Endometrial cancer (EC) is a component of several cancer syndromes especially the Lynch syndrome, caused by the germline mutations in corresponding cancer predisposition genes. This study aims to outline the mutation prevalence, clinical and biological characteristics of the cancer susceptibility genes in Chinese EC patients, and to establish a screening criterion for identifying affected individuals.
The pathologic diagnosed EC patients meeting at least one of the following criteria were involved: (1) diagnosed before 50 years, (2) personal or (3) family history of Lynch related cancers, (4) loss of any MMR protein expression by immunohistochemistry (IHC). Next generation sequencing (NGS) was used for the germline mutation screening in 29 genes (APC, ATM, AXIN2, BLM, BMPR1A, BRCA1, BRCA2, BUB1B, CDH1, CDKN2A, CHEK2, EPCAM, GALNT12, GREM1, MLH1, MLH3, MSH2, MSH3, MSH6, MUTYH, PALB2, PMS1, PMS2, POLD1, POLE, PTEN, SMAD4, STK11 and TP53). Multiplex ligation-dependent probe amplification (MLPA) method were used for quantitative detection of genomic deletions and duplications.
Of the 199 patients recruited, 71 (35.7%) were diagnosed before 50 years, 26 (13.1%) had a second LS related cancer, 50 (25.1%) had a family history and 157 (78.9%) performed dMMR by IHC. We identified 43 (21.6%) deleterious mutations, of which, 41 located in LS associated genes (10 MLH1, 17 MSH2, 11 MSH6 and 3 PMS2) and 2 located in non-LS genes (1 BRCA1 and 1 PALB2). 58 uncertain significance variations were also identified in 53 patients (26.6%) while 20 (34.5%) of them were located in LS genes. Two suspected genomic deletion in MSH2 were detected and were still under further verification. 18 (72%) deleterious mutations were detected in the 25 patients meeting 3 or 4 inclusion criteria and 12 (25%) were detected in 48 patients meeting 2 criteria.
To our knowledge, this is the first NGS based study focus on inherited EC in Asian population. The high frequency of positive results indicated that multi-gene panel testing could be recommended to the patients with high risk of hereditary EC. The selection criterion used in current study is feasible and at a high sensitivity for screening the suspected inherited individuals.
Clinical trial identification
Legal entity responsible for the study
Fudan University Shanghai Cancer Center.
Has not received any funding.
All authors have declared no conflicts of interest.