Genome-wide association studies have been employed to develop numerous risk prediction models using polygenic risk scores (PRSs) for multifactorial diseases. However, healthcare providers lack ...confidence in their understanding of PRS risk stratification for multifactorial diseases, which underscores the need to assess the readiness of PRSs for clinical use. To address this issue, we surveyed the perceptions of healthcare providers as stakeholders in the clinical implementation of genetic-based risk prediction for multifactorial diseases. We conducted a web-based study on the need for risk prediction based on genetic information and the appropriate timing of testing for 12 multifactorial diseases. Responses were obtained from 506 stakeholders. Positive perceptions of genetic risk testing were found for adult-onset chronic diseases. As per participant opinion, testing for adult-onset diseases should be performed after the age of 20 years, whereas testing for psychiatric and allergic disorders that manifest during childhood should be performed from birth to 19 years of age. The stakeholders recognized the need for genetic risk testing for diseases that develop in adulthood, believing that the appropriate testing time is after maturity. This study contributes to the discussion on the clinical implementation of the PRS for genetic risk prediction of multifactorial diseases.
Abstract
Background
Few prospective reports of universal screening for Lynch syndrome exist for patients with endometrial cancer. In this study, we performed immunohistochemical staining for DNA ...mismatch repair-related genes (MLH1, MSH2, MSH6 and PMS2), to determine the extent to which Lynch syndrome can be diagnosed in endometrial cancer patients through universal screening.
Methods
We recruited 116 consecutive patients assumed to have uterine corpus malignancy from October 2019 to February 2021 in a prospective observational study. We performed immunohistochemical for mismatch repair-related proteins on samples from 100 patients who had surgicopathologically confirmed diagnoses of endometrial cancer. Samples with missing immunohistochemical results for any of the proteins had subsequent universal screening tests for microsatellite instability, DNA methylation of the MLH1 promoter region and mismatch repair genetics.
Results
We identified 19 (19.0%) patients with lost results for any of the proteins. All 19 patient samples had subsequent screening tests. We identified the microsatellite instability-high phenotype in 84.2% (16/19) of these patients and MLH1 methylation in 57.9% (11/19). Mismatch repair genetic testing detected two pathological variants, in MSH2 and MSH6, which indicated that the prevalence of Lynch syndrome was 2.0% in our cohort. Two cases of unclassified variant (MSH6) and one case of benign variant (PMS2) were also detected.
Conclusions
Initial screening by immunohistochemical is an effective method in universal screening for Lynch syndrome in endometrial cancer patients.
Background
When considering
BRCA1/2
genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH ...of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked.
Methods
Among 945 patients who received genetic testing of
BRCA1/2
at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers.
Results
FH of prostate, pancreatic, and skin cancer was significantly higher in the
BRCA2
pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows:
BRCA1
PV/
BRCA2
PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (
P
< 0.0001, Kruskal–Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (
P
= 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (
P
= 0.00129), respectively.
Conclusions
When considering
BRCA1/2
genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.
In Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). ...Consequently, the demand for risk-reducing salpingo-oophorectomy (RRSO) has increased. This study aimed to clarify the changes in the demand and timing of genetic testing and RRSO associated with public insurance coverage for HBOC in Japan.
This retrospective analysis included 350 women with germline
(g
) pathogenic variants (PVs) who had visited gynaecologists; they received g
genetic testing at 45.1±10.6 (20-74) years. The use of medical testing and preventive treatment was compared between the preinsurance and postinsurance groups using Mann-Whitney U and Fisher's exact tests.
The findings indicate that RRSO rates doubled from 31.4% to 62.6% among patients with g
-PV. The implementation rate was 32.4% among unaffected carriers and 70.3% among BC-affected patients. Younger patients received genetic testing with significantly shorter intervals between BC diagnosis and genetic testing and between genetic testing and RRSO.
Overall, the insurance coverage for HBOC patients with BC has increased the frequency of RRSO in Japan. However, a comparison between the number of probands and family members indicated that the diagnosis among family members is inadequate. The inequality in the use of genetic services by socioeconomic groups is an issue of further concern.
Since Lynch syndrome (LS) takes the form of autosomal dominant inheritance, appropriate diagnosis and surveillance may enable early detection and treatment of cancer in the proband or their ...relatives. Early diagnosis of endometrial carcinoma is important for fertility preservation in women with LS. We report on two patients who were diagnosed with endometrial carcinoma in the early 30s in the middle of infertility treatment. They had MSH2 germline pathogenic variant. Both endometrial carcinomas were found in early stage, but total hysterectomy and postoperative adjuvant chemotherapy were required. It should be considered that their parents had not been diagnosed with LS, despite the treatment of LS-related tumors in our hospital. With appropriate diagnosis of LS and proper surveillance, it is possible that fertility-sparing treatment could have been performed with an earlier diagnosis of endometrial cancer. We realized again that the appropriate diagnosis of the proband could lead a significant impact on medical management, not only for the patient individual but also for the relatives.
: The advancement of multidisciplinary treatment has increased the need to develop tests to monitor tumor burden during treatment. We herein analyzed urinary microRNAs within extracellular vesicles ...from patients with esophageal squamous cell carcinoma (ESCC) and normal individuals using a microarray.
Patients with advanced ESCC who underwent esophagectomy (A), endoscopic submucosal resection (ESD) (B), and healthy donors (C) were included. Based on microRNA expression among the groups (Analysis 1), microRNAs with significant differences between groups A and C were selected (Analysis 2). Of these candidates, microRNAs in which the change between A and C was consistent with the change between B and C were selected for downstream analysis (Analysis 3). Finally, microRNA expression was validated in patients with recurrence from A (exploratory analysis).
For analysis 1, 205 microRNAs were selected. For Analyses 2 and 3, the changes in 18 microRNAs were consistent with changes in tumor burden as determined by clinical imaging and pathological findings. The AUC for the detection of ESCC using 18 microRNAs was 0.72. In exploratory analysis, three of eighteen microRNAs exhibited a concordant trend with recurrence.
The current study identified the urinary microRNAs which were significantly expressed in ESCC patients. Validation study is warranted to evaluate whether these microRNAs could reflect tumor burden during multidisciplinary treatment for ESCC.
To elucidate the segregation behavior of solutes in Al-Si and Al-Cu binary alloys, specimens of several hypo-eutectic Al-Si alloys water-quenched at different stages of solidification or air-cooled ...from melt to room temperature were prepared and the distributions of Si concentration were analyzed across the primary dendrites. The Si distribution in the dendrites of the specimens water-quenched during primary solidification showed that Si concentration declined from the surface toward the center of the dendrite. In contrast, the specimens water-quenched after eutectic solidification or air-cooled from melt to room temperature showed that Si concentration increased from the surface toward the center of the dendrite. The diffusion distance of Si in the dendrites during the cooling process from the finish of solidification to room temperature was calculated according to Fick's second law and showed good agreement with the measured value. Therefore, the segregation behavior with high Si concentration in the center of the dendrite was attributed to the diffusion of Si from the center to the surface of the dendrite, resulting in the precipitation on the adjacent Si phase during eutectic solidification.
Six phenylalanine analogues containing 2′-methyl-, 2′,6′-dimethyl-, 2′-ethyl-6′-methyl-, 2′-isopropyl-6′-methyl-, 2′,4′,6′-trimethyl-, and 3′,5′-dimethyl-L-phenylalanine were synthesized ...enantioselectively through asymmetric hydrogenation of acetamidoacrylate derivatives. Enzymatic digestion and X-ray analysis supported the L-configuration of the phenylalanine derivatives obtained.
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