Dr. Montagna is a senior scientist at the Immunology and Molecular Oncology Unit of the Veneto Institute of Oncology. Since 1990 his major research projects focused on the genetic basis of cancer. The first studies aimed at the understanding of genomic imprinting dysregulation and identification of new loci involved in the pathogenesis of hepatoblastoma. The study of the genetic factors predisposing to breast and ovarian cancer started in 1995 at the International Agency for Research on Cancer in Lyon and became the major scientific interest over the last 25 years. In 2005 he joined the CIMBA international consortium whose main goal is to perform large-scale genomic studies in order to identify genetic modifiers of the risk associated to BRCA1/2 mutations. Few years later he became a member of the ENIGMA consortium with a focus on the investigation of the clinical relevance of BRCA1 and BRCA2 sequence variants of uncertain significance. Since 1994 he published 119 scientific papers on peer-reviewed journals. As team leader of the IOV Hereditary Breast and Ovarian Cancer Unit, Dr. Montagna recently spent much of his efforts in translating the most recent research scientific achievements on breast and ovarian cancer predisposition into clinical-diagnostic pathways dedicated to risk assessment and genetic testing for cancer prevention/early detection and targeted therapy.
Dr. Marco Montagna, PhD
Genetic bases of cancer
A better understanding of the genetic mechanisms of cancer predisposition will allow more and more precise risk assessments leading to personalized prevention/surveillance strategies as well as targeted cancer treatments.
Genetic predisposition to the hereditary breast and ovarian cancer syndrome.
A minor fraction of all breast cancers (5-10%) develops because of a predisposing germline mutation conferring a high risk of disease through the family generations. While the BRCA genes explain on average from 1/4 to 1/5 of the hereditary breast cancers, the largest part of the remaining “heritability” is still missing. The prevalence of “germline” mutations among ovarian cancer patients is somehow higher, with BRCA1 and BRCA2 mutations accounting for up to 14% of all the ovarian cancer patients. Though BRCA1/2 carriers face an important risk of disease, a large variation in phenotype, including type and age of tumor onset, is usually observed among and within families. In a fraction of all high-risk families the identification of BRCA1 or BRCA2 variants of uncertain significance (VUS) preclude the predictive test of healthy family members. All these factors, including low mutational rate, phenotype variability and variant interpretation, currently contribute to limit the usefulness of the genetic test.
The study of a cohort of more than 6000 high-risk families collected over the last 25 years allowed for the definition of the mutational spectrum of BRCA1/2 genes in the population of North-east Italy. In particular, the team pioneered studies on the contribution of BRCA1 and BRCA2 major genomic rearrangements that remove or duplicate one or more exons most often caused by mechanisms based on Alu-mediated rearrangements (Montagna et al. Oncogene 1999; Montagna et al., Hum Mol Genet 2003). The characterization of BRCA1/2 VUS by a multifactorial likelihood approach allowed classification of those pathogenic variants that recur in the Veneto Region (Malacrida et al., JCO 2008; Agata et al. Sci Rep. 2020). Finally, genome-wide NGS and genotyping studies contributed to the identification of genetic factors conferring low to moderate risk of disease and modifying the penetrance of major genes such as BRCA1 and BRCA2 (Zhang et al, Nat. Genet. 2020).
Conclusions and perspectives
Because of the high risk of breast and ovarian cancer, the identification of carriers of predisposing mutations represents a primary goal of all health care systems. The increase in the number of informative tests in high risk families can be achieved only by a combined approach that, in addition to new genes identification, focuses on a better understanding of the pathogenic relevance of gene variants as well as on the study of the joint effects of all genetic components into polygenic risk models.
- Agata S, Tognazzo S, Alducci E, Matricardi L, Moserle L, Barana D and Montagna M. Segregation analysis of the BRCA2 c.9227G>T variant in multiple families suggests a pathogenic role in breast and ovarian cancer predisposition. Sci Rep. 2020; 10:13987
- Fachal L, Aschard H, Beesley J, Barnes DR, Allen J, Kar S, Pooley KA, Dennis J, Michailidou K, Turman C, Soucy P, Lemaçon A, Lush M, Tyrer JP, Ghoussaini M, Moradi Marjaneh M, Jiang X, Agata S, Aittomäki K,.. Montagna M, et al. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nat Genet. 2020; 52:56-73.
- Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, Borg Å, Bortesi B,.. Montagna M, et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019; 40:1557-1578.