International Journal of Molecular Sciences (Jul 2021)

Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

  • Chiara Guglielmi,
  • Rosa Scarpitta,
  • Gaetana Gambino,
  • Eleonora Conti,
  • Francesca Bellè,
  • Mariella Tancredi,
  • Tiziana Cervelli,
  • Elisabetta Falaschi,
  • Cinzia Cosini,
  • Paolo Aretini,
  • Caterina Congregati,
  • Marco Marino,
  • Margherita Patruno,
  • Brunella Pilato,
  • Francesca Spina,
  • Luisa Balestrino,
  • Elena Tenedini,
  • Ileana Carnevali,
  • Laura Cortesi,
  • Enrico Tagliafico,
  • Maria Grazia Tibiletti,
  • Stefania Tommasi,
  • Matteo Ghilli,
  • Caterina Vivanet,
  • Alvaro Galli,
  • Maria Adelaide Caligo

DOI
https://doi.org/10.3390/ijms22147693
Journal volume & issue
Vol. 22, no. 14
p. 7693

Abstract

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With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

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