Sudden infant death "syndrome"-Insights and future directions from a Utah population database analysis.

"Sudden Infant Death syndrome" (SIDS) represents the commonest category of infant death after the first month of life. As genome scale sequencing greatly facilitates the identification of new candidate disease variants, the challenges of ascribing causation to these variants persists. In order to determine the extent to which SIDS occurs in related individuals and their pedigree structure we undertook an analysis of SIDS using the Utah Population Database, recording, for example, evidence of enrichment for genetic causation following the back-to-sleep recommendations of 1992 and 1994. Our evaluation of the pre- and post back-to-sleep incidence of SIDS in Utah showed a decrease in SIDS incidence on the order of eightfold following back-to-sleep. An odds ratio of 4.2 for SIDS recurrence among sibs was identified from 1968 to 2013 which was similar to the odds ratio of 4.84 for death due to other or unknown cause among sibs of SIDS cases for the same time period. Combining first through thid degree relatives yielded an odds ratio of SIDS recurrence of 9.29 in the post-back-to-sleep (1995-2013) subset of SIDS cases where similar calculations of first-third degree relatives for the entire time period of 1968-2013 showed an odds ratio of 2.95. Expanded multigenertional pedigrees showing enrichment for SIDS were also identified. Based on these findings we hypothesize that post back-to-sleep SIDS, especially recurrences within a family, are potentially enriched for genetic causes due to the impact of safe sleeping guidelines in mitigating environmental risk factors. © 2016 Wiley Periodicals, Inc.

Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients.

BACKGROUND: The inevitable side effects of the currently used chemotherapy are associated with serious syndromes. Genotoxic effects and consequent genetic instability may play an important role in these syndromes. The aim of the study was to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients. METHODS: Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Statistical analysis included the use of; Fisher's exact test, Chi Square, and an inter-rater reliability test using Cohen's kappa coefficient. RESULTS: Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas 18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2 (hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident. CONCLUSIONS: The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors.

Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study.

Microsatellite instability (MSI) is a mutator phenotype that results from a defective mismatch repair (MMR) pathway. The present study examined the incidence of MSI and loss of heterozygosity (LOH) according to five markers from the panel of the National Cancer Institute (NCI) in 38 colorectal cancer (CRC) patients from the United Arab Emirates (UAE). MSI and LOH were analyzed using fragment analyses in a multiplex PCR setting on a capillary array electrophoresis platform. The expression of the MMR proteins, hMLH1 and hMSH2, was analyzed using immunohistochemistry. The cohort consisted of 17 females (44.7%) and 21 males (55.3%) with mean ages of 59.9 and 63.3 years, respectively. The overall MSI incidence was 31.3% (95% CI, 16.1-50.0), and included three patients with high MSI (MSI-H; 9.4%; 95% CI, 2.0-25.0) and seven patients with low MSI (MSI-L; 21.9%; 95% CI, 10.7-39). LOH was detected in three patients, while the remaining 25 patients (65.8%) showed no instability and were therefore classified as microsatellite stable (MSS). MSI was detected in the following screened markers: Bat25 in seven patients, Bat26 in three patients, adenomatous polyposis coli (APC; D5S346) in five patients, AFM093xh3 (D2S123) in two patients and Mfd15 (D17S250) in three patients. Of the five MSI-positive patients, four (80%) were evidently younger, aged 38, 48, 49 and 59 years, respectively. The MSI-H incidence (9.4%) was lower compared with that of other ethnic groups. In terms of the MMR proteins, hMLH1 expression was deficient in seven patients, of whom three were MSI-H patients, and hMSH2 was deficient in three patients. Fisher's exact test showed significant associations between hMLH1 and MSI when classified as MSS, MSI-L or MSI-H (P=0.0003). No such association was observed with abnormal MMR protein expression, age, cancer stage or gender.

High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study.

BACKGROUND: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. METHODS: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. RESULTS: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. CONCLUSION: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.