Fabrice Kwiatkowski

Statistical algorithms for the analysis of deleterious genetic mutations

We present algorithms for model selection and parameter estimation concerning deleterious genetic mutations. Three models are considered: single gene mutation, double cross-effect mutations or no genetic cause. Each of these models include unknown parameters that must be estimated simultaneously. Available data are phenotypes along family pedigrees but no genotypic data. We compare classical fit methods based on statistical summaries of the data and a neural network approach. We show the performance of our algorithms on simulated datasets of reasonable size. We also consider real data concerning breast/ovarian cancer.

Oncogenetic pedigrees: Relation between design and ability to predict mutation

We consider the risk of a disease caused by the presence within the genome of one deleterious mutation or two interacting mutations. For an individual, the probability of being mutated/doubly mutated can be estimated by knowing the phenotype of the other members in the family pedigree. We study the performance of this process as a function of the size, the shape of the family tree and the parameters of the model. We carry out simulations using the parameters pertaining to breast/ovarian cancer in BRCA-mutated families.

Association between hereditary predisposition to common cancers and congenital multimalformations

In a previous article we reported that mutations favoring cancer at adulthood seemed to improve fertility and limit miscarriages. Because spontaneous abortion may result from anomalies in embryo, we questioned if an increased frequency of congenital malformation could be evidenced among cancer‐prone families. Oncogenetics database (≈193 000 members) of the comprehensive cancer center Jean Perrin was crossed with regional registry of congenital malformations (≈10 000). Among children born between 1986 and 2011, 176 children with malformation matched in both databases. In breast/ovaries cancer‐prone families, the risk for malformations was multiplied by 2.4 [1.2‐4.5] in case of a BRCA1 mutation. Frequencies of malformation in BRCA2 and MMR mutated families were similar to families without a cancer syndrome. In comparison to malformations concerning a unique anatomical system, multimalformations were significantly more frequent in case of BRCA or MMR mutations: compared to families without cancer syndrome, the risk of multimalformations was multiplied by 4.1 [0.8‐21.7] for cancer‐prone families but with no known deleterious mutation, by 6.9 [1.2‐38.6] in families with a known mutation but an unknown parental mutational status and by 10.4 [2.3‐46.0] when one parent carried the familial mutation. No association with the type of anatomical system was found, nor with multiple births. These results suggest that BRCA and MMR genes play an important role in human embryogenesis and that if their function is lowered because of heterozygote mutations, congenital malformations are either more likely (BRCA1 mutations) and/or more susceptible to concern several anatomical systems.