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Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility. Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Using the PanScan datasets, we tested for association of 38 variants within 37 genomic regions known to be susceptibility factors for type 2 diabetes. We further examined whether type 2 diabetes variants predispose to pancreatic cancer risk stratified by diabetes status. Correspondingly, we examined the association of fourteen pancreatic cancer susceptibility variants within eight genomic regions in the GENEVA Type 2 Diabetes dataset. Four plausible associations of diabetes variants and pancreatic cancer risk were detected at a significance threshold of p = 0.05, and one pancreatic cancer susceptibility variant was associated with diabetes risk at threshold of p = 0.05, but none remained significant after correction for multiple comparisons. Currently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.

Germline mutations in CDKN2A have been reported in pancreatic cancer families, but genetic counseling for pancreatic cancer risk has been limited by lack of information on CDKN2A mutation carriers outside of selected pancreatic or melanoma kindreds. Lymphocyte DNA from consecutive, unselected white non-Hispanic patients with pancreatic adenocarcinoma was used to sequence CDKN2A . Frequencies of mutations that alter the coding of p16INK4 or p14ARF were quantified overall and in subgroups. Penetrance and likelihood of carrying mutations by family history were estimated. Among 1537 cases, 9 (0.6%) carried germline mutations in CDKN2A , including three previously unreported mutations. CDKN2A mutation carriers were more likely to have a family history of pancreatic cancer ( P =0.003) or melanoma ( P =0.03), and a personal history of melanoma ( P =0.01). Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer (95% confidence interval (CI) 8–86%), and 39% for melanoma (95% CI 0–80). Among cases who ever smoked cigarettes, the risk for pancreatic cancer was higher for carriers compared with non-carriers (HR 25.8, P =2.1 × 10 −13 ), but among nonsmokers, this comparison did not reach statistical significance. Germline mutations in CDKN2A among unselected pancreatic cancer patients are uncommon, although notably penetrant, especially among smokers. Carriers of germline mutations of CDKN2A should be counseled to avoid tobacco use to decrease risk of pancreatic cancer in addition to taking measures to decrease melanoma risk.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL. In this single‐institution study of CLL patients receiving ibrutinib therapy outside the context of a clinical trial, approximately 40% patients initiated ibrutinib at a reduced dose (<420 mg daily, primarily due to concomitant medications that may increase ibrutinib toxicity and physician prescribing patterns). In addition, approximately 50% patients subsequently undergo a dose modification and/or a dose interruption after initiation of ibrutinib therapy. Finally, although ibrutinib starting dose and dose modifications did not impact event free survival and overall survival, temporary dose interruptions during therapy were associated with shorter event free survival and shorter overall survival.

MBL is a precursor condition to chronic lymphocytic leukemia (CLL), characterized by monoclonal B-cells in blood. Mosaic chromosomal alterations (mCAs) are a form of clonal hematopoiesis that include gains, losses, and copy-neutral loss-of-heterozygosity of large DNA segments. Both MBL and mCAs have been found to increase the risk of CLL and lymphoid malignancies, and the aim of our study was to investigate how mCAs relate to MBL, which is currently unknown. We analyzed genetic, flow cytometric, and hematologic data from 4632 individuals from the Mayo Clinic Biobank and CLL Database. MBL was detected using flow cytometry and classified as high-count (HC) or low-count (LC) MBL based on clone size. mCAs were detected primarily from whole blood DNA using sensitive SNP-array-based analyses. mCAs commonly altered in CLL (deletion of 6q, 11q, 13q, 17p, and trisomy 12) were specific (>99%) to individuals with MBL and CLL. HC-MBL and LC-MBL individuals were 881-fold and 8-fold, respectively, more likely to harbor CLL-associated mCAs than those without MBL. The cell fraction bearing these mCAs typically exceeded the B-cell fraction, suggesting their origin prior to the B-cell lineage. Integrating genetic and blood count data enabled detecting HC-MBL with high specificity in a biobank sample. These results quantify the contribution of mCAs to MBL and could enable large studies of HC-MBL without the need for flow cytometric screening.

Despite the considerable effort to characterize the genomic landscape of chronic lymphocytic leukemia (CLL), published data have been almost exclusively derived from patients of European Ancestry (EA), with significant underrepresentation of minorities, including patients of African Ancestry (AA). To begin to address this gap, we evaluated whether differences exist in the genetic and transcriptomic features of 157 AA and 440 EA individuals diagnosed with CLL. We sequenced 59 putative driver genes and found an increased frequency of high-impact mutations in AA CLL, including genes of the DNA damage repair (DDR) pathway. Telomere erosion was also increased in AA CLL, amplifying the notion of increased genomic instability in AA CLL. Furthermore, we found transcription enrichment of the Tumor Necrosis Factor-alpha (TNFα) Signaling via NF-κB pathway in AA CLL compared to EA CLL, suggesting that tumor promoting inflammation plays an important role in AA CLL. In summary, these results suggest that genomic instability and NF-kB activation is more prevalent in AA CLL than EA CLL.

Monoclonal B-cell lymphocytosis (MBL) and clonal hematopoiesis of indeterminate potential (CHIP) are prevalent clonal precursors associated with increased risk of lymphoid malignancies. However, the relationship between MBL and CHIP and their combined impact on lymphoid malignancy risk remains poorly understood. We screened participants from the Mayo Clinic Biobank to identify MBL using eight-color flow cytometry; CHIP was detected using whole-exome sequencing of whole-blood DNA in 291 genes related to myeloid or lymphoid malignancies. Incident myeloid or lymphoid hematological malignancies were identified using ICD codes and confirmed via medical record review. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Cox regression was used to estimate hazard ratios (HR). Analyses were adjusted for age and sex. In 10,067 participants, 15% had MBL, and 9% had CHIP. No evidence of an association between MBL and CHIP (OR = 1.00; 95% CI: 0.82–1.20) was observed. With a median follow-up of 5.4 years, 138 participants developed hematological malignancies (94 lymphoid). MBL (HR = 3.48; 95% CI: 2.27–5.34; P  < 0.001) and CHIP (HR = 1.89; 95% CI: 1.10–3.27; P  = 0.022) were each associated with incident lymphoid malignancy. Compared to individuals with no precursors, the combined presence of MBL and CHIP significantly amplified lymphoma risk (HR = 7.18; 95% CI: 3.33–15.47; P  < 0.001), more than doubling the risk among individuals with MBL alone (HR = 3.30; 95% CI: 2.06–5.30; P  < 0.001). In contrast, the risk associated with CHIP alone was attenuated and no longer statistically significant (HR = 1.63; 95% CI: 0.77–3.47; P  = 0.20). MBL and CHIP are independent hematological precursor conditions. While their combined presence amplifies the risk of lymphoid malignancy, CHIP alone may not be a strong independent risk factor.

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. A better understanding of expected outcomes in these patients is necessary to establish a benchmark for evaluating novel agents currently available and in development. We evaluated outcomes of 144 patients with CLL treated at Mayo Clinic with 2018 iwCLL disease progression on ibrutinib. The median overall survival (OS) for the entire cohort was 25.5 months; it was 29.8 months and 8.3 months among patients with CLL progression (n = 104) and Richter transformation (n = 38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline compared to relapsed/refractory setting (not reached versus 28.5 months; p = 0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p = 0.24). Among patients with CLL disease progression on ibrutinib, OS was significantly longer when next-line treatment was chimeric antigen receptor T-cell therapy (median not reached) or venetoclax-based treatment (median 29.8 months) compared to other approved treatments, such as chemoimmunotherapy, phosphoinositide 3’-kinase inhibitors, and anti-CD20 monoclonal antibodies (9.1 months; p = 0.03). These findings suggest an unmet need for this growing patient population.

The distinction between chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with isolated Hodgkin/Reed–Sternberg cells (CLL-HRS; background milieu with a paucity of inflammatory cells) and overt transformation to classic Hodgkin lymphoma (CLL-HL; mixed inflammatory background) is incompletely understood. This retrospective study examined the clinicopathologic features of CLL-HRS (n = 15) and CLL-HL (n = 31) patients seen over the past three decades from a single institution. The phenotypic features of Reed–Sternberg cells in both groups were similar, including expression of CD30, CD15, and PAX5, as well as EBV status. However, a spectrum of background CLL/SLL infiltration amongst the HRS cells was noted on pathologic review, and four patients had both diagnoses, either concurrently or in succession. The median overall survival (OS) of patients with CLL-HRS was 17.5 months compared to 33.5 months for patients with CLL-HL (P = 0.24). Among patients with CLL-HRS, those who received Hodgkin-directed therapy had a significantly longer median OS (57 months) compared to those who received CLL-directed therapy (8.4 months, P = 0.02). Our clinical and pathologic findings suggest a biologic continuum between CLL-HRS and CLL-HL and indicate that CLL-HRS patients may benefit from Hodgkin-directed therapy.

Background Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging due to biological and technical sources of heterogeneity that vary across the genome within and between samples. Methods We developed an approach called CNPBayes to identify latent batch effects in genome-wide association studies involving copy number, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. Results Applying a hidden Markov model (HMM) to identify CNVs in a large multi-site Pancreatic Cancer Case Control study (PanC4) of 7598 participants, we found CNV inference was highly sensitive to technical noise that varied appreciably among participants. Applying CNPBayes to this dataset, we found that the major sources of technical variation were linked to sample processing by the centralized laboratory and not the individual study sites. Modeling the latent batch effects at each CNV region hierarchically, we developed probabilistic estimates of copy number that were directly incorporated in a Bayesian regression model for pancreatic cancer risk. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Suppressor Candidate 3 ( TUSC3 ). Conclusions Laboratory effects may not account for the major sources of technical variation in genome-wide association studies. This study provides a robust Bayesian inferential framework for identifying latent batch effects, estimating copy number, and evaluating the role of copy number in heritable diseases.