Natalia V. Bogdanova

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

В исследовании участвовало 88 детей в возрасте от одного года до 14 лет (Ме = 7,5 лет) с дизурическими расстройствами, у которых диагноз цистит был подтвержден эндоскопически. Основную группу составили 46 детей, получавших растительный лекарственный препарат Канефрон Н в качестве средства монотерапии острого заболевания, а далее как профилактическое средство на протяжении 6 мес. В контрольную группу вошли 42 ребенка, получавших антибактериальные препараты (АБП) и без профилактических мероприятий. Отмечена достаточность растительного препарата для купирования симптомов заболевания, а также значимое снижение вероятности суммарных рецидивов (р=0,005), особенно обострений цистита (р=0,041), в том числе повторных (р=0,038). Выявлены также преимущества Канефрона Н на основании сравнительной оценки динамики микрофлоры мочи в остром периоде и при обострениях в течение катамнестического наблюдения. Полученные результаты свидетельствуют о целесообразности применения Канефрона Н у детей с циститом с лечебной и профилактической целью.

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

To assess the prognostic value of “liquid biopsies” for the benefit of salvage RT in oligometastatic prostate cancer relapse, we enrolled 44 patients in the study between the years 2016 and 2020. All the patients were diagnosed as having an oligometastatic prostate cancer relapse on prostate-specific membrane antigen (PSMA)-targeted PET-CT and underwent irradiation at the Department of Radiotherapy at the Hannover Medical School. Tumor cells and total RNA, enriched from the liquid biopsies of patients, were processed for the subsequent quantification analysis of relative transcript levels in real-time PCR. In total, 54 gene transcripts known or suggested to be associated with prostate cancer or treatment outcome were prioritized for analysis. We found significant correlations between the relative transcript levels of several investigated genes and the Gleason score, PSA (prostate-specific antigen) value, or UICC stage (tumor node metastasis -TNM classification of malignant tumors from Union for International Cancer Control). Furthermore, a significant association of MTCO2, FOXM1, SREBF1, HOXB7, FDXR, and MTRNR transcript profiles was found with a temporary and/or long-term benefit from RT. Further studies on larger patients cohorts are necessary to prove our preliminary findings for establishing liquid biopsy tests as a predictive examination method prior to salvage RT.

Ziel/Aim Die DNA damage response (DDR) beinhaltet ein komplexes Netzwerk von Mechanismen zur Detektion von DNA Schäden und zur Generierung einer spezifischen zellulären Antwort wie z.B. Apoptose. Ziel dieser Studie war eine Charakterisierung der DDR-Foci in peripheren Blutlymphozyten unter Lu-177-PSMA Radioligandentherapie (RLT). Zudem wurde die prädiktive Wertigkeit der DDR-Marker für das Outcome der RLT exploriert. Methodik/Methods 35 Patienten mit metastasiertem kastrationsrefraktären Prostatakarzinom wurden prospektiv eingeschlossen (20 RLT-naive Patienten, 15 Patienten unter laufender RLT). DDR-Marker (γ-H2AX und 53BP1 Foci) wurden nach Antikörpermarkierung mittels Fluoreszenzmikroskopie in Blutlymphozyten prätherapeutisch sowie+1 und+24 h nach RLT bestimmt. Die prädiktive Wertigkeit der DDR-Marker für einen frühen Progress (PSA-Anstieg>25% und/oder PET Progress (PPP-Kriterien) nach 2 Zyklen) und der prätherapeutischen F-18-PSMA-1007 PET/CT (mittlerer SUV_max) wurde untersucht. Ergebnisse/Results Die Anzahl der Foci zeigte eine deutliche interindividuelle Heterogenität und einen typischen Verlauf mit frühem Anstieg nach Exposition und Abfall nach 24 h. 8/20 (40%) RLT-naive Patienten zeigten einen frühen Progress. Eine niedrige prätherapeutische Focianzahl [γ-H2AX (P=0,037); 53BP1 (P=0,032)], aber nicht die Kinetik der DDR-Foci, sowie ein niedriger SUV_max (P=0,016) waren mit einem frühen Therapieversagen assoziiert. In einer Kaplan-Meier Analyse war eine niedrige Focianzahl (53BP1, P=0,023) mit einem verkürzten PFS verbunden; diese zeigte sich in einer multivariaten Cox-Regression als einziger unabhängiger Prädiktor (Hazard Ratio: 0,208; P=0,026). Bei nicht-RLT-naiven Patienten errreicht die Focianzahl vor erneuter RLT keine Signifikanz (P≥0,089). Schlussfolgerungen/Conclusions Surrogatmarker der individuellen Strahlensensibilität sind bei RLT-naiven Patienten mit einem frühen Therapieversagen assoziiert. Publication Date: 14 April 2022 (online) © 2022. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10⁻³). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10⁻⁴). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

DNA double-strand break (DSB) induction and repair have been widely studied in radiation therapy (RT); however little is known about the impact of very low exposures from repeated computed tomography (CT) scans for the efficiency of repair. In our current study, DSB repair and kinetics were investigated in side-by-side comparison of RT treatment (2 Gy) with repeated diagnostic CT scans (≤20 mGy) in human breast epithelial cell lines and lymphoblastoid cells harboring different mutations in known DNA damage repair proteins. Immunocytochemical analysis of well known DSB markers γH2AX and 53BP1, within 48 h after each treatment, revealed highly correlated numbers of foci and similar appearance/disappearance profiles. The levels of γH2AX and 53BP1 foci after CT scans were up to 30% of those occurring 0.5 h after 2 Gy irradiation. The DNA damage repair after diagnostic CT scans was monitored and quantitatively assessed by both γH2AX and 53BP1 foci in different cell types. Subsequent diagnostic CT scans in 6 and/or 12 weeks intervals resulted in elevated background levels of repair foci, more pronounced in cells that were prone to genomic instability due to mutations in known regulators of DNA damage response (DDR). The levels of persistent foci remained enhanced for up to 6 months. This “memory effect” may reflect a radiation-induced long-term response of cells after low-dose x-ray exposure.

Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (¹⁷⁷Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (⁶⁸Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX⁺ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.

In addition to several well-established breast cancer (BC) susceptibility genes, the contribution of other candidate genes to BC risk remains mostly undefined. BARD1 is a potentially predisposing BC gene, however, the rarity of its mutations and an insufficient family/study size have hampered corroboration and estimation of the associated cancer risks. To clarify the role of BARD1 mutations in BC predisposition, a comprehensive case-control association study of a recurring nonsense mutation c.1690C>T (p.Q564X) was performed, comprising ~14,000 unselected BC patients and ~5900 controls from Polish and Belarusian populations. For comparisons, two BARD1 variants of unknown significance were also genotyped. We detected the highest number of BARD1 variants in BC cases in any individual BARD1-specific study, including 38 p.Q564X mutations. The p.Q564X was associated with a moderately increased risk of BC (OR = 2.30, p = 0.04). The estimated risk was even higher for triple-negative BC and bilateral BC. As expected, the two tested variants of unknown significance did not show significant associations with BC risk. Our study provides substantial evidence for the association of a deleterious BARD1 mutation with BC as a low/moderate risk allele. The p.Q564X was shown to be a Central European recurrent mutation with potential relevance for future genetic testing.