Olson, Janet E.

Background: Breast cancer survivors face a risk of significant psychological distress, which can persist for years after their initial diagnosis. Although numerous guidelines and tools exist to help screen for and measure distress in patients with cancer, additional longitudinal studies are needed to better characterize the trajectory of distress over time. Patients and Methods: We conducted a longitudinal study to evaluate distress and health-related quality of life in patients with breast cancer. Annual assessments included global mental and physical health scores using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10), posttraumatic stress symptoms using the Impact of Event Scale-Revised (IES-R), and depressive symptoms using the Patient Health Questionnaire-2 (PHQ-2). Eligible participants had stage 0–III breast cancer, with baseline surveys administered within 1 year of diagnosis. Annual follow-up surveys were conducted through year 4 after the baseline survey. Only patients who completed the baseline survey and at least one follow-up survey were included in this analysis. Individuals with stage IV or recurrent breast cancer were excluded. Results: A total of 2,140 individuals were included. Over time, global mental health scores declined slightly, with differences in T-scores from baseline ranging from 0.4 to 0.9. In contrast, global physical health scores improved, with differences in T-scores ranging from 0.3 to 0.6. Mean scores remained in the normative range. Depressive symptoms remained stable throughout the study period, while posttraumatic stress symptoms showed improvement over time. Conclusions: This study provides important longitudinal data on distress subtypes in breast cancer survivors with nonmetastatic disease. Although global mental health declined slightly, depression symptoms remained stable, and posttraumatic stress symptoms improved. Investigation of distress subtypes over time merits further study to advance detection of significant distress across the cancer continuum.

Purpose The Sangre Por Salud (SPS) Biobank was established to facilitate biomedical research opportunities for the Latino community by creating an easily accessible prospective cohort for scientists interested in studying health conditions and health disparities in this population. Participants Individuals self-identifying as Latino, aged 18–85 years, were prospectively recruited from the primary care Internal Medicine clinic at Mountain Park Health Center in Phoenix, Arizona. After obtaining informed consent, detailed medical history questionnaires were captured, and blood samples were obtained for common laboratory tests. Participants authorised the research team to access their electronic health records for research purposes. In addition, participants had serum, plasma and DNA samples isolated and stored at the Mayo Clinic Arizona Biorepository Laboratory for long-term storage and future access. As part of the study, participants consented and agreed to be contacted for potential participation in future research studies. Findings to date 3756 participants provided informed consent, of whom 3733 completed all study questionnaires, an oral glucose tolerance test and had blood collected and stored. The SPS cohort is predominantly composed of females (72%), with a median age at time of consent of 42 years. All participants self-identified as Hispanic/Latino, 45% were married, 53% were employed for wages and 60% had less than a high school degree. Around 25% of participants met diagnostic criteria for overweight (BMI 25–29 kg/m 2 ), and 49% met for obesity (BMI≥30 kg/m 2 ). At time of recruitment, hypertension, hyperlipidaemia and depression affected 22%, 20% and 13% of the cohort, respectively. Future plans We plan to regularly update the participants’ electronic health records and self-reported health data to longitudinal research. Additionally, we plan to obtain a more comprehensive genomic analysis on the entire cohort, ensuring greater research interest and investigation into the underlying genetic factors that contribute to disease susceptibility in this cohort.

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

PURPOSE Over 50% of households in the United States have at least one musician—many musicians are also breast cancer survivors. This group has not been well studied, and given the level of fine sensory-motor skill required for musicianship, we hypothesized that musicians experience unique manifestations of breast cancer treatment toxicities. METHODS A nine-item Musical Toxicity Questionnaire (MTQ) was distributed to patients who had consented to participate in the Mayo Clinic Breast Cancer Registry. The MTQ screened participants by asking if they played a musical instrument or sang in the last 10 years: questions populated for those who answered yes. Respondents were asked if they noticed difficulty with their musical endeavor during or after breast cancer treatment, defined as acute musical toxicity (AMT). The questionnaire asked which side effect and cancer-directed therapy most influenced musical ability, what musical attributes were affected, and the timeline of resolution. Multivariable and classification tree analyses assessed relationships between AMT and treatment characteristics. RESULTS Of 1,871 survey respondents, 29% (535/1,871) self-identified as musicians. Over a quarter (27%, 144/535) reported AMT, and for 57% (82/144), AMT had not resolved at the time of survey. Of the treatments each participant received, chemotherapy was most often reported as most negatively impactful (63/89 who received chemotherapy, 71%). Decreased endurance was the most common musical difficulty (64% of those with AMT, 92/144), followed by decreased accuracy, trouble playing/singing quickly, and difficulty using proper technique. Multivariable and classification tree analyses revealed that receipt of chemotherapy was most strongly correlated with AMT. CONCLUSION These results will help oncology care teams counsel musicians, answer questions about impacts on musicality, and provide a timeline for resolution of musical symptoms.

Background: Monoclonal B-cell lymphocytosis (MBL) is a common premalignant condition that can be classified into chronic lymphocytic leukemia (CLL)-type (CD5, CD23, and CD20 co-expression), and non-CLL-type (CD5-negative) based on flow cytometry immunophenotypes. CLL-type MBL is relatively well characterized with increased risk of hematologic (especially lymphoid) malignancies, serious infections, and decreased response to vaccinations. However, the prevalence, genetic predispositions, and clinical consequences of non-CLL-type MBL remain to be fully elucidated. Herein, we report findings in non-CLL-type MBL in a large screening cohort. Methods: We screened 10,330 individuals (40 years or older with no prior history of hematologic cancers) for MBL with highly sensitive flow cytometry, in the Mayo Clinic Biobank, with patients recruited from primary care-based clinics. Individuals were genotyped by Regeneron Genetics. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Among those individuals residing in the 27 counties surrounding Rochester, Minnesota, we identified incident hematologic malignancies and melanomas using ICD codes and the Rochester Epidemiology Project, a population based medical records linkage system. All diagnoses were manually reviewed for confirmation. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, adjusted for age and sex. Results: We identified 1,736 individuals with MBL and 8,341 individuals without MBL. Among those with MBL, 246 (14.2%) had non-CLL-type MBL as the major clone. The median age of non-CLL-type MBL was 77 years (range, 47-95). The prevalence of non-CLL-type MBL significantly increased with age, with 0.5% prevalence among those between 40 to 59 years of age, 2.3% prevalence among those between 60 and 79 years, and 7.8% prevalence in those 80 years of age or older. The prevalence of non-CLL-type MBL was significantly higher (P < .001) among males (3.1%) than females (2.0%). Using the genome-wide complex trait analysis tool, the heritability of non-CLL-type MBL was estimated to be ~26%, suggesting inherited genetics plays a role in etiology. To identify common inherited variants, we first evaluated the known CLL susceptibility variants, many of which also associated with CLL-type MBL. Among the 42 variants, none were statistically associated (all P > .05) with non-CLL-type MBL. We next conducted a genome-wide association study to identify novel variants, and the most significant variant resided in 10q26.3 (minor allele frequency [MAF]control = 0.7%, MAFMBL = 3.5%, OR = 6.4, 95% CI 3.6-11.3, P = 5.7 * 10-8). Among the 6,478 individuals (192 with non-CLL-type MBL and 6,286 without MBL) followed for incident hematologic malignancies, 36 developed lymphoid and 23 developed myeloid malignancies after a median of 4.2 years of follow up. Similar to CLL-type MBL, non-CLL-type MBL was associated with a 5.2-fold risk for lymphoid malignancies (95% CI 2.0-13.0, P < .001). Elevated but not significant risks were observed for myeloid malignancies (HR = 2.3, 95% CI 0.5-10.3, P = 0.27). The lymphoid malignancies developed by individuals with non-CLL-type MBL included diffuse large B-cell lymphoma, multiple myeloma, marginal zone lymphoma, and other low-grade lymphomas. We recently reported that individuals with CLL-type MBL are at higher risk for developing melanoma (HR = 1.9, 95% CI 1.3-2.8). Interestingly, non-CLL-type MBL had no evidence of an association with melanoma risk (HR = 0.4, 95% CI 0.1-1.8). We did not observe a significant difference in overall survival between individuals with non-CLL-type MBL vs those without MBL. Conclusions: In the largest screening cohort to date, we evaluated the etiology and clinical outcomes of non-CLL-type MBL, an understudied yet common condition that occurs in ~4 million adults in the United States. Non-CLL-type MBL is more common in men and older individuals, and evidence supports that inherited genetics plays an etiological role with 10q26.3 locus identified as a novel susceptibility locus. Individuals with non-CLL-type MBL had significantly increased risk of lymphoid malignancies, similar to CLL-type MBL, but, distinct from CLL-type MBL, no evidence of an increased risk of melanoma. Our study provides insights into the prevalence, genetic predispositions and clinical consequences of non-CLL-type MBL and how it differs from the classic CLL-type MBL.

Background: Cardiomyopathies (CM) are a leading cause of heart failure. Identification of genetic risk preemptively may allow detection of the earliest phenotypic manifestations through implementation of interval-based cardiac screening. Previous population-based genetic screening studies have limited follow-up and inadequate phenotyping. Hypothesis: Disease penetrance of CM variants is significantly higher than previously reported. Aims: To determine the prevalence, penetrance, and disease expression of incidental CM-related genetic variants in an unselected, richly phenotyped, adult population. Methods: We analyzed a random sample of 10,000 patients from a quaternary medical center-based biobank cohort for reportable variants in 22-cardiomyopathy genes. Prioritization of genetic variants was performed using Semi-Automated Variant Interpretation, a novel software that has been previously developed and validated at our center. Prioritized variants were then manually curated by 2 independent variant interpretation specialists. Clinical phenotypes and outcomes of participants with likely pathogenic/pathogenic (LP/P) variants were determined. Results: LP/P cardiomyopathy variants were present in 1% of our cohort (n=104) within the following genes: TNNT2 (n=1), DES (n=2), LMNA (n=2), MYL2 (n=2), TNNI3 (n=2), DSG (n=4), FLNC (n=4), DSC2 (n=6), SCN5A (n=7), PKP2 (n=10), DSP (n=12), MYH7 (n=14), TTN (n=17), MYBPC3 (n=21). Only 1 participant carried two different LP/P variants. A definitive disease penetrance defined as heart failure or cardiomyopathy was found in 34% of genotype positive (G+) individuals. Possible disease penetrance defined as presence of structural heart disease identified by echocardiography was found in an additional 16% of participants (concentric left ventricular hypertrophy, diastolic dysfunction, biatrial and left atrial enlargement). Combined definitive and possible disease penetrance was found in 50% of G+ individuals. Arrhythmias and/or cardiac conduction disease (atrial fibrillation, atrioventricular block, ventricular arrhythmia) were present in 31% of G+ individuals. Conclusion: Cardiomyopathy associated LP/P variants are present in a small subset of a large quaternary medical center population as previously reported but unlike prior studies, disease penetrance manifesting as cardiac structural abnormalities and heart failure is high in G+ individuals.

Abstract Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS). Experimental Design: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort. Results: Germline PV were observed in 6.5% and 4.6% of women with DCIS in the clinical testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PV frequencies were significantly lower among women with DCIS than those with IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PV were significantly associated with an increased risk of DCIS (OR > 2.0), but only BRCA2 PV were associated with high risk (OR > 4) in both cohorts. The cumulative incidence of CBC among carriers of PV in high-penetrance genes with DCIS was 23% over 15 years. Conclusions: The enrichment of PV in ATM, BRCA1, BRCA2, CHEK2, and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of CBC in carriers of PV in high-penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

PURPOSE Chronic lymphocytic leukemia (CLL)–phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL. METHODS Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening. Eight-color flow cytometry was used to screen for MBL. Individuals with MBL were classified as low-count MBL (LC-MBL) or high-count MBL on the basis of clonal B-cell percent. Incident melanomas were identified using International Classification of Diseases codes and confirmed via medical records review. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI. RESULTS Of the 7,334 participants screened, 1,151 were identified with a CD5-positive MBL, of whom 1,098 had LC-MBL. After a median follow-up of 3.2 years (range, 0-13.5), 131 participants developed melanoma, of whom 36 individuals were positive for MBL. The estimated 5-year cumulative incidence of melanoma was 3.4% and 2.0% among those with and without MBL, respectively. After adjusting for age, sex, and history of previous melanoma, individuals with MBL exhibited a 1.86-fold (95% CI, 1.25 to 2.78) risk of melanoma. This elevated risk persisted when analysis was restricted to those without a history of melanoma (HR, 2.05 [95% CI, 1.30 to 3.23]). Individuals with LC-MBL had a 1.92-fold (95% CI, 1.29 to 2.87) increased risk of developing melanoma overall and a 2.74-fold increased risk (95% CI, 1.50 to 5.03) of melanoma in situ compared with those without MBL. CONCLUSION LC-MBL is associated with an approximately two-fold increased risk of melanoma overall and a 2.74-fold increased risk of melanoma in situ.

Background: Large biobanks that link biological specimens with specimen donors’ health histories are a critical tool for precision medicine, and many health care institutions have invested significant resources in setting up and building up large collections for this purpose. As biobanks require consented participation from thousands of individual donors, much research has focused on the values and preferences of new and prospective donors who are actively contemplating an invitation to participate in the collection. Few studies, however, have focused on participants’ opinions about their biobank participation in the months and years following enrollment. Methods: We conducted a survey in a large, established biobank and evaluated participants’ levels of decisional regret regarding their decision to enroll in the biobank. Results: We found very low levels of decisional regret among established biobank participants. Multivariable regression analysis found that age, length of time in the biobank, lower educational attainment, inadequate health literacy, and previous invitations to research participation were all significant predictors of elevated regret. Discussion: Among those with elevated regret, several demographic factors may point to elevated likelihood of decisional regret. More research is needed to identify factors associated with long-term satisfaction with biobank participation and with elevated risk of regret and/or withdrawal from the collection.