Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy

Abstract

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2, TP53, ATM and CHEK2. NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.

Klinische Anwendungsbeispiele einer Next-Generation-Sequencing-basierten Multi-Genpanel-Analyse

“…Viele dieser Keimbahnmutationen sind mit Tumorsyndromen assoziiert [15,16]. Diese familiäre Disposition führt zu einem hohen, lebenslangen Risiko, tatsächlich zu erkranken.…”

“…Validierte und nach den Empfehlungen des American College of Medical Genetics and Genomics ausgerichtete NGS-Multi-Genpanels (z. B. APC, BRCA1, BRCA2, MEN1, MLH1, MLH2, MLH6, MUTYH, NTRK1, PMS2, PTEN, RET, RB1, SDHB, SDHC, SDHD, SDHAF2, STK11, TP53, TSC1, TSC2, VHL, WT1) zur Abklärung von hereditären Tumordispositionssyndromen sind bereits in die tägliche Rou- [16,24]. NGS-Studien zeigen, dass HBOC mit vielen Keimbahnmutationen assoziiert sein kann.…”

“…NGS-Studien zeigen, dass HBOC mit vielen Keimbahnmutationen assoziiert sein kann. Entsprechende Gene mit hoher Penetranz inkludieren BRCA1 und BRCA2, TP53, PTEN, STK11 und CDH1, Gene mit moderater oder niedriger Penetranz sind ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51 D, NF1, NBN und sogenannte "Mismatch-Repair-Gene" (MMR) [16,25,26,27].…”

Klinische Anwendungsbeispiele einer Next-Generation-Sequencing-basierten Multi-Genpanel-Analyse

“…Dank der Entwicklung von NGS können mittels NGS-Multi-Genpanel-Analyse gleichzeitig weitere mit diesem Krankheitsbild einhergehende Keimbahnmutationen (z. B. CHEK2, BRIP1, ATM and PALB2 und weitere) in betroffenen Familien detektiert werden [16,24]. NGS-Studien zeigen, dass HBOC mit vielen Keimbahnmutationen assoziiert sein kann.…”

Effect on Germline Mutation Rate in a High-Risk Chinese Breast Cancer Cohort after Compliance with The National Comprehensive Cancer Network (NCCN) 2023 v.1 Testing Criteria

“…Hereditary cancers are often caused by pathogenic or likely pathogenic (P/LP) variants in genes involved in regulating cell growth and/or DNA repair [1][2][3]. P/LP variants in these genes are often associated with increased risk for certain cancers (i.e., breast, ovarian, prostate, colon, and pancreatic cancers) with an early onset and exhibit an autosomal dominant inheritance pattern [4,5]. Assessment of an individual's risk for hereditary cancer is based on a thorough evaluation of the personal and family history.…”