Cancer classification in the genomic era: five contemporary problems

Abstract Classification is an everyday instinct as well as a full-fledged scientific discipline. Throughout the history of medicine, disease classification is central to how we develop knowledge, make diagnosis, and assign treatment. Here, we discuss the classification of cancer and the process of categorizing cancer subtypes based on their observed clinical and biological features. Traditionally, cancer nomenclature is primarily based on organ location, e.g., “lung cancer” designates a tumor originating in lung structures. Within each organ-specific major type, finer subgroups can be defined based on patient age, cell type, histological grades, and sometimes molecular markers, e.g., hormonal receptor status in breast cancer or microsatellite instability in colorectal cancer. In the past 15+ years, high-throughput technologies have generated rich new data regarding somatic variations in DNA, RNA, protein, or epigenomic features for many cancers. These data, collected for increasingly large tumor cohorts, have provided not only new insights into the biological diversity of human cancers but also exciting opportunities to discover previously unrecognized cancer subtypes. Meanwhile, the unprecedented volume and complexity of these data pose significant challenges for biostatisticians, cancer biologists, and clinicians alike. Here, we review five related issues that represent contemporary problems in cancer taxonomy and interpretation. (1) How many cancer subtypes are there? (2) How can we evaluate the robustness of a new classification system? (3) How are classification systems affected by intratumor heterogeneity and tumor evolution? (4) How should we interpret cancer subtypes? (5) Can multiple classification systems co-exist? While related issues have existed for a long time, we will focus on those aspects that have been magnified by the recent influx of complex multi-omics data. Exploration of these problems is essential for data-driven refinement of cancer classification and the successful application of these concepts in precision medicine.http://deepblue.lib.umich.edu/bitstream/2027.42/134599/1/40246_2015_Article_49.pd

Suicide prevention and mood disorders: Self-exclusion agreements for firearms as a suicide prevention strategy

Suicide involves a complex set of behaviors and emotions that lead up to actions that may be based on planning and forethought or the result of impulse. While there are a host of antecedent circumstances the presence of a mood disorder, primarily depression, is the most common factor in suicide. While management of depression is recognized as important prevention strategy in depression, the means by which suicide occurs must be a critical element of prevention. Policies that lower access to the means for suicide will decrease the fatality. Guns are associated with half of suicides and the case fatality rate of gun associated suicide is over 90% compared to 7% for all other means. This emphasizes the importance of offering strategies that limit access to guns to those at higher risk for suicide. A declaration of formal self-exclusion for access to firearms (guns and ammunition) offers the individual at greater risk for suicide to place themselves on an official list that would prevent them from purchasing lethal weapons. A person with depression, when well, might wish to enroll voluntarily to prevent themselves, when ill, from procuring a weapon to harm themselves or others. This recognizes the autonomy of the person and protects both the individual, the family, and society

The changing pattern of ano-rectal cancer, squamous cell carcinoma of the eye, and Hodgkin’s lymphoma as non-AIDS-defining cancers, by HIV status, in Tanzania over 11 years (2002-2012): a retrospective case-report study

Abstract Background In Tanzania, 5.1% of adults aged 15-49 are infected with HIV. While rates of HIV-related malignancies have declined globally with antiretroviral therapy (ART), including Tanzania, rates of non-AIDS-defining cancers (NADCs) are believed to have increased. Therefore, we determined trends of three NADCs in Tanzania: ano-rectal cancer, squamous cell carcinoma of the eye, and Hodgkin’s lymphoma. Methods This study was conducted at the Ocean Road Cancer Institute (ORCI) in Dar es Salaam. All medical records of patients diagnosed with ano-rectal cancer, squamous cell carcinoma of the eye, and Hodgkin’s lymphoma between 2002 and 2012 were reviewed regarding HIV status, cancer clinical characteristics and management. Analysis was conducted to determine trends and proportions in these three NADCs and patient characteristics. Results We identified 980 NADCs. The relative proportion of these three NADCs at ORCI out of all cancers treated increased from 2.37% in 2002 to a peak of 4.34% in 2009. The prevalence of HIV in patients diagnosed with these NADCs also increased—from 6.67% in 2002 to 20.87% in 2010—and 85% of squamous cell carcinoma of the eye cancer patients with a reported HIV status were HIV-positive. Conclusions The frequency and proportions of these three NADCs in Tanzania have increased over the past 11 years, as has the prevalence of HIV positivity amongst these NADC patients. The current and possibly increasing burden of NADCs in Tanzania and other low- and middle-income countries with high HIV rates should be a focus for future cancer prevention and control and HIV therapy programs.http://deepblue.lib.umich.edu/bitstream/2027.42/111050/1/13027_2014_Article_524.pd

Individual and family characteristics associated with BRCA1/2 genetic testing in high‐risk families

Background Little is known about family members' interrelated decisions to seek genetic testing for breast cancer susceptibility. Methods The specific aims of this cross‐sectional, descriptive, cohort study were (i) to examine whether individual and family characteristics have a direct effect on women's decisions to use genetic testing for hereditary susceptibility to breast cancer and (ii) to explore whether family characteristics moderate the relationships between individual characteristics and the decision to use genetic testing. Participants were women (>18 years old) who (i) received genetic testing for hereditary breast cancer and who agreed to invite one of their female relatives into the study and (ii) female relatives who had NOT obtained genetic testing and were identified by pedigree analysis as having >10% chances of hereditary susceptibility to breast cancer. Results The final sample consisted of 168 English‐speaking, family dyads who completed self‐administered, mailed surveys with validated instruments. Multivariate conditional logistic regression analyses showed that the proposed model explained 62% of the variance in genetic testing. The factors most significantly associated with genetic testing were having a personal history of cancer; perceiving genetic testing to have more benefits than barriers; having greater family hardiness; and perceiving fewer negative consequences associated with a breast cancer diagnosis. No significant interaction effects were observed. Conclusions Findings suggest that both individual and family characteristics are associated with the decision to obtain genetic testing for hereditary breast cancer; hence, there is a need for interventions that foster a supportive family environment for patients and their high‐risk relatives. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98211/1/pon3139.pd

Effects of postpartum mobile phone‐based education on maternal and infant health in Ecuador

ObjectiveTo evaluate the effects of a mobile phone‐based intervention on postnatal maternal health behavior and maternal and infant health in a middle‐income country.MethodsA prospective evaluation enrolled consecutive postpartum women at two public hospitals in Quito, Ecuador, between June and August 2012. Inclusion criteria were live birth, no neonatal intensive care admission, and Spanish speaking. Intervention and control groups were assigned via random number generation. The intervention included a telephone‐delivered educational session and phone/text access to a nurse for 30 days after delivery. Maternal and infant health indicators were recorded at delivery and 3 months after delivery via chart review and written/telephone‐administered survey.ResultsOverall, 102 women were assigned to the intervention group and 76 to the control group. At 3 months, intervention participants were more likely to attend the infant’s postnatal check‐up (P = 0.022) and to breastfeed exclusively (P = 0.005), and less likely to feed formula (P = 0.016). They used more effective forms of contraception (more implants P = 0.023; fewer condoms P = 0.036) and reported fewer infant illnesses (P = 0.010). There were no differences in maternal acute illness or check‐up attendance.ConclusionMobile phone‐based postnatal patient education is a promising strategy for improving breastfeeding, contraceptive use, and infant health in low‐resource settings; different strategies are needed to influence postpartum maternal health behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135151/1/ijgo93.pd

Regulation of pancreatic cancer cell migration and invasion by RhoC GTPase and Caveolin-1

Abstract Background In the current study we investigated the role of caveolin-1 (cav-1) in pancreatic adenocarcinoma (PC) cell migration and invasion; initial steps in metastasis. Cav-1 is the major structural protein in caveolae; small Ω-shaped invaginations within the plasma membrane. Caveolae are involved in signal transduction, wherein cav-1 acts as a scaffolding protein to organize multiple molecular complexes regulating a variety of cellular events. Recent evidence suggests a role for cav-1 in promoting cancer cell migration, invasion and metastasis; however, the molecular mechanisms have not been described. The small monomeric GTPases are among several molecules which associate with cav-1. Classically, the Rho GTPases control actin cytoskeletal reorganization during cell migration and invasion. RhoC GTPase is overexpressed in aggressive cancers that metastasize and is the predominant GTPase in PC. Like several GTPases, RhoC contains a putative cav-1 binding motif. Results Analysis of 10 PC cell lines revealed high levels of cav-1 expression in lines derived from primary tumors and low expression in those derived from metastases. Comparison of the BxPC-3 (derived from a primary tumor) and HPAF-II (derived from a metastasis) demonstrates a reciprocal relationship between cav-1 expression and p42/p44 Erk activation with PC cell migration, invasion, RhoC GTPase and p38 MAPK activation. Furthermore, inhibition of RhoC or p38 activity in HPAF-II cells leads to partial restoration of cav-1 expression. Conclusion Cav-1 expression inhibits RhoC GTPase activation and subsequent activation of the p38 MAPK pathway in primary PC cells thus restricting migration and invasion. In contrast, loss of cav-1 expression leads to RhoC-mediated migration and invasion in metastatic PC cells.http://deepblue.lib.umich.edu/bitstream/2027.42/112733/1/12943_2005_Article_110.pd

Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

Background: It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone.Results: We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator.Conclusions: A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies.Fil: Wynn, Michelle L.. University of Michigan Medical School; Estados UnidosFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. University of Michigan Medical School; Estados UnidosFil: Sepulchre, Jacques Alexandre. Centre National de la Recherche Scientifique; FranciaFil: García, Héctor J.. University of Michigan; Estados UnidosFil: Merajver, Sofia D.. University of Michigan Medical School; Estados Unido

Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

Abstract Background It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone. Results We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator. Conclusions A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective manner. We believe our results support the position that such characterizations should consider retroactivity as a robust potential source of off-target effects induced by kinase inhibitors and other targeted therapies.http://deepblue.lib.umich.edu/bitstream/2027.42/112707/1/12918_2011_Article_826.pd

Trends in Breast Cancer Stage and Mortality in Michigan (1992–2009) by Race, Socioeconomic Status, and Area Healthcare Resources

The long-term effect of socioeconomic status (SES) and healthcare resources availability (HCA) on breast cancer stage of presentation and mortality rates among patients in Michigan is unclear. Using data from the Michigan Department of Community Health (MDCH) between 1992 and 2009, we calculated annual proportions of late-stage diagnosis and age-adjusted breast cancer mortality rates by race and zip code in Michigan. SES and HCA were defined at the zip-code level. Joinpoint regression was used to compare the Average Annual Percent Change (AAPC) in the median zip-code level percent late stage diagnosis and mortality rate for blacks and whites and for each level of SES and HCA. Between 1992 and 2009, the proportion of late stage diagnosis increased among white women [AAPC = 1.0 (0.4, 1.6)], but was statistically unchanged among black women [AAPC = −0.5 (−1.9, 0.8)]. The breast cancer mortality rate declined among whites [AAPC = −1.3% (−1.8,−0.8)], but remained statistically unchanged among blacks [AAPC = −0.3% (−0.3, 1.0)]. In all SES and HCA area types, disparities in percent late stage between blacks and whites appeared to narrow over time, while the differences in breast cancer mortality rates between blacks and whites appeared to increase over time

Promoters of and barriers to cervical cancer screening in a rural setting in Tanzania

ObjectiveTo investigate promoters and barriers for cervical cancer screening in rural Tanzania.MethodsWe interviewed 300 women of reproductive age living in Kiwangwa village, Tanzania. The odds of attending a free, 2‐day screening service were compared with sociodemographic variables, lifestyle factors, and knowledge and attitudes surrounding cervical cancer using multivariable logistic regression.ResultsCompared with women who did not attend the screening service (n = 195), women who attended (n = 105) were older (OR 4.29; 95% CI, 1.61–11.48, age 40–49 years versus 20–29 years), listened regularly to the radio (OR 24.76; 95% CI, 11.49–53.33, listened to radio 1–3 times per week versus not at all), had a poorer quality of life (OR 4.91; CI, 1.96–12.32, lowest versus highest score), had faced cost barriers to obtaining health care in the preceding year (OR 2.24; 95% CI, 1.11–4.53, yes versus no), and held a more positive attitude toward cervical cancer screening (OR 4.64; 95% CI, 1.39–15.55, least versus most averse).ConclusionEfforts aimed at improving screening rates in rural Tanzania need to address both structural and individual‐level barriers, including knowledge and awareness of cervical cancer prevention, cost barriers to care, and access to health information.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135344/1/ijgo221.pd