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Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility. Pleiotropic loci and genome-wide genetic correlations have identified shared heritability across some types of cancers. Here, the authors perform genome-wide association studies and characterize pan-cancer heritability and pleiotropy in individuals of European ancestry across 18 cancer types from two large cohorts.

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies. While genetic loci shared between cancer types have been identified, cross-cancer relationships for polygenic risk scores have not been well studied. Here, the authors have developed polygenic risk scores for 16 cancers in two large cohorts and identified positive and inverse cross-cancer associations.

BackgroundAdults diagnosed with type 2 diabetes at a younger age are at increased risk for poor outcomes. Yet, little is known about the early experiences of these individuals, starting with communication of the diagnosis. Addressing this knowledge gap is important as this initial interaction may shape subsequent disease-related perceptions and self-management.ObjectiveWe examined diagnosis disclosure experiences and initial reactions among younger adults with newly diagnosed type 2 diabetes.ParticipantsPurposive sample of adult members of Kaiser Permanente Northern California, an integrated healthcare delivery system, diagnosed with type 2 diabetes before age 45 years.ApproachWe conducted six focus groups between November 2017 and May 2018. Transcribed audio recordings were coded by two coders using thematic analysis.Key ResultsParticipants (n = 41) were 38.4 (± 5.8) years of age; 10 self-identified as Latinx, 12 as Black, 12 as White, and 7 as multiple or other races. We identified variation in diagnosis disclosure experiences, centered on four key domains: (1) participants’ sense of preparedness for diagnosis (ranging from expectant to surprised); (2) disclosure setting (including in-person, via phone, via secure message, or via review of results online); (3) perceived provider tone (from nonchalant, to overly fear-centered, to supportive); and (4) participants’ emotional reactions to receiving the diagnosis (including acceptance, denial, guilt, and/or fear, rooted in personal and family experience).ConclusionsFor younger adults, the experience of receiving a diabetes diagnosis varies greatly. Given the long-term consequences of inadequately managed diabetes and the need for early disease control, effective initial disclosure represents an opportunity to optimize initial care. Our results suggest several opportunities to improve the type 2 diabetes disclosure experience: (1) providing pre-test counseling, (2) identifying patient-preferred settings for receiving the news, and (3) developing initial care strategies that acknowledge and address the emotional distress triggered by this life-altering, chronic disease diagnosis.

Best practices to facilitate high-quality shared decision-making for lung cancer screening (LCS) are not well established. In our LCS program, patients are first referred to attend a free group education class on LCS, taught by designated clinician specialists, before a personal shared decision-making visit is scheduled. We conducted an evaluation on the effectiveness of this class to enhance patient knowledge and shared decision-making about LCS. For quality improvement purposes, participants were asked to complete one-page surveys immediately before and after class to assess knowledge and decision-making capacity regarding LCS. To evaluate knowledge gained, we tabulated the distributions of correct, incorrect, unsure, and missing responses to eight true-false statements included on both pre- and post-class surveys and assessed pre-post differences in the number of correct responses. To evaluate decision-making capacity, we tabulated the distributions of post-class responses to items on decision uncertainty. From June 2017 to August 2018, 680 participants completed both pre- and post-class surveys. Participants had generally poor baseline knowledge about LCS. The proportion who responded correctly to each knowledge-related statement increased pre- to post-class, with a mean difference of 0.9 (paired t test, p < 0.0001) in the total number of correct responses between surveys. About 70% reported having all the information needed to make a screening decision. Our results suggest that a well-designed group education class is an effective system-level approach for initially educating and equipping patients with appropriate knowledge to make informed decisions about LCS.

ABSTRACT Genetic factors that influence etiologic mechanisms shared across cancers could affect the risk of multiple cancer types. We investigated polygenic risk score (PRS)-specific pleiotropy across 17 cancers in two large population-based cohorts. The study population included European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and the UK Biobank (48,969 cases, 359,802 controls). We selected known independent risk variants from published GWAS to construct a PRS for each cancer type. Within cohorts, each PRS was evaluated in multivariable logistic regression models with respect to the cancer for which it was developed and each other cancer type. Results were then meta-analyzed across cohorts. In the UK Biobank, each PRS was additionally evaluated relative to 20 cancer risk factors or biomarkers. All PRS replicated associations with their corresponding cancers (p<0.05). Eleven cross-cancer associations – ten positive and one inverse – were found after correction for multiple testing (p<0.05/17=0.0029). Two cancer pairs showed bidirectional associations; the melanoma PRS was positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS was positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS was inversely associated with lung cancer. We identified 65 associations between a cancer PRS and non-cancer phenotype. In this study examining cross-cancer PRS associations in two cohorts unselected for phenotype, we validated known and uncovered novel patterns of pleiotropy. Our results have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies. STATEMENT OF SIGNIFICANCE By examining cross-cancer polygenic risk score associations, we validated known and uncovered novel patterns of pleiotropy. Our results may inform investigations of risk prediction, shared etiology, and precision prevention strategies. Footnotes * ↵* Shared senior authorship * Financial Support: This work was supported by the National Institutes of Health (grant numbers K07CA188142, K24CA169004, R01CA088164, R01CA201358, R25CA112355, RC2AG036607, and U01CA127298) and the UCSF Goldberg-Benioff Program in Cancer Translational Biology. Support for participant enrollment, survey administration, and biospecimen collection for the Research Program on Genes, Environment and Health was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional community benefit programs. * Expanded methods, minor changes in response to initial reviewer comments

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.