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. 2023 Jan 26;15(3):773.
doi: 10.3390/cancers15030773.

Performance Metrics of the Scoring System for the Diagnosis of the Beckwith-Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development

Maria Luca  1 , Diana Carli  1 , Simona Cardaropoli  2 , Donatella Milani  3 , Guido Cocchi  4 , Chiara Leoni  5 , Marina Macchiaiolo  6 , Andrea Bartuli  6 , Luigi Tarani  7 , Daniela Melis  8 , Piera Bontempo  9 , Gemma D'Elia  9 , Elisabetta Prada  3 , Raffaele Vitale  2 , Angelina Grammegna  10 , Pierpaola Tannorella  11 , Angela Sparago  12 , Laura Pignata  12 , Andrea Riccio  12   13 , Silvia Russo  11 , Giovanni Battista Ferrero  14 , Alessandro Mussa  2   15
Affiliations

Performance Metrics of the Scoring System for the Diagnosis of the Beckwith-Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development

Maria Luca et al. Cancers (Basel). .

Abstract

Different scoring systems for the clinical diagnosis of the Beckwith-Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).

Keywords: Beckwith–Wiedemann syndrome spectrum; genomic imprinting; score; tumor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of the cohort. In the inner circle, patients with a negative test are in yellow, and patients with a positive test are blue; in the outer circle, patients with less than 4 points and a negative test are in gray; patients with a clinical diagnosis and/or positive test are in blue.
Figure 2
Figure 2
Molecular subgroups per each point of the consensus score [10]. Percentages of the negative cases (in gray) refer to the total. Percentages in the four subgroups refer to the total of positive cases, including gain of methylation at imprinting center 1 (IC1-GoM, in green), loss of methylation at imprinting center 2 (IC2-LoM in orange), paternal uniparental disomy of the 11p15.5 chromosomal region (UPD(11)pat, in blue), and pathogenic variants in CDKN1C (CDKN1c mut, in red).
Figure 3
Figure 3
Molecular breakdown for each of the points of the consensus scoring system [10]. Percentages of the negative cases (in gray) refer to the total, while percentages in the four subgroups refer to the total of positive cases including gain of methylation at imprinting center 1 (IC1-GoM, in green), loss of methylation at imprinting center 2 (IC2-LoMm in orange), paternal uniparental disomy of the 11p15.5 chromosomal region (UPD(11)pat, in blue), and pathogenic variants in CDKN1C (CDKN1c mut, in red).
Figure 4
Figure 4
Receiver Operating Characteristic (ROC) curves of the several scoring systems for BWSp proposed over time, evaluated against the outcomes of the molecular tests [2,3,10,14,15,16,17]. Each of the ROC curves of the various scoring system (in black) is compared with the ROC curve of the consensus criteria by Brioude et al. 2018 [10] (red line). The ROC curve characteristics, area under the curve (AUC), standard error (st.Err), 95% Confidence Interval (95%CI), and p-value are given in Table 4.
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