Novel Germ-Line Mutations in Genes Controlling the Estrogen Metabolism in Lynch Syndrome-Related Endometrial Cancer

Presentation Number: SUN-0040
Date of Presentation: June 22nd, 2014

Balazs Jori1, Marinus Blok2, Koen Vijver van De2, Bert Delvoux1, Bart de Koning2, Rick Kamps2, Toon Van Gorp1, Roy Kruitwagen1, Encarna Gomez-Garcia2 and Andrea Romano*1
1Maastricht University Medical Centre, 2Maastricht University Medical Centre, Maastricht, Netherlands


Women carrying a Lynch Syndrome (LS) mutation have increased lifetime risk to develop - among others - endometrial cancer (EC). LS mutations can occur in four different mismatch-repair (MMR) genes and screening of these genes in currently used for genetic counselling. However, cancer risk predictions are broad and inaccurate and some woman carrying one given mutation can develop EC some other not.

We hypothesised that EC risk is modified by additional germ-line variants besides the MMR gene mutations.

To identify novel germ-line variants, the peripheral blood DNA from 38 EC patients belonging to LS families was analysed by targeted sequencing. Per patient, 154 genes involved in endometrial carcinogenesis were captured (Agilent® Haloplex™ capture system) and subjected to massive parallel sequencing using Illumina® HiSeq™. Raw data were analysed with Softgenetics ® NEXTgene ™ and Agilent ® SureCall ™. The panel of 154 genes included genes involved in estrogen metabolism and signalling, besides onco- and tumour-suppressors

After excluding common variants and synonymous mutations, two protein-coding variants per patient were identified, corresponding to a mutation rate of 3.9/MB. Genes like APC, MLL, LEPR and NOTCH1 carried distinct mutations in 10% of the patients. In addition, genes involved in estrogen metabolism and signalling (CYP1A1, CYP19A1, COMT, NCOR1, NCOR2, NCOA2, STS) resulted mutated in 40% of the patients analysed. Extra genes where mutations occurred frequently were identified (RET, ATM). The tumour material of these patients is being currently analysed for loss-of-heterozygosity, for protein aberration, inactivation or overexpression analyses.

In conclusions, additional germ-line mutations can modify the EC risk of a MMR LS mutation. The high prevalence of these mutations in specific genes/pathways can be used for a better cancer risk prediction by analysing these genes in routine genetic testing of LS family members.


Nothing to Disclose: BJ, MB, KV, BD, BD, RK, TV, RK, EG, AR