TUMOSPEC: A Nation-Wide Study of Hereditary Breast and Ovarian Cancer Families with a Predicted Pathogenic Variant Identified through Multigene Panel Testing

Abstract

Assessment of age-dependent cancer risk for carriers of a predicted pathogenic variant (PPV) is often hampered by biases in data collection, with a frequent under-representation of cancer-free PPV carriers. TUMOSPEC was designed to estimate the cumulative risk of cancer for carriers of a PPV in a gene that is usually tested in a hereditary breast and ovarian cancer context. Index cases are enrolled consecutively among patients who undergo genetic testing as part of their care plan in France. First- and second-degree relatives and cousins of PPV carriers are invited to participate whether they are affected by cancer or not, and genotyped for the familial PPV. Clinical, family and epidemiological data are collected, and all data including sequencing data are centralized at the coordinating centre. The three-year feasibility study included 4431 prospective index cases, with 19.1% of them carrying a PPV. When invited by the coordinating centre, 65.3% of the relatives of index cases (5.7 relatives per family, on average) accepted the invitation to participate. The study logistics were well adapted to clinical and laboratory constraints, and collaboration between partners (clinicians, biologists, coordinating centre and participants) was smooth. Hence, TUMOSPEC is being pursued, with the aim of optimizing clinical management guidelines specific to each gene.

Somatic NGS Analysis of DNA Damage Response (DDR) Genes ATM, MRE11A, RAD50, NBN, and ATR in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemo-Radiotherapy

“…The latter is a somatic missense variant in the pincer domain that causes substitution of leucine with valine at codon 147 (p.Leu1472Val). This variant has been reported previously in patients with breast, ovarian, melanoma, and prostate cancer [ 33 , 34 , 35 , 36 ].…”

Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia–Telangiectasia Mutated Variant Carriers

“…This is because such variants have also been associated with breast cancer in large case-control studies, and the risk estimates are close to the risk estimates associated with the so-called PV [25,29]. National and international initiatives are ongoing to clarify the role of such variants and of other VUSs identified through multi-gene panel testing [33][34][35][36].…”

Overview of the Genetic Causes of Hereditary Breast and Ovarian Cancer Syndrome in a Large French Patient Cohort

“…In fact, the French GGC does not retain these genes in the diagnostic panel requiring additional knowledge for the moment. These genes are currently included in the national TUMOSPEC research protocol, which was designed to estimate the cumulative cancer risk for carriers of P/LP variants in such genes usually tested in the context of HBOC [ 46 ].…”