Oncogene Overlap Analysis of Circulating Cell-free Tumor DNA to Explore the Appropriate Criteria for Defining MET Copy Number-Driven Lung Cancer.

INTRODUCTION: Defining clinically relevant MET amplification levels in non-small cell lung cancer (NSCLC) remains challenging. We hypothesize that oncogene overlap and MET amplicon size decline with increase in MET plasma copy number (pCN), thus enriching for MET-dependent states. PATIENTS AND METHODS: We interrogated cell-free DNA NGS results of 16,782 patients with newly diagnosed advanced NSCLC to identify those with MET amplification as reported using Guardant360. Co-occurring genomic mutations and copy number alterations within each sample were evaluated. An exploratory method of adjusting for tumor fraction was also performed and amplicon size for MET was analyzed when available. RESULTS: MET amplification was detected in 207 (1.2%) of samples. pCN ranged from 2.1 to 52.9. Of these, 43 (20.8%) had an overlapping oncogenic driver, including 23 (11.1%) METex14 skipping or other MET mutations. The degree of (non-MET) oncogene overlap decreased with increases in pCN. Patients with MET pCN ≥ 2.7 had lower rates of overlapping drivers compared to those with MET pCN < 2.7 (6.1% vs. 16.3%, P = .033). None of the 7 patients with pCN > 6.7 had an overlapping driver. After adjusting for tumor fraction, adjusted pCN (ApCN) was also lower for those with overlapping drivers than those without (median ApCN 4.9 vs. 7.3, P =.024). There was an inverse relationship between amplicon size and pCN. CONCLUSIONS: We propose that a high MET pCN and/or ApCN, together with the absence of overlapping oncogenic drivers and small MET amplicon size, will enrich for patients most likely to derive benefit from MET targeted therapy.

Keeping Secrets or Educating Others: A Dyadic Analysis of Group Entitativity's Influence on Spouses' Label Management Connected to AATD.

In 1963, Goffman argued that forming a group based on shared stigma may provide benefits. However, there is no empirical research on whether perception that a separate, unique, coherent group exists (i.e., group entitativity) influences coping, such as educating others or secrecy, for the stigmatized individual or his or her spouse. Further, little is known about how spouses influence each other in terms of promoting the education of others about a stigmatizing condition, especially when it comes to the role of believing that stigma-based groups, to which they may both belong, exist. This study provides a step toward bridging this gap in the research by applying the label management model in efforts to understand coping for couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). This study included 50 married couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). We found that group entitativity related to those with AATD counterbalanced the influence of genetic stigma on spouses' intentions to keep the diagnosis secret or to educate others about it. Intrapersonal and interpersonal influences appeared among spouses. Attention is needed on the power of creating groups for stigmatized persons and their relatives. Indeed, people live within a dynamic world of group entities, and multiple social identities including spousal and familial. While attention has been paid to the diffusion of stigmas to loved ones, less has been paid to the uplift of group entities for them.

Classifying married adults diagnosed with alpha-1 antitrypsin deficiency based on spousal communication patterns using latent class analysis: insights for intervention.

Married adults are increasingly exposed to test results that indicate an increased genetic risk for adult-onset conditions. For example, a SERPINA1 mutation, associated with alpha-1 antitrypsin deficiency (AATD), predisposes affected individuals to diseases such as chronic obstructive pulmonary disease (COPD) and cancer, which are often detected in adulthood. Married adults are likely to discuss genetic test results with their spouses, and interpersonal research suggests that spouses' communication patterns differ. Latent class analysis was used to identify subgroups of spousal communication patterns about AATD results from a sample of married adults in the Alpha-1 Research Registry (N = 130). A five-class model was identified, and the subgroups were consistent with existing spousal-communication typologies. This study also showed that genetic beliefs (e.g., genetic stigma), emotions, and experiences (e.g., insurance difficulties) covaried with membership in particular subgroups. Understanding these differences can serve as the foundation for the creation of effective, targeted communications interventions to address the specific needs and conversational patterns of different kinds of couples.

Alpha-1 couples: interpersonal and intrapersonal predictors of spousal communication and stress.

Couples often discuss genetic test results, and then manage their implications together. This interdependence can lead to common, shared experiences, similar intrapersonal processes to manage shared stressors, or interpersonal influences between spouses, leading to different outcomes. This study sought to reveal the intracouple, intrapersonal, and interpersonal influences of genetic stigma and negative feelings on spousal communication and perceived stress with 50 couples in which one spouse is a member of a genetic disease registry. The results were analyzed with dyadic analysis, including multilevel modeling. The findings showed that registered members and their spouses were not statistically different in their mean levels of perceived genetic stigma, negative feelings about alpha-1 antitrypsin deficiency (AATD), conversations with each other about the AATD test results, and their perceived stress. The findings also showed that their intracouple consistencies were not high, and their intrapersonal and interpersonal influences on communication and stress differed. The social implications of genetic research at the interpersonal level are discussed.

Genetics' influence on patient experiences with a rare chronic disorder: a photovoice study of living with alpha-1 antitrypsin deficiency.

Patients with rare chronic disorders and their caregivers increasingly form communities to support and exchange social experiences. Because up to 10% of the United States population is affected by one of 5000 to 6000 rare disorders, efforts to understand the individuals and affected communities are important. This study was conducted using community-based participatory research approaches within a community of patients and caregivers living with alpha-1 antitrypsin (AAT) deficiency. Patient populations at some risk for lung transplant include individuals who smoked cigarettes and patients who underwent liver transplant in infancy and later adulthood due to accumulation of misfolded AAT within hepatocytes.