da je prevalenca zarodnih PR/VPR v genih ATM in PALB2 podobna kot je poročana v drugih populacijah. Potrdili smo, da je pri nosilcih zarodnih PR/VPR v genu ATM pogostejši ER-pozitivni rak dojk, med tem ko nosilke zarodnih PR/VPR v genu PALB2 zelo pogosto razvijejo TNRD, še posebej nosilke PALB2 c.1451T>A p.(Leu484*) in c.172_175delTTGT p.(Gln60Argfs*7). V kohorti PALB2 je bil pogost bilateralni rak dojk. Rak jajčnikov je bil v obeh kohortah bolj pogost kot v splošni populaciji, vendar pa se ni pojavil zelo zgodaj. Na mestu je zato pogovor o preventivni odstranitvi jajčnikov in jajcevodov, vendar šele po menopavzi, kar ugodno vpliva na hormonski status žensk. Izsledki raziskave bodo tako lahko v veliko pomoč pri načrtovanju preventivnih ukrepov in zdravljenja v populaciji nosilcev zarodnih okvar v genih ATM in PALB2.

• Jezik: Slovenski jezik
• Ključne besede: sindrom dednega raka dojk in/ali jajčnikov, ATM, PALB2, rak dojk, trojno negativni rak dojk, bilateralni rak dojk, rak jajčnikov
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: MF - Medicinska fakulteta
• Leto izida: 2025
• PID: 20.500.12556/RUL-175247
• Datum objave v RUL: 23.10.2025

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Clinicopathological characteristics of carriers of germline ATM and PALB2 pathogenic variants

Izvleček

Introduction. Hereditary breast and/or ovarian cancer syndrome (HBOC) is present in 5–10% of breast cancer patients and in approximately 20–30% of patients with epithelial ovarian cancer. In addition to BRCA1 and BRCA2 genes, which are the most studied, numerous other genes are known that, in the presence of a germline pathogenic/likely pathogenic variant (PV/LPV), also considerably increase the risk of developing cancer, such as ATM, PALB2, and CHEK2 genes. In the present study, we aimed to analyze the prevalence and spectrum of germline PV/LPV in the ATM and PALB2 genes, to determine the occurrence of various types of cancer among PV/LPV carriers, and to investigate their histopathological characteristics in the Slovenian population, as these data are not yet available. Methods. In this retrospective cohort study, we included carriers of germline PV/LPV in the ATM and PALB2 genes who were diagnosed at the Institute of Oncology Ljubljana during HBOC testing between 2015 and 2022. Individuals were tested with a panel of 19 genes associated with an increased risk for breast and/or ovarian cancer. Cascade testing was offered to relatives of carriers of germline PV/LPV in one of the HBOC genes. Using descriptive statistical analysis, we characterized the clinical and genetic features of carriers of germline PV/LPV in the ATM and PALB2 genes as well as the pathological characteristics of tumors in those patients. The incidence of ovarian cancer was compared for each cohort separately with the incidence in Slovenia. The excess risk for carriers of germline PV/LPV in the ATM and PALB2 genes was calculated using the method of standardized incidence ratio. Results. Between January 1st 2015, and January 31st 2022, 5099 individuals from 4610 families were tested with the HBOC panel. A germline PV/LPV in one of the studied genes was detected in 19.1% of families. Most frequently, germline PV/LPV in BRCA1 gene was detected in 8.1% (386/4,610) of families, followed by germline PV/LPV in BRCA2 gene (224/4,610; 4.9%), CHEK2 (83/4,610; 1.8%), ATM (69/4,610; 1.5%), and PALB2 (40/4,610; 0.9%). We identified 23 distinct germline PV/LPV in the ATM gene and 13 in the PALB2 gene. Triple-negative breast cancer (TNBC) was diagnosed in 9.1% of the ATM cohort and in 41.2 % of the PALB2 cohort. The difference in the occurrence of a new primary breast cancer between ATM-positive patients who had been treated with radiotherapy and those who had not was not statistically significant (p=0.43). Among 19.4% of PALB2-positive patients, a new primary breast cancer was diagnosed, and there was no difference in the occurence of a secondary tumor between primarily ER-positive and ER-negative patients (p = 0.88). In both investigated cohorts, the incidence of ovarian cancer was higher than in the general population. Median age at diagnosis was 61 years (range 51–78) among ATM-positive patients and 57 years (range 48–68) among PALB2-positive patients. Conclusions. For the first time we described the occurrence, spectrum, and characteristics of germline PV/LPV carriers in the ATM and PALB2 genes, and analyzed the clinical characteristics of ATM- and PALB2-positive cancer patients in Slovenia. We determined that the prevalence of germline PV/LPV in the ATM and PALB2 genes is similar to that reported in other populations. We confirmed that ER-positive breast cancer is more common among carriers of germline PV/LPV in the ATM gene, whereas carriers of germline PV/LPV in the PALB2 gene very frequently develop TNBC, especially carriers of PALB2 c.1451T>A p.(Leu484) and c.172_175delTTGT p.(Gln60Argfs7). Bilateral breast cancer was common in the PALB2 cohort. Ovarian cancer was more common in both cohorts than in the general population, although it did not occur at a very early age. Therefore, a discussion regarding prophylactic removal of the ovaries and fallopian tubes is appropriate, but only after menopause, which favorably influences the hormonal status of women. The findings of this study may thus be of great help in planning preventive measures and treatment for the population of carriers of deleterious variants in the ATM and PALB2 genes.

• Ključne besede: hereditary breast and/or ovarian cancer syndrome, ATM, PALB2, breast cancer, tripple negative breast cancer, bilateral breast cancer, ovarian cancer