Citations

Abstract CLL is a highly heritable cancer with first degree relatives of CLL cases having a 7.5-fold increased CLL risk. Genome-wide association studies (GWAS) and linkage studies have been performed to study inherited predisposition; however a larger proportion of heritability to CLL remains unexplained. Rare coding variants might account for the missing heritability information. Inherited loss of function variants in shelterin complex genes (POT1, ACD, TERF1, TINF2, TERF2, TERF2IP- involved in telomere regulation), CDK1 (critical for cell division) and ATM (tumor suppressor gene) have been found to co-segregate in CLL families and be enriched in CLL cases using exome-wide sequencing data. Our study evaluates rare germline variants from these suspect genes segregating in CLL families who are followed at the Mayo Clinic. Using whole exome sequencing (WES), we sequenced 93 CLL families with at least 2 reported CLL cases consisting of 443 individuals: 160 with CLL, 73 with monoclonal B-cell lymphocytosis (MBL), and 210 relatives. DNA was extracted from buccal cells, coding exons were selectively captured using Agilent 50Mb and SureSelect Human All Exon V4 capture kits; sequencing was performed using Illumina HiSeq 2000. Mayo Clinic's DNASeq pipeline uses Novoalign (initial read alignment), Picard (marking duplicate reads), and the Genome Analysis Toolkit (GATK) for local realignment, recalibration, and variant calling. The variant discovery step leverages GATK's HaplotypeCaller in per sample mode and all of the samples across the cohort are jointly genotyped together. All called variants are evaluated with GATK's Variant Quality Score Recalibration tool and annotated for biological relevance (BIOR). Quality control included removing variants that had <75% call rate across the two capture kits, <8x coverage, or phred score<10, resulting in 317,666 remaining variants. Of these, over 80% of the coding sequence had a median read depth of 23 reads. In our pedigrees, we searched for rare variants within the genes described above. We identified suspect variants with the following criteria: 1) enriched in CLL and MBL samples compared to unaffected samples; 2) multiple affected members with the variant within a family; 3) variants present in all sequenced affecteds within the family; 4) rarely seen in an in-house database of non-cancer controls or 1K Genomes; and 5) predicted to have a functional damaging effect (using SIFT). We identified three novel rare missense variants, defined as functionally deleterious, which each co-segregated within a CLL family. Specifically, these variants from shelterin complex genes; POT1 (rs116916706), TERF2IP (rs138458227), and TERF2 (rs749171225), met the criteria. This study further highlights telomere dysregulation as a key process in CLL development. Investigating rare variants within CLL pedigrees with WES can help identify germline variants impacting predisposition to familial CLL. Citation Format: Alyssa I. Clay-Gilmour, Daniel R. O'Brien, Sara J. Achenbach, Celine M. Vachon, Kari G. Chaffee, Timothy G. Call, Jose F. Leis, Aaron D. Norman, Brian F. Kabat, Sameer A. Parikh, Neil E. Kay, Esteban Braggio, James R. Cerhan, Susan L. Slager. Rare germline variants segregating in chronic lymphocytic leukemia (CLL) families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1226.

AbstractOur aim was to evaluate whether quality of life (QOL) scores at diagnosis predict survival among patients with aggressive lymphoma. Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE and systematically followed for event‐free and overall survival (OS). QOL was measured with the Functional Assessment of Cancer Treatment‐General (FACT‐G), which measures 4 domains: physical, social/family, emotional, and functional well‐being (WB); a single item Linear Analogue Self‐Assessment (LASA) measuring overall QOL; and a spiritual WB LASA. From 9/2002 to 12/2009, 701 patients with aggressive lymphoma who completed baseline QOL questionnaires were enrolled. At a median follow‐up of 71 months (range 6‐128), 316 patients (45%) had an event and 228 patients (33%) died. All baseline QOL measures but emotional WB were significantly associated with OS (all P < 0.04); of which all but LASA spiritual remained significant after adjusting for IPI and NHL subtype. The strongest associations were with total FACT‐G (adjusted HR = 0.86, 95% CI: 0.79‐0.94, P = 0.00062) and functional WB (adjusted HR = 0.88, 95% CI: 0.83‐0.93, P < .0001). QOL LASA was associated with OS (adjusted HR = 0.92, 95% CI: 0.87‐0.97, P = 0.0041). Patients with clinically deficient QOL (overall QOL ≤50) had a median OS of 92 months compared with 121 months for patients with QOL >50 (P = 0.0004). In this large sample of patients with aggressive lymphoma, we found that baseline QOL is independently predictive of OS. QOL should be assessed as a prognostic factor in patients with aggressive lymphoma.

95 Background: While PA is known to improve quality of life in lymphoma pts, its impact on OS is not known. We studied the effect of PA on OS in lymphoma pts enrolled at diagnosis in the Iowa/Mayo Molecular Epidemiology Resource. Methods: Godin Leisure Score Index (LSI; Range 0-50) was calculated based on level of PA pre-diagnosis (baseline) and 3 years post diagnosis (FU3), with pts grouped by tertile into high, moderate, or low PA. At FU3, pts also reported perceived change in PA since diagnosis. OS was measured as time from assessment (baseline or FU3) until death from any cause. Associations between LSI tertiles and OS were assessed using Cox models adjusted for lymphoma subtype, age and sex. Results: PA level was available for 3060 pts at baseline and 1371 pts at FU3. 95% had an ECOG performance status < 2, 37% had an aggressive subtype, 29% had BMI ≥ 30, and 54% were age > 60. Indolent lymphoma pts with higher PA at baseline had no difference in OS. Higher PA at FU3 had improved OS (moderate vs low HR 0.63, CI 0.42-0.93; high vs low HR 0.53, CI 0.33-0.86). Pts with BMI < 30 who had higher PA at baseline showed no difference in OS. Higher PA at FU3 had improved OS for pts with BMI < 30 (moderate vs low HR 0.68 CI, 0.48-0.98; high vs low HR = 0.41, CI 0.26-0.64). For pts > 60 years, high vs low baseline PA showed improved OS (HR 0.77, CI 0.63-0.93). Higher PA at FU3 (moderate vs low HR 0.68 CI 0.48-0.96, high vs low HR 0.53 CI 0.34-0.83) was associated with OS. At FU3, compared to no change, perceived reduction of PA was associated with worse OS for indolent lymphoma (HR 2.13, CI 1.56-2.91), BMI < 30 (HR 1.95, CI 1.45-2.62), BMI > 30 (HR 2.00, CI 1.21-3.30), age ≤ 60 (HR 3.06, CI 1.72-5.46), and age > 60 (HR 1.98, CI 1.52-2.58). Perceived increase in PA was not associated with OS. Higher PA in pts with aggressive lymphoma, BMI ≥30, and age < 60 was not significantly associated with OS but trended similarly. All results were similar when analyzing by continuous LSI score. Conclusions: Higher levels of PA, especially at FU3, were associated with superior OS. The effect was more pronounced in pts with indolent lymphoma, BMI < 30, or age > 60. Perceived reduction in PA was associated with worse outcomes. PA should be incorporated into lymphoma survivorship plans.

SummaryWe evaluated the association of Human Pegivirus (HPgV) viraemia with risk of developing lymphoma, overall and by major subtypes. Because this virus has also been associated with better prognosis in the setting of co‐infection with human immunodeficiency virus, we further assessed the association of HPgV with prognosis. We used risk factor data and banked plasma samples from 2094 lymphoma cases newly diagnosed between 2002 and 2009 and 1572 frequency‐matched controls. Plasma samples were tested for HPgV RNA by reverse transcription polymerase chain reaction (RT‐PCR), and those with RNA concentrations <5000 genome equivalents/ml were confirmed using nested RT‐PCR methods. To assess the role of HPgV in lymphoma prognosis, we used 2948 cases from a cohort study of newly diagnosed lymphoma patients (included all cases from the case‐control study). There was a positive association of HPgV viraemia with risk of lymphoma overall (Odds ratio = 2·14; 95% confidence interval [CI] 1·63–2·80; P < 0·0001), and for all major subtypes except Hodgkin lymphoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma, and this was not confounded by other lymphoma risk factors. In contrast, there was no association of HPgV viraemia with event‐free survival (Hazard ratio [HR] = 1·00; 95% CI 0·85–1·18) or overall survival (HR = 0·97; 95% CI 0·79–1·20) for lymphoma overall, or any of the subtypes. These data support the hypothesis for a role of HPgV in the aetiology of multiple lymphoma subtypes.

Objective Using surveys to collect self-reported information on health and disease is commonly used in clinical practice and epidemiological research. However, the inconsistency of self-reported information collected longitudinally in repeated surveys is not well investigated. We aimed to investigate whether a socioeconomic status based on current housing characteristics, HOUsing-based SocioEconomic Status (HOUSES) index linking current address information to real estate property data, is associated with inconsistent self-reporting. Study setting and participants We performed a prospective cohort study using the Mayo Clinic Biobank (MCB) participants who resided in Olmsted County, Minnesota, USA, at the time of enrolment between 2009 and 2013, and were invited for a 4-year follow-up survey (n=11 717). Primary and secondary outcome measures Using repeated survey data collected at the baseline and 4 years later, the primary outcome was the inconsistency in survey results when reporting prevalent diseases, defined by reporting to have ‘ever’ been diagnosed with a given disease in the baseline survey but reported ‘never’ in the follow-up survey. Secondary outcome was the response rate for the 4-year follow-up survey. Results Among the MCB participants invited for the 4-year follow-up survey, 8508/11 717 (73%) responded to the survey. Forty-three per cent had at least one inconsistent self-reported disease. Lower HOUSES was associated with higher inconsistency rates, and the association remained significant after pertinent characteristics such as age and perceived general health (OR=1.46; 95% CI 1.17 to 1.84 for the lowest compared with the highest HOUSES decile). HOUSES was also associated with lower response rate for the follow-up survey (56% vs 77% for the lowest vs the highest HOUSES decile). Conclusion This study demonstrates the importance of using the HOUSES index that reflects current SES when using self-reporting through repeated surveys, as the HOUSES index at baseline survey was inversely associated with inconsistent self-report and the response rate for the follow-up survey.

Abstract A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend &lt; 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

Key Points PRS, based on the known CLL loci, predicts CLL risk with high discrimination. This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

Key Points In FL, no prognostic index has been built based solely on a large cohort of patients treated with initial immunochemotherapy. The PRIMA-PI is a simplified index based on β2m and bone marrow involvement for patients treated with immunochemotherapy.