Prevalence of pathogenic variants of FAN1 among more than 5000 consecutive patients referred to one genetic clinic for suspected hereditary predisposition to colorectal, breast/ovarian or other cancers

Marine Le Mentec1, Alice Fievet2, Emmanuelle Mouret-Fourme1, Chrystelle Colas1, Antoine De Pauw1, Dominique Stoppa-Lyonnet1, Bruno Buecher1

1Institut Curie, Paris, France. 2Institut Gustave Roussy, Paris, France


Despite significant advances in the molecular diagnosis of hereditary colorectal cancer (CRC), numerous clinical situations suggestive of major genetic predisposition remain unexplained. In 2015, FAN-1 (FANCD2/FANCIAssociated Nuclease 1) gene was proposed as a potential major gene of predisposition to colorectal polyps/cancer (1).

We assessed and compared the prevalence of pathogenic variants of FAN1 in consecutive patients who were referred to our cancer genetic clinic between May 2015 and November 2017 because their personal and/or familial history was suggestive of a genetic predisposition to CRC (Group1), breast or breast/ovarian cancer (Group 2) or other cancers/conditions (Group 3).

Molecular analysis consisted in screening for pathogenic variants a panel of 56 genes, including FAN1, using new generation sequencing (NGS).

FAN1 analysis was performed in a total of 5136 patients. The frequency of heterozygotes in Group 1 was not significantly different from that of other patients (Group 2 and 3) or from the expected frequency in the general population. Heterozygous patients from Group 1 have no personal history of CRC. No CRC was reported in their relatives, nor in the first/second degree relatives of the 16 index cases in Groups 2 or 3 with a pathogenic variation of FAN1.

The results of our study argue against the implication of pathogenic variants of FAN1 in unexplained cases of suspected genetic predisposition to colorectal polyps/cancer. Therefore, the French Groupe Génétique et Cancer decided not to include FAN1 in the recently designed consensus panel of colorectal cancer susceptibility genes.

Abstract references

1 – Segui N, et al. Gastroenterology 2015; 149: 563-566