Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency

Background & aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120 7 depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000 7 depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk

Gender medicine in corneal transplantation: influence of sex mismatch on rejection episodes and graft survival in a prospective cohort of patients

To evaluate the effect of donor-to-recipient sex mismatched (male donor corneas to female recipients) on the incidence of rejection episodes and failures up to 1 year after corneal transplantation. Prospective observational cohort study, with donor corneas randomly assigned and surgeons blind to the sex of donor. A unique eye bank retrieved and selected the donor corneas transplanted in 4 ophthalmic units in patients with clinical indication for primary or repeated keratoplasty for optical reasons, perforating or lamellar, either anterior or posterior. Rejection episode defined as any reversible or irreversible endothelial, epithelial or stromal sign, with or without development of corneal edema, and graft failure as a permanently cloudy graft or a regraft for any reason detected or acknowledged during a postoperative ophthalmic visit at any time up to 1 year after surgery were recorded.156 (28.6%) patients resulted donor-to-recipient gender mismatched for H-Y antigen (male donor to female recipient). During the 12 months follow-up, 83 (14.7%, 95% CI 12.0-17.9) grafts showed at least 1 rejection episode and 17 (3.2%, 95% CI 2.0-5.0) failed after immune rejection, among 54 (9.6%, 95% CI 7.4-12.3) grafts failed for all causes. No significant differences between matched and mismatched patients were found for cumulative incidence of both rejection episodes (15.2% and 13.5%) and graft failures following rejection (3.2% and 2.6%), respectively. Multivariable analyses showed that H-Y matching either is not a predictive factor for rejection or graft failure nor seems to influence incidence of failures on respect to patient's risk category. The lack of influence of donor-to-recipient mismatched on the rate of rejections and graft failures resulting from this study do not support the adoption of donor-recipient matching in the allocation of corneas for transplantation

Cholesterol absorption status and fasting plasma cholesterol are modulated by the microsomal triacylglycerol transfer protein −493 G/T polymorphism and the usual diet in women

An important inter-individual variability in cholesterol absorption has been reported. It could result from polymorphisms in genes coding for proteins involved in the absorption process and in interaction with dietary intakes. To assess whether the extent of cholesterol absorption or synthesis is modified in adult women according to the −493 G/T polymorphism in the microsomal triglyceride transfer protein gene (MTP) and/or the habitual diet. Cholestanol and sitosterol, as well as desmosterol and lathosterol, surrogate markers of cholesterol absorption or synthesis, respectively, were analyzed in the fasting plasma of 69 middle-aged women under a Western-type diet (WD) and after 3 months on a low-saturated fat, low-cholesterol/Mediterranean-type diet (LFLCD). Genotypes for MTP −493G/T polymorphism were determined. Under an usual WD, subjects homozygous for the MTP −493 T allele exhibited higher (P < 0.05) fasting serum concentrations of cholestanol (199.0 ± 30.0 vs. 133 ± 7.4 × 102 mmol/mol cholesterol) and lathosterol (188.7 ± 21.8 vs. 147.6 ± 9.1 × 102 mmol/mol cholesterol), as well as total cholesterol (7.32 ± 0.22 vs. 6.63 ± 0.12 mmol/l) compared to G carrier subjects. After 3 months on a LFLCD, level of absorption markers decreased in TT subjects with no change in synthesis ones, leading to values comparable to those measured in G carriers. The lowering of plasma total and LDL cholesterol due to dietary change was 2.4- and 2.3-fold greater in TT women than in G carriers. The polymorphism −493G/T in MTP modulates the level of cholesterol absorption but not synthesis in women under a WD, an effect abolished under a prudent LFLCD