Earlier onset and multiple primaries in familial as opposed to sporadic esophageal cancer

AIM: To study the differences in onset age and multiple primary cancers between familial and sporadic esophageal squamous cell carcinoma(ESCC).METHODS: The differences in onset age and multiple primary cancers were analyzed between ESCC patients with(n = 766) and without(n = 1776) a family history of the cancer. The cases analyzed constituted all consecutive patients who had undergone cure-intent surgery at the Department of Thoracic Surgery of the 4th Hospital of Hebei Medical University from January 1 1975 to December 31 1989. Because we also originally aimed to examine the difference in survival time, only older subjects with a long follow-up period were selected.RESULTS: Overall, patients with ESCC and a positive family history of the cancer had a significantly younger age at onset and more multiple primary cancers than those without a positive family history(51.83 ± 8.39 vs 53.49 ± 8.23 years old, P = 0.000; 5.50% vs 1.70%, P = 0.000). Both of these differences were evident in subgroup analyses, however, no correlations were observed. While age at onset differed significantly by family history in males, smokers, and drinkers, the difference in multiple primary cancers by family history was significant in nonsmoking, nondrinking, and younger onset patients. In multivariate analysis, age over 50 years, tobacco smoking, and multiple primary cancers were found to be significant predictors of familial cancer: the corresponding OR(95%CI) and P-value were 0.974(0.963-0.985) and 0.000; 1.271(1.053-1.535) and 0.012; and 4.265(2.535-7.176) and 0.000, respectively.CONCLUSION: Patients with ESCC and a positive family history of the cancer had a significantly younger onset age and more multiple primary cancers than those without a positive family history. Sub-group analyses indicated that younger onset age may be due to the interaction of genetic predisposition and environmental hazards, and multiple primary cancers may only be due to genetic predisposition.

GCH1 variants contribute to the risk and earlier age-at-onset of Parkinson's disease:a two-cohort case-control study

Background:Common and rare variants of guanosine triphosphate cyclohydrolase 1(GCH1)gene may play important roles in Parkinson's disease(PD).However,there is a lack of comprehensive analysis of GCH1 genotypes,especially in non-coding regions.The aim of this study was to explore the genetic characteristics of GCH1,including rare and common variants in coding and non-coding regions,in a large population of PD patients in Chinese mainland,as well as the phenotypic characteristics of GCH1 variant carriers.Methods:In the first cohort of this case-control study,we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls;then in the second cohort,whole-genome sequencing was performed in sporadic late-onset PD samples(1962 patients),as well as 1279 controls.Variants at target GCH1 regions were extracted,and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test.We also performed a meta-analysis to correlate deleterious GCH1 variants with age at onset(AAO)in PD patients.Results:For coding variants,we identified a significant burden of GCH1 deleterious variants in early-onset or familial PD cases compared to controls(1.2%VS 0.1%,P<0.0001).In the analysis of possible regulatory variants in GCH1 non-coding regions,rs12323905(P=0.001,odds ratio=1.19,95%CI 1.07-1.32)was significantly associated with PD,and variant sets in untranslated regions and intron regions,GCH1 brain-specific expression quantitative trait loci,and two possible promoter/enhancer(GH14J054857 and GH14J054880)were suggestively associated with PD.Genotype phenotype correlation analysis revealed that the carriers of GCH1 deleterious variants manifested younger AAO(P<0.0001),and had milder motor symptoms,milder fatigue symptoms and more autonomic nervous dysfunctions.Meta-analysis of six studies demonstrated 6.4-year earlier onset in GCH1 deleterious variant carriers(P=0.0009).Conclusions:The results highlight the importance of deleterious variants and non-coding variants of GCH1 in PD in Chinese mainland and suggest that GCH1 mutation can influence the PD phenotype,which may help design experimental studies to elucidate the mechanisms of GCH1 in the pathogenesis of PD.

Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations:A literature reanalysis

Background:The hereditary spastic paraplegias(HSPs)are a group of clinically and genetically heterogeneous disorders.Approximately 10% of the autosomal dominant(AD)HSPs(ADHSPs)have the spastic paraplegia 3A(SPG3A)genotype which is caused by ATL1 gene mutations.Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear.The study aims to investigate the genotypephenotype correlation in SPG3A patients.Methods:We performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.Results:Most HSPs-SPG3A patients exhibited an early age at onset(AAO)of<10 years old,and showed an autosomal dominant pure spastic paraplegia.We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes,with distal atrophy being the most common complicated symptom.The AAO of each mutation group was not statistically significant(P>0.05).The mutational spectrum associated with ATL1 gene mutation is wide,and most mutations are missense mutations,but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.Conclusions:Our findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients.We also find that exons 4,7,8 and 12 are mutation hotspots in ATL1 gene.