Effect of actionable somatic mutations on racial/ethnic disparities in head and neck cancer prognosis

Wu, Eileen; Park, Jong Y.; Zeitouni, Joseph; Gómez, Carmen; Reis, Isildinha M.; Zhao, Wei; Kwon, Deukwoo; Lee, Eunkyung; Nelson, Omar L.; Lin, Hui‐Yi; Franzmann, Elizabeth; Savell, Jason; McCaffrey, Thomas V.; Goodwin, W. Jarrard; Hu, Jennifer J.

doi:10.1002/hed.24420

Cited by 13 publications

(19 citation statements)

References 45 publications

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“…One caveat of our analysis is that this inference applies to a population as though our data were a representative sample of the population. HPV infection prevalence varies with socioeconomic factors [54], racial disparities [35, 55] and genetic polymorphisms [56, 57] associated with outcomes in head and neck cancer so greater attention to representative sampling would provide more precise estimates of the frequencies of mutations within populations [58] and the net realized selection intensities in each population.…”

Section: Discussionmentioning

confidence: 99%

“…Identification of targets via prevalence of substitutions assures that the altered gene will be relevant for the affected population, but gives little characterization of the efficacy of targeting the altered gene product at the level of the individual patient. In contrast, quantification of the effects that mutations confer upon the cancer phenotype should assist with prioritization of future precision-targeted therapies [33–35], as well as identify rare substitutions that are significant drivers of tumorigenesis and tumor maintenance.…”

Section: Introductionmentioning

confidence: 99%

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APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

et al. 2019

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Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities—PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

et al. 2019

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“…Mutations are acquired in response to various environmental stressors causing random DNA replication and DNA repair errors [28], thereby leading to the development of disease subtypes by clonal expansion of cells with a survival advantage [29]. HNSCC patients of different race showed a distinct mutation spectrum [22]. These gene mutations along with HPV infection are established to further contribute to inter-and intra-tumoral heterogeneity [18,[20][21][22][23].…”

Section: African American With Hnscc Tumors Harbor Higher Somatic Mutation Frequency Than Whitesmentioning

confidence: 99%

“…Evidence from clinical trials suggested that the response to immunotherapy in HNSCC [16,17] depends on availability of neo-antigens and a local immunosuppressive tumor microenvironment. While multiple studies have reported the influence of genetic changes, epigenetic modifications and mutations in specific protein domains [18][19][20][21][22][23] in HNSCC disparity, the influence of a global somatic mutational signature on the intricate association between immune response and metabolic alterations is still elusive. Hence, the current study aims to comprehensively investigate the key genetic and epigenetic variations that drive the differential immune phenotype among AA and Whites with a predicted contribution to intratumoral metabolic milieu, resulting in disparate patient outcome.…”

Section: Introductionmentioning

confidence: 99%

Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer

et al. 2020

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“…With personalized medicine on the horizon, it is also important to realize that racial disparities may extend to the realm of molecular medicine as well. Racial differences in the prevalence of specific head and neck cancer mutations, for example, have been found . As our field's understanding of cancer genetics grows, the importance of including racial and ethnic minorities in research efforts becomes even more critical–ensuring that the genetic diversity of the highest risk groups is included in major genetic studies and clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Disparities in health in the United States: An overview of the social determinants of health for otolaryngologists

Bergmark

Sedaghat

2017

Laryngoscope Investig Oto

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ObjectivesSocial determinants of health include social and demographic factors such as poverty, education status, race and ethnicity, gender, insurance status, and other factors that influence (1) development of illness, (2) ability to obtain and utilize healthcare, and (3) health and healthcare outcomes. In otolaryngology, as in other subspecialty surgical fields, we are constantly confronted by patients’ social and demographic circumstances including poverty, language barriers, and lack of health insurance and yet there is limited research on how these factors impact health equity in our field, or how attention to these patient characteristics may improve health equity. This review provides the reader with a framework to understand the social determinants of health including how socioeconomic status, insurance status, race, gender, and other factors impact health.Data Sources and Review MethodsFoundational papers on the social determinants of health are reviewed, as well as otolaryngology publications focused on health and healthcare disparities.ResultsThe social determinants of health have a major impact on patient health as well as healthcare utilization, but there is a relative lack of data on these factors and how they can be addressed within otolaryngology. Incorporating tools to measure social and demographic characteristics and actually report on these measures is a first simple step to increase the data on the social determinants of health as they pertain to otolaryngology.ConclusionMore research is needed on the social determinants of health, and how they impact otolaryngic disease. Medicare's Accountable Care Organization models will increasingly change the way in which physicians are reimbursed, making the social determinants of health central not only to our moral conscience but also the bottom line.Level of Evidence4

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Effect of actionable somatic mutations on racial/ethnic disparities in head and neck cancer prognosis

Abstract: We have provided the proof-of-principal data to link racial/ethnic-specific somatic mutations and HNSCC prognosis and pave the way for precision medicine to overcome HNSCC survival disparities. © 2016 Wiley Periodicals, Inc. Head Neck 38:1234-1241, 2016.

Cited by 13 publications

References 45 publications

APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma

Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer

Disparities in health in the United States: An overview of the social determinants of health for otolaryngologists

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