Vachon, Celine M.

PURPOSE Breast density is a widely established independent breast cancer risk factor. With the increasing utilization of digital breast tomosynthesis (DBT) in breast cancer screening, there is an opportunity to estimate volumetric breast density (VBD) routinely. However, current available methods extrapolate VBD from two-dimensional (2D) images acquired using DBT and/or depend on the existence of raw DBT data, which is rarely archived by clinical centers because of storage constraints. METHODS We retrospectively analyzed 1,080 nonactionable three-dimensional (3D) reconstructed DBT screening examinations acquired between 2011 and 2016. Reference tissue segmentations were generated using previously validated software that uses 3D reconstructed slices and raw 2D DBT data. We developed a deep learning (DL) model that segments dense and fatty breast tissue from background. We then applied this model to estimate %VBD and absolute dense volume (ADV) in cm 3 in a separate case-control sample (180 cases and 654 controls). We created two conditional logistic regression models, relating each model-derived density measurement to likelihood of contralateral breast cancer diagnosis, adjusted for age, BMI, family history, and menopausal status. RESULTS The DL model achieved unweighted and weighted Dice scores of 0.88 (standard deviation [SD] = 0.08) and 0.76 (SD = 0.15), respectively, on the held-out test set, demonstrating good agreement between the model and 3D reference segmentations. There was a significant association between the odds of breast cancer diagnosis and model-derived VBD (odds ratio [OR], 1.41 [95 % CI, 1.13 to 1.77]; P = .002), with an AUC of 0.65 (95% CI, 0.60 to 0.69). ADV was also significantly associated with breast cancer diagnosis (OR, 1.45 [95% CI, 1.22 to 1.73]; P < .001) with an AUC of 0.67 (95% CI, 0.62 to 0.71). CONCLUSION DL-derived density measures derived from 3D reconstructed DBT images are associated with breast cancer diagnosis.

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 &lt; .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 &gt; .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 &lt; .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: Immune dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and several studies suggest that hypogammaglobulinemia at the time of CLL diagnosis may predict shorter time to first therapy (TTFT; Parikh et al, 2015). However, it is unclear if hypogammaglobulinemia can predict TTFT independent of the CLL-International Prognostic Index (CLL-IPI) and the tumor mutational load (TML). We sought to determine if serum immunoglobulin (Ig) levels at diagnosis can independently predict outcomes in patients with CLL and its precursor, high-count monoclonal B-cell lymphocytosis (MBL). Methods: We used the Mayo Clinic CLL Database to identify newly diagnosed CLL/MBL consented within 2 years of diagnosis. Next generation sequencing (NGS) was performed using a 59 gene panel (SureSelect) to detect mutated CLL genes. Serum Ig levels were quantitated by radial immunodiffusion (Immunoplates). Serum Ig levels below the lower limit of normal were defined as hypogammaglobulinemia. We used Chi-squared or Fisher's exact tests to compare discrete variables and the Kruskal Wallis test for continuous variables. TTFT was calculated from date of diagnosis to date of first treatment or date last known to be untreated. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for TTFT and overall survival (OS) associations. Results: We identified 895 newly diagnosed patients (588 CLL and 307 MBL) who had undergone NGS for recurrent somatic mutations and had serum Ig levels available at the time of diagnosis. The median absolute B-cell count was 6.7 x109/L; 613 (69%) were male, 375 (42%) had unmutated IGHV genes, and 81 (9%) had TP53 disruption. Based on CLL-IPI, 412 (46%) patients had low risk, 285 (32%) had intermediate risk, and 198 (22%) had high/very high risk. The most commonly mutated genes were NOTCH1 (14%), SF3B1 (11%), TP53 (10%), NFKBIE (8%), ATM (6%), and BIRC3 (6%). Based on the number of genes with high impact or hotspot mutations, we classified 40%, 29%, and 31% patients with TML scores of 0, 1, or 2+, respectively. At CLL/MBL diagnosis, the median serum IgG, IgA, and IgM was 891 mg/dL (111-2620), 121 mg/dL (1-1150), and 44 mg/dL (5-1320), respectively; 284 (32%) patients had low serum IgG, 128 (17%) had low serum IgA, and 322 (42%) had low serum IgM. Low serum IgA was associated with mutations in NOTCH1, SF3B1, ATM, BIRC3 and NFKBIE, low IgM was associated with SF3B1 and BIRC3 mutations (all comparisons, P &lt; .05), and low IgG was associated with BIRC3 mutation (P = .05). The median follow-up for the cohort was 8.4 years. A total of 359 patients progressed requiring therapy (299 CLL and 60 MBL), and 265 patients died (177 CLL and 88 MBL). The TTFT was significantly shorter for patients with low serum IgG compared to normal serum IgG at diagnosis (median 4.4 vs 10.8 years) and similar findings were observed in individuals with low serum IgA (1.7 vs 10.8 years) and those with low serum IgM (4.6 vs 11.1 years). On univariable analysis, the following were associated with a shorter TTFT: low serum IgG (HR: 1.8, 95% CI 1.4-2.2), low serum IgA (HR: 3.5, 95% CI 2.7-4.4), low serum IgM (HR: 1.9, 95% CI 1.5-2.3), TML score of 1 (HR: 1.7, 95% CI 1.3-2.2), TML of 2+ (HR: 4.4, 95% CI 3.4-5.7), CLL-IPI intermediate risk (HR: 3.7, 95% CI 2.8-4.8), and CLL-IPI high/very high risk (HR: 7.6, 95% CI 5.8-10.1) (all comparisons, P &lt; .0001). In multivariable analyses after adjusting for CLL-IPI and TML, low serum levels of IgG (HR: 1.8, 95% CI: 1.5-2.3), IgA (HR: 2.4, 95% CI: 1.8-3.0), and IgM (HR: 1.8, 95% CI: 1.5-2.3) were independently associated with a shorter TTFT (all comparisons, P &lt; .0001). No significant differences in OS were detected between patients with low and normal serum IgG, IgM, and IgA on univariate analysis. Similar results for TTFT and OS were observed after adding clonal B-cell count to the Cox model. Conclusions: Our study shows that low serum Ig levels at the time of initial diagnosis is predictive of TTFT independently of the CLL-IPI and TML, which can further risk stratify individuals with newly diagnosed CLL/MBL. Additionally, low serum IgA, IgM, and IgG levels at diagnosis are significantly associated with specific somatic mutations in individuals with newly diagnosed CLL/MBL.

Background: Chronic lymphocytic leukemia (CLL) is one of the most common leukemias in the United States (US), with an estimated incidence of 20,700 cases in 2024. Population-based studies conducted in Olmsted County (OC), Minnesota, reported an increase in CLL incidence over a 55-year period (1935 through 1989), which was attributed to increased detection of early-stage cases in individuals over age 50. In an updated study from 2000 to 2010 in OC, we reported no further increase in the incidence of CLL using the 2008 International Workshop on CLL (IWCLL 2008) guidelines. Additionally, when we compared the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria with the IWCLL 2008 guidelines incorporating the monoclonal B-cell lymphocytosis designation, we found that the use of the IWCLL 2008 guidelines reduced the overt CLL incidence, modified the distribution of Rai Stages at diagnosis, and shortened the median time to first treatment (TTFT). Over the last two decades, 5-year survival for CLL has increased due to new therapies and improved supportive care. Herein we provide updated data on the incidence, prevalence, and natural progression of CLL in OC and studied similar features in an expanded 6-county region around Mayo Clinic, Rochester. Methods: We utilized the Rochester Epidemiology Project (REP), a population-based medical records linkage system, to identify CLL cases from 2000 to 2020 using International Classification of Diseases codes. We included individuals residing in OC and the expanded 7-county region (REP-7, including OC), for which data became available starting in 2010. CLL cases were included if they met the IWCLL 2008 criteria. All CLL diagnoses were confirmed by manual review of medical records and data on CLL-related factors were collected, including treatment status, prior history of other cancers, and overall survival (OS). Age- and sex-specific incidence rates were derived from REP census data and adjusted to the 2020 US white population. OS analyses were conducted using the Kaplan-Meier method. TTFT was calculated with death as a competing risk. Cox regression was used to evaluate the effect of decade on TTFT and OS among patients in OC. Results: From 2010-2020, 242 patients were diagnosed with CLL in REP-7, and between 2000-2020, 174 patients were diagnosed in OC. Among the 242 CLL patients in REP-7, the median age at diagnosis was 71 years (range 30-96),158 (65%) were male, 236 (99%) were white, and 74 (31%) had a history of other cancer, with non-melanoma skin cancer being the most common. After age and sex adjustment to the 2020 US white population, the CLL incidence in REP-7 and OC from 2010 to 2020 was 7.8 and 8.1 per 100,000 individuals, respectively. In OC, the age- and sex-adjusted CLL incidence from 2000 to 2020 was 7.5 per 100,000 individuals, showing no significant trend changes over time. Among the 242 patients diagnosed with CLL in REP-7 between 2010 and 2020, 102 received treatment with a median TTFT of 9.8 years. In OC from 2000 to 2020, 79 out of 174 patients received treatment with a median TTFT of 9.4 years. When comparing across two decades in OC, the median TTFT was 12.8 years for the period from 2000 to 2009, decreasing to 5.9 years between 2010 and 2020, but was not significantly different after accounting for age and sex. The median OS for patients diagnosed with CLL in REP-7 from 2010 to 2020 was 11 years. The median OS for patients in OC between 2000 to 2020 was 12.6 years. When comparing across decades in OC, the median OS was 8.9 years for the period from 2000 to 2009, increasing to 13.6 years for those diagnosed between 2010 and 2020, but this trend was not significantly different after accounting for age and sex. Prevalence data for REP-7 and OC were analyzed as of 01/01/2020. Additionally, prevalence data for OC were available for 01/01/2010. In REP-7, the prevalence of CLL was 97 per 100,000 individuals on 01/01/2020. In OC, the CLL prevalence was 86 per 100,000 individuals on 01/01/2010, and 100 per 100,000 individuals on 01/01/2020. Conclusions: We observed no substantial increase in the incidence rates of CLL in REP-7 from 2010 to 2020, nor in the 20 years of available data from OC. However, the prevalence of CLL in OC increased by 16% from 2010 to 2020. Additionally, evidence indicated a longer OS among newly diagnosed CLL cases in OC compared to previous decades, suggesting a potential impact of improved therapeutic approaches on OS.

Introduction: Over 80,000 new cases of Non-Hodgkin's Lymphoma (NHL) are diagnosed annually, but modifiable risk factors are largely unknown. Circadian disruption has been identified as a risk factor for several cancers, including breast and prostate cancer, and affects immune cells such as Natural Killer (NK) cells and T-helper cells. Disruptions in circadian rhythms can lead to aberrant immune cell trafficking and proliferation. Despite this biological connection, evidence linking circadian disruptions to NHL remains inconclusive. Only single Mendelian Randomization (MR) study (PMID: 32895918) has explored the causal relationship between sleep traits and overall NHL risk, without examining NHL subtypes. Studies have shown distinct risk factor profiles among NHL subtypes. Therefore, this study aims to investigate the causal relationship between sleep traits and NHL subtypes in European populations using MR. Methods: We conducted a two-sample MR analyses using genome-wide association studies (GWAS) summary data on sleep traits and NHL subtypes. The GWAS summary statistics on sleep traits were obtained from publicly available UKBiobank datasets. The sleep traits analyzed included chronotype (N=449,734), insomnia (N=237,627), sleep duration (N=446,118), daytime sleepiness (N=452,071), short sleep (N=411,934), and long sleep (N=339,926). Only independent, genome-wide significant SNPs (p &lt; 5×10-8) were considered as valid instruments. The NHL subtype-specific summary statistics came from the InterLymph including follicular lymphoma (FL: N=6,508 cases / 64,183 controls), mantle cell lymphoma (MCL: N=1,169 cases / 61,603 controls), and Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: N=1,697 cases / 59,333 controls). Our primary analysis used the random-effects inverse-variance weighted (IVW) method. In addition, we employed MR-Egger to adjust for directional pleiotropy. Heterogeneity in the MR results was evaluated with Cochran's Q statistic. Results: The IVW method did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes (FL,MCL,WM/LPL), but did yield several intriguing associations. Chronotype (early rising) showed a tendency towards a marginally an increased NHL risk across subtypes [Odds ratio (OR) range: 1.07 - 2.56]. Conversely, a decreased risk was noted for long sleep (≥ 9 hours vs. 7-8 hours) [OR range: 0.19 - 0.62], insomnia [OR range: 0.72 - 0.88], and short sleep (excludes MCL) [OR range: 0.12 - 0.72]. Confidence limit for long sleep was wide due to small number of variants (N=8). The MR-Egger regression analysis did not provide evidence of significant directional horizontal pleiotropy. The F-statistics for all sleep traits were greater than 10 indicating absences of weak instrument bias. Conclusions: Our study found no statistically significant associations between sleep traits and three NHL subtypes (FL, MCL, WM/LPL) in European populations. However, we observed potential influences of chronotype, long and short sleep, and insomnia on NHL risk. These findings align with and extend previous MR study by providing subtype-specific insights. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses using the InterLymph population. These efforts aim to further elucidate the complex relationship between sleep characteristics and NHL risk across diverse subtypes and populations.

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 &gt; 2.0), but only BRCA2 PV were associated with high risk (OR &gt; 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.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.

Abstract Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited. Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case–control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium. Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had &gt;20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (&lt;20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population. Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification. Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.

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.

7011 Background: Monoclonal B-cell lymphocytosis (MBL) is a precursor to chronic lymphocytic leukemia (CLL) but also a risk factor for other lymphoid malignancies. Clonal hematopoiesis (CH), originally defined as the presence of mutations in myeloid driver genes, is a precursor to myeloid malignancies. Recently, CH that includes genes associated with lymphoid malignancies has been reportedly associated with risk of lymphoid malignancies, and particularly CLL. Little is known about the association between CH and MBL and their joint effects on risk of hematological malignancies (HM). Methods: Study participants were from the Mayo Clinic Biobank, a large-scale biorepository of patients who provided a peripheral blood sample. CH at enrollment was determined using whole-exome sequencing (50x coverage). Myeloid-CH (M-CH) was based on mutations located in 56 genes associated with myeloid malignancies. Lymphoid-CH (L-CH) was based on 235 genes associated with lymphoid malignancies. Individuals were screened for MBL using eight-color flow cytometry in two different cohorts of Biobank participants. Cohort 1 (N=3883) included participants who had available sample for MBL screening at enrollment. Cohort 2 (N=5684) were participants recontacted to provide a sample for MBL screening. Incident HM 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), with time defined as date between MBL sample and the first of incident HM, death, or 9/30/2023. Analyses were adjusted for age at MBL screening and sex. Results: In total, 9567 individuals (39% male, median age 66 years) were screened for MBL with available CH, of whom 17% were positive for MBL, 7% were positive for M-CH, and 2% were positive for L-CH. We found no evidence of an association between M-CH and MBL (OR=1.11, 95% CI:0.91-1.34) nor L-CH and MBL (OR=1.05, 95% CI:0.70-1.55). When subset to Cohort 1, where the same sample was used for both CH and MBL screening, the results held (M-CH OR=1.11, 95% CI: 0.83-1.48; L-CH OR=0.82, 95% CI:0.40-1.53). Next, we investigated the effect of each of these precursors with incident HM. Median follow-up was 4 years, and 78 individuals developed incident HM (31 myeloid, 49 lymphoid overall, 8 CLL). When modeling both precursors, both L-CH (HR=6.23, 95% CI:2.46-15.79) and MBL (HR=3.89, 95% CI:2.17-6.99) were independently associated with incident lymphoid malignancy. When excluding CLL events, the association held (L-CH: HR=5.94, 95% CI:2.11-16.77; MBL: HR=2.95, 95% CI:1.54-5.66). Only M-CH was significantly associated with incident myeloid malignancies. Conclusions: In the largest cohort with MBL and CH precursors measured, we found no evidence of an association between them. However, both MBL and L-CH were strong independent risk factors for incident lymphoid malignancies.