National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract

In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, “Gastro Intestinal” (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.