Multiple Genetic Tumour Syndromes (MGTS): when to suspect them?

Emanuela Lucci-Cordisco1,2, Fulvia Brugnoletti2, Alessandro Vaisfeld2, Ariannna Panfili2, Simona Amenta2, Roberta Pietrobono2, Maria Grazia Pomponi1, Maurizio Genuardi1,2

1UOC Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy. 2Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore , Roma, Italy


The use of multigene panels allowed the identification of carriers of pathogenic variants (PVs) in 2 or more cancer predisposing genes (CPGs) causing hereditary cancer syndromes. We define this condition Multiple Genetic Tumour Syndromes (MGTS).

Objective: To characterise the phenotype associated with MGTS.

Methods: The clinical and molecular characteristics of 6 MGTS cases identified in a clinical series were reviewed.

Results: a second PV was actively searched in all patients. The NF1 gene was involved in two cases, associated with RET and MSH2 PVs, respectively. Both patients presented clinical NF1 in addition to known familial RET PV and personal and family history of early-onset (EO) colon cancer (CRC), respectively. The latter patient also developed three independent soft tissue sarcomas,that are uncommon in both NF1 and Lynch syndrome. The other cases involved BRCA1 and/or BRCA2: 1) EO-BC, ovarian cancer (BRCA1 + BRCA2); 2) macrocephaly, skin lesions, CRC, pancreatic cancer in the proband, whose father had BC (BRCA2 + PTEN);  3) EO-BC and renal cancer with lung cysts in 2 siblings (BRCA1 + FLCN); 4) bilateral BC, pheochromocytoma, and medullary thyroid cancer (BRCA1 + RET ).

Conclusions: Our data indicate that the phenotypes of patients with MGTS can be 1) the sum of the different syndromes or 2) driven by one of the two genes involved or 3) they might represent a multiplicative effect. MGTS should be actively searched in all patients with complex/atypical phenotypes or a suggestive family history, that cannot solely be explained by defects in a single CPG.