Noureddine Boukhatem - Constitutional Oncogenetics

Yves-Jean BIGNON

Director of the oncogenetics department

Centre Jean-Perrin in Clermont-Ferrand

October 2020

This book offers a concise and precise state of the art in the field of genetic predisposition to cancer. It provides an up-to-date overview of a field that is still in the process of maturing. The emphasis is on clinical aspects in relation to the practice of oncogenetic counseling as undertaken in France based on my experience in three oncogenetic services (the Centre Jean-Perrin in Clermont-Ferrand, the Institut Gustave-Roussy and the Institut Curie in Paris).

In Parts 1and 2, which are the focus of this book, we catalogue the genetic predisposition syndromes for cancer. We deal with the syndromes in order of frequency, as deduced from statistics on patients and their relatives carrying a genetic alteration predisposing to cancer and identified in 2016 by the various accredited centers reported by the Institut National du Cancer.

Thus, in Part 1, we start with breast/ovarian cancer predisposition syndrome and Lynch syndrome, of which the suspicion of their presence is the primary reason for oncogenetic consultations. Genetic alterations predisposing to these two syndromes identified in index patients and their relatives in 2016 in France represented 67% of all genetic predispositions to cancer (breast/ovary 53% and Lynch 14%). We then deal with the other syndromes for which the percentage of genetic alterations identified as predisposing them is greater than 1%. In Part 2, we describe the syndromes for which the percentage of genetic alterations predisposing them is less than 1%.

DEFINITION.– The term index case (patient zero) is used to refer to the first person in an outbreak to have been infected with a pathogen. Here, the index case or index patient is the first person in a family where a genetic abnormality (mutation in the broadest sense) has been detected .

DEFINITION.– The term relative refers to a person who has a family (blood) relation to the index case .

DEFINITION.– The term syndrome refers to a group of several symptoms characteristic of a specific disease, constituting a recognizable clinical entity and attributable to a certain cause .

DEFINITION.– The term genetic predisposition refers to an increased likelihood or probability of developing a particular disease due to the presence of one or more mutations in the gene and/or a family history indicating an increased risk of the disease. It is also known as genetic susceptibility.

In this book, we consider the syndromes of genetic predisposition to cancers that were diagnosed in France in 2016 (see Table I.1). These syndromes are classified here (see Table I.2) according to statistics on index patients and their relatives carrying a genetic alteration predisposing to cancer, identified in the various accredited centers in France in 2016.

The national organization of oncogenetics in France, under the aegis of the INCa, is a unique and efficient model enabling complete care of the families concerned. Figure I.1, reproduced from the INCa report cited above, gives a summary of the path of index patients and their relatives through the oncogenetic circuit.

Table I.1 Statistics on index patients and their relatives carrying a genetic alteration predisposing to cancer, identified in in 2016 by the various accredited centers in France

COMMENT ON TABLE I.1.– Genes: names of the genes directly linked to the predisposition mentioned and which were reported in a diagnostic report, in France, in 2016. IC+: Index cases identified in 2016 as carriers of a genetic alteration in the genes mentioned; REL+: relatives identified in 2016 as carriers of a genetic alteration in the genes mentioned; AR: allelic status for genes with autosomal recessive transmission; BI: index or relatives carrying biallelic mutations; MONO: index or relatives carrying a monoallelic mutation; *constitutional hypermethylation of the promoter of the MLH1 gene; **CEBPA, ETV6, GATA2, KIT, MPL, SBDS, SH2B3, SRP72, WAS, etc.; ***BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, SOS2, etc.