Insights into disparities observed with COVID‐19

The onset of human disease by infection with SARS‐CoV‐2 causing COVID‐19 has revealed risk factors for disease severity. There are four identified factors that put one at high risk for infection and/or mortality creating a disparity: age, co‐morbidities, race/ethnicity and gender. Data indicate that the older a person is, and/or the presence of obesity and diabetes, cardiovascular disease and chronic kidney disease place one at higher risk for COVID‐19. In the United States, specific race/ethnicities, particularly African Americans and Native Americans, are strong COVID‐19 risk components. Male gender has also emerged as a severity risk factor. For age and racial/ethnicities, the accumulation of health co‐morbidities is common precipitating mechanisms. In particular, underlying socio‐economic structures in the United States likely drive development of co‐morbidities, putting affected populations at higher risk for severe COVID‐19. Sudden cardiac death triggered by a common sodium channel variant in African Americans with COVID‐19 has not been evaluated as a cause for racial disparity. There is no evidence that racial/ethnic differences for COVID‐19 are caused by ABO blood groups, use of angiotensin‐converting enzyme (ACE) inhibitors or from amino acid substitutions in the SARS‐CoV‐2 spike protein. There is growing evidence that androgen‐enabled expression of ACE2 receptors and the serine protease TMPRSS2, two permissive elements engaging the SARS‐CoV‐2 spike protein for infection, may contribute to severe COVID‐19 in men. Overall, COVID‐19 has generated disparities for who is infected and the severity of that infection. Understanding the mechanisms for the disparity will help nullify the differences in risk for COVID‐19.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167121/1/joim13199.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167121/2/joim13199_am.pd

Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer.

BACKGROUND: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown. METHODS: Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX). RESULTS: Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21). CONCLUSIONS: p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death

Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways.

BACKGROUND: 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H). AIMS: To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability. METHODS: A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and beta catenin immunohistochemistry was determined in the three groups. RESULTS: MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and beta catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant beta catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01). CONCLUSIONS: MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp