Genome-wide association studies (GWAS) have identified germline genetic variants for follicular lymphoma (FL) susceptibility. We conducted a GWAS of prognosis in FL patients to identify genetic predictors of event-free survival (EFS) as well as failure within the first 24 months after treatment initiation (EFS24) using patients treated with rituximab-based immunochemotherapy from three clinical trials and one prospective observational study (N = 1054). Statistical approaches consisted of a pooled GWAS of the four cohorts and a leave-one-cohort-out (LOCO) strategy to identify robust findings that replicated across the four cohorts. The top SNPs for EFS and EFS24 were marked by rs72625024 at 3q27.3 near FETUB and HRG (P = 9.37 × 10−8) and rs114695031 at 14q32.13 near TCL6 (P = 1.93 × 10−8), respectively. These two loci, which were discovered and validated in all 4 LOCO rounds, map near long-non-coding RNAs with putative tumor suppressor functions. Our results pinpoint potential novel biology and the contribution of host genetics to prognosis in FL.

Abstract Introduction: Oral targeted agents are active in MCL; however, most fail to induce deep or durable remissions as monotherapy. We developed the multi-agent ViPOR regimen to target B-cell receptor (BCR) signaling, BCL2, and CD20, and showed it to be safe and able to induce durable remissions in R/R DLBCL (Melani et al. NEJM. 2024). We hypothesized that fixed-duration ViPOR would be able to induce durable remissions in pts with MCL due to its dependence on BCR signaling and BCL2. Methods: TN and R/R MCL pts with adequate organ function were eligible. Venetoclax 400mg was given PO D2-14 on C2-6 with an initial 12d ramp-up on C2, with fixed-dose ibrutinib 560mg PO D1-14, prednisone 100mg PO D1-7, obinutuzumab 1000mg IV D1-2, and lenalidomide 15mg PO D1-14 on C1-6. ViPOR q21d x 6C was given without maintenance. TLS prophylaxis was given to all pts and R/R pts received G-CSF. Baseline CT, PET, BM, and tumor biopsy were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, and q12m x 2y. MRD was assessed in ctDNA from paired plasma and PBMC samples using clonoSEQ at baseline, during treatment, and in f/u. Results: 41 pts (21 R/R & 20 TN) were enrolled. Median (range) age was 67y (41-82) with 71% male. Blastoid morphology, Ki-67 >30%, and TP53 aberration was noted in 27%, 37%, and 38%, respectively. High-risk MIPI and MCL35 proliferation score was seen in 32% and 20%, respectively. Median (range) prior therapy in R/R was 3 (1-7), with prior BTKi in 43% and 52% of pts refractory to last treatment. Among all pts, heme AEs included G3-4 (% cycles) thrombocytopenia (14%), neutropenia (13%), and anemia (10%), with no febrile neutropenia observed across 216 cycles. G3 non-heme AEs in >10% pts included hypokalemia (28%) and rash (13%). Common any grade non-heme AEs (% pts) included hypokalemia (92%), diarrhea (65%), and rash (54%). G3 A.fib and G3 VTE occurred in 2 pts each, with no major bleeding noted. No TLS or treatment-related mortality occurred. Dose reductions occurred in 27%, and 90% of pts completed all 6C. ORR and CR rate were 100% (21/21) and 95% (20/21), respectively, in R/R and both 100% (20/20) in TN MCL. CRs occurred across all MIPI and MCL35 risk groups and high-risk subsets. With a median f/u of 43m, 80% of CRs are ongoing, with a 3y TTP and PFS of 70% and 53%, respectively, in R/R, and both 95% in TN MCL. Among all pts, 3y TTP was 60% in pts with elevated Ki-67 >30%, 70% in blastoid, and 71% in pts with TP53 aberration. MRD was evaluable in 98% (40/41) of pts, with undetectable MRD (uMRD) achieved in 18%, 79%, and 95% of pts after C1, C2, and at EOT, respectively. Median (range) duration of uMRD was 24m (0-53), and all 5 pts with relapse after CR experienced molecular relapse prior to imaging, with a median (range) lead-time of 4m (0-6). Conclusions: Fixed-duration ViPOR x 6C induces a high rate of uMRD CRs in R/R and TN MCL, including high-risk subsets. ViPOR with a 12d venetoclax ramp-up on C2 is safe in MCL pts of all ages without significant TLS or febrile neutropenia. Citation Format: Christopher Melani, Rahul Lakhotia, Stefania Pittaluga, James D. Phelan, Jagan Muppidi, Max Gordon, Yandan Yang, Weihong Xu, Theresa Davies-Hill, Da Wei Huang, Craig J. Thomas, Michele Ceribelli, Frances A. Tosto, Anna M. Juanitez, Amynah Pradhan, Atekelt Tadese, Colleen A. Ramsower, Lisa M. Rimsza, Allison Jacob, Elaine S. Jaffe, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson. Combination targeted therapy with ViPOR in relapsed/refractory (R/R) and treatment-naïve (TN) mantle cell lymphoma (MCL): Analysis of safety, efficacy, and minimal residual disease (MRD) [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A027.

Follicular lymphoma (FL) patients are at risk of disease transformation to aggressive high-grade lymphoma (tFL). While several genetic alterations have been implicated in tFL, the role of microenvironmental interactions and post-transcriptional regulation by non-coding RNAs remains poorly understood. We performed the first matched profiling of mRNAs and short non-coding RNAs (miRNAs) in paired FL and tFL samples (n = 11 pairs). This revealed differential expression of 1,075 mRNAs and 19 miRNAs, including repression of miR-29 family in tFL (miR-29a/b/c). Further analysis uncovered that MYC directly transcriptionally represses miR-29 in tFL, resulting in the upregulation of its target TRAF4. TRAF4 upregulation contributes to CD40 signaling being strongly activated in tFL and supports malignant B-cell proliferation. Notably, this increased CD40 pathway activity in 90% of tFL and contrasted with the reduced T-cell numbers in tFL niches. Thus, the MYC-miR-29-TRAF4 axis and increased CD40 signaling propensity may serve as tFL cells’ adaptation to reduced numbers of CD40L+ T-cells. Moreover, lower levels of all miR-29s(a/b/c) were associated with shorter overall survival (OS) and progression-free survival in FL (n = 185), including in a multivariate analysis. Low miR-29c was also associated with shorter OS in a validation cohort (n = 92) from the first-line R-CHOP therapy clinical trial (SWOG S0016, NCT00006721).

High-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS), is defined by morphologic features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL). Lymphomas with a complex 11q aberration or concurrent MYC- and BCL2- or BCL6- rearrangements are excluded from this category. However, the reproducibility of the diagnosis of HGBCL, NOS is unknown to date. Expert hematopathologists of the Lymphoma/Leukemia Molecular Profiling Project reviewed 92 cases submitted as HGBCL, NOS. At least 3/4 hematopathologists reviewing cases independently confirmed the diagnosis in 30/92 (33%) cases, while 13 cases (14%) were reclassified as DLBCL. The remaining 49 cases were jointly reviewed by the consensus panel of 10 to 15 pathologists, confirming an additional 9 HGBCL, NOS. The remaining cases were reclassified as DLBCL or other aggressive B-cell lymphomas or were excluded due to insufficient material. In aggregate, only 39/92 (42%) of initially submitted cases were confirmed as HGBCL, NOS, demonstrating poor interobserver agreement. Interestingly, however, there were no significant differences between the initially submitted cohort and those ultimately confirmed by the pathology review panel concerning dark zone signature (DZsig) expression, frequency of MYC -rearrangements and cell of origin, among others. Despite the finding that pathologists can identify cytomorphological features associated with adverse biological characteristics, the poor reproducibility of high-grade morphology and molecular heterogeneity suggests that HGBCL, NOS does not represent a distinct clinicopathologic entity and that more objective markers of distinct biologic features, such as the DZsig, may better separate cases into relevant diagnostic categories than morphology alone.

Anaplastic large cell lymphomas (ALCLs) are CD30+ T-cell lymphomas that share pathologic features but differ in presentation, outcome, and genetics. Current classification incorporates clinical presentation and ALK status, but inadequately addresses molecular heterogeneity and therapeutic vulnerabilities. We studied 689 ALCLs in the Lymphoma/Leukemia Molecular Profiling Project and performed expert consensus review, genetic subtyping (ALK, DUSP22, TP63, and triple-negative), and immunohistochemistry for phospho-STAT3Tyr705. RNAseq with unsupervised gene expression profiling in a sub-cohort (N=393) identified two main molecular types of ALCL that could be predicted with 91% accuracy based on the presence (Type I) or absence (Type II) of phospho-STAT3Y705 expression (P<0.0001). Type I ALCLs included ALK+ ALCL and a subset of triple-negative ALCLs (TN-I); Type II ALCLs included tumors with DUSP22 and/or TP63 rearrangements and the remaining triple-negative ALCLs (TN-II). Type I ALCLs were enriched for JAK-STAT3 (FDR<0.0001), whereas Type II ALCLs were enriched for non-tyrosine kinase pathways, particularly epigenetic regulators such as EZH2 (FDR<0.0001). EZH2 and H3K27me3 were overexpressed by immunohistochemistry (P<0.0001). Prognosis in systemic ALCL was favorable for DUSP22-rearranged ALCL (5-year OS, 95%; N=49) and ALK+ ALCL (88%; N=101), intermediate for triple-negative ALCL (TN-I, 52% and TN-II, 37%; N=92), and poor for TP63-rearranged ALCL (0%; P<0.0001; N=15). We introduce an integrated molecular classification that preserves currently diagnosed ALCL entities but identifies four molecularly distinct ALK− ALCL subtypes (DUSP22-rearranged, TP63-rearranged, TN-I, and TN-II). This classification can be easily implemented on paraffin tissue in routine practice or clinical trials and stratifies ALCL into diagnostically, prognostically, biologically, and potentially therapeutically relevant subtypes.

We hypothesized that a set of immunohistochemistry (IHC) stains could be used to distinguish Burkitt lymphoma (BL), the quintessential B-cell lymphoma with a germinal center B-cell (GCB) dark zone (DZ) expression signature, from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). This might also be applicable to high-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 rearrangements (double-hit lymphomas [DHLs]) and triple-hit lymphomas (THLs). A 5-marker IHC algorithm was designed from gene lists that distinguish physiologic DZ from light zone GCBs. In training and validation cohorts, we distinguished BL from DLBCL, NOS with high sensitivity and specificity. Because DHLs/THLs are enriched for the gene expression DZ signature (DZsig), we evaluated 19 DHLs/THLs and 4 HGBCLs, NOS. Most (83%) cases were IHC DZ. The NanoString DLBCL90 assay was performed on 34 cases to correlate IHC DZ results with the molecular DZsig. The IHC DZ call was significantly associated with the DZsig (P = .0011). The sensitivity and specificity of IHC to recognize DZsig+ cases among DLBCL, NOS and DHLs with BCL2 rearrangements/THLs were 91% and 100%, respectively. The IHC DZ algorithm can support a diagnosis of BL and identifies MYC-BCL2 DHLs/THLs with a molecular DZsig.

ABSTRACT:Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

Abstract: Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma, NOS (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin classification, 59% were germinal center B-cell–like (GCB), and 25% were activated B-cell–like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC rearrangement (47% vs 6%); dark zone signature (DZsig) expression (45% vs 7%); and more frequent mutation of ID3, MYC, CCND3, and TP53, all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, and those classified as DLBCL-like were frequently BCL2-rearranged. Among DZsig− GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.

Acquisition of drug resistance, particularly to immunomodulatory drugs (IMiDs) in multiple myeloma (MM), is an important challenge in patient treatment. IMiDs are the canonical molecular glue that bind to cereblon (CRBN) and redirect its E3 ubiquitin ligase activity to neo-substrates, such as IKZF1/IFZF3. Genetic changes in the CRBN gene have been associated with IMiD resistance, including the exon 10-spliced CRBN transcripts that increase in incidence in parallel with IMiD-refractory states. Herein, we designed a new probe against CRBN splice isoform to detect exon 10 deletion and validated the variant expression using NanoString and messenger RNA (mRNA) sequencing analysis. We analyzed 74 MM samples, including 28 cases of newly diagnosed MM and 46 cases of relapsed and end-stage MM. Four cases were identified with 40% exon 10-deleted mRNA as compared with total CRBN mRNA (1 from newly diagnosed, 3 from relapsed and end-stage). Sequencing of complementary DNAs from 2 samples unexpectedly demonstrated additional deletion of exon 8. Extensive molecular-modeling and coimmunoprecipitation studies identified the mechanisms of CRBN dysfunction in protein structures, including impact on the interaction between CRBN with the E3 ligase machinery on deletion of exon 8 or dual deletion of exons 8 and 10. In summary, we developed a feasible approach to detect exon 10-deleted CRBN isoform on a gene expression platform and unexpectedly identified a variant with alterations of exon 10 and 8 transcripts in both newly diagnosed and refractory cases. This variant is present at diagnosis and could have separate, yet likely additive, effects on drug resistance.

Background:Primary central nervous system lymphoma (PCNSL) is clinically challenging due to its location and small biopsy size, leading to a lack of comprehensive molecular and biologic description. We previously demonstrated that 91% of PCNSL belong to the activated B-cell-like (ABC) molecular subtype of diffuse large B-cell lymphoma (DLBCL). Methods:Here we investigated the expression of 739 cancer related genes in HIV(-) patients in 25 ABC-PCNSL and 43 ABC-systemic DLBCL, all tumors were EBV(-). Results:We found 135 genes which were identified as differentially expressed between these ABC-PCNSL and ABC-systemic DLBCL (p<0.05). The ABC-PCNSL showed higher gene expression in several cancer-related gene sets including genes related to Hedgehog, DNA damage repair, Wnt and MAPK signaling. Whole exome sequencing showed distinct genetic features of PCNSL compared to DLBCL, CXCR4 mutations in particular, that have been associated with ibrutinib resistance. In a focused analysis, PCNSL and DLBCL cases that fall into the "MCD" genetic subtype showed substantial overlap. These data provide detailed information about unique characteristics of PCNSL in HIV(-) patients as compared to comparable DLBCL subtypes.

Background. FL is associated with a heterogeneous clinical course, and currently available prognostic indicators are unable to reliably separate patients who exhibit early therapy resistance (POD24, defined as progression within 24 months from diagnosis) from those who achieve “functional cure” following initial therapy. NGS methods developed in recent years enabled quantification of MRD. The ClonoSeq assay (Adaptive Biotechnology, Inc.) has been FDA-cleared to track MRD in several hematologic malignancies. Here we demonstrate that MRD analysis by ClonoSeq assay predicts outcomes in a prospective cohort of patients with advanced stage FL enrolled on SWOG S0016 clinical trial. Methods. SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with CHOP-RIT (CHOP + I 133-tositumomab) in patients with FL. Between 2001 and 2008, 531 patients with previously untreated advanced-stage FL (bulky stage II, III-IV) of any pathologic grade were randomly assigned to receive 6 cycles of R-CHOP or CHOP-RIT. We used high-throughput sequencing (HTS) of the IGH and IGK/L loci (ClonoSeq assay) from tumor biopsy specimenstaken prior to treatment to define CDR3 rearrangements that tag the tumor. Subsequently, 1-year bone marrow specimens were screened for residual disease. The baseline dominant clone was defined as ≥10 estimated number of genomes (ENG) and comprised ≥5% of the library. MRD-positive state (MRDp) was defined as a minimum Hamming distance (HD) ≤6 in a patient's post-library (in any clone also detected in a pre-library) and conserved pre-existing SHM (if HD>0). Undetectable MRD (MRDu, at <10 -4) was defined as CRD3 HD>6 in a post-library with a depth >10,000 ENG. Five-year progression-free survival was the primary endpoint (PFS; defined as the time from registration to the first observation of progression or death due to any cause). Landmark analysis was defined at 1 year after registration and used for imputing the 5-year PFS and OS. Overall survival (OS) was defined as the time from registration to date of death due to any cause or last follow-up. PFS and OS estimates and 95% confidence interval were calculated using the Kaplan-Meier method and compared for MRDp and MRDu disease using two-sided log-rank test. HR and 95% CI were calculated using Cox regression model. Results. Tumor biopsy tissue was available for 189 patients. Of these, 24 patients were not evaluable (16 did not consent for banking, 6 were ineligible and 4 had an early event). In 36 patients, pre-libraries did not yield a trackable clone. In total, MRD status could not be ascertained in 47 patients due to absence of a clear trackable clone in either pre- or post-library, contributing to a 28.8% failure rate. Of 116 patients which yielded a trackable clone in both libraries, 83 were MRDu and 33 were MRDp. Baseline characteristics (age, sex, race, β2M, B symptoms, bulky disease, grade 3, stage, and FLIPI risk) were similar between MRDp and MRDu patients; however, MRDp patients were more likely to exhibit morphologic baseline bone marrow involvement by FL (82% vs. 55%, p=0.01). The estimated 5-year PFS was 72% in MRDu patients and 30% in MRD+ patients (Figure); 10-year PFS was 56% and 17%, correspondingly. Meanwhile, 5-year OS was not different (96% for MRDu, 81% for MRD+, p=0.91). Patients with MRDu had a significantly higher best overall response rate than MRDp patients (96% vs 79%, p=0.005), but complete response (CR) rates were similar (41% vs. 30.3%). Patients who received CHOP-RIT had better PFS regardless of MRD status (HR=0.48, p=0.01 for MRDu; HR=0.38, p=0.02 for MRDp), while OS was not statistically different. Five-year PFS was superior in patients who achieved MRDu (75% for CR and 70% for PR) compared with MRDp patients, regardless of response (34%). Patients who had MRDp status had a significantly increased risk of experiencing POD24 relative to MRDu patients (RR=6.5, 95% CI 3.0-14.0; p<0.0001). Conclusion. Here we for the first time demonstrate that MRDu status, as assessed by Clonoseq, predicts improved 5- and 10-year PFS in patients with FL initially treated with chemoimmunotherapy. MRD+ status in the bone marrow at a 1-year timepoint was associated with POD24. Despite a relatively high failure rate to detect trackable sequences using current technology (~29%), MRD assessment by NGS is a promising prognostic tool in FL. *co-senior authors

BACKGROUND:Diffuse large B-cell lymphoma (DLBCL) is clinically heterogeneous, and gene expression profiling has identified at least two biologically distinct DLBCL subtypes defined by their cell of origin (COO): germinal center B cell (GCB) and activate B cell (ABC) or non-GCB. We evaluated a variety of putative DLBCL risk factors for etiologic heterogeneity by the COO in a clinic-based study of newly diagnosed DLBCL cases (N = 638) and frequency-matched controls (N = 2,253). METHODS:The COO was determined on formalin-fixed, paraffin-embedded tumor tissue, with DLBCL classified as GCB (N = 283), non-GCB (N = 188), or undetermined/missing (N = 167; mainly because of lack of tissue). Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS:We identified heterogeneity by the COO for low socioeconomic status (SES), which was only associated with non-GCB DLBCL (OR = 1.88 for low vs. average SES; 95% CI, 1.08-3.27); alcohol use, which was only associated with GCB DLBCL (OR = 0.48 for former drinkers; 95% CI, 0.29-0.80 and OR = 0.47 for current drinkers; 95% CI, 0.32-0.71); and borderline heterogeneity for the regular use of regular/extra-strength aspirin, which was only associated with non-GCB DLBCL (OR = 0.36; 95% CI, 0.16-0.85). In contrast, there was no significant heterogeneity by the COO for family history, medical history, or other lifestyle factors. CONCLUSIONS:Although requiring confirmation, most risk factors for DLBCL did not show etiologic heterogeneity by the COO, with some notable exceptions including alcohol use, SES, and perhaps regular use of regular/extra-strength aspirin showing associations. IMPACT:Mechanistically, these findings suggest that most of the DLBCL risk factors evaluated here influence lymphomagenesis prior to differentiation into COO subtypes, with selected factors acting later.

We investigated the prevalence of rare inherited pathogenic variants (PV) in 19 cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and their association with the risk of lymphoid malignancies (LM) overall and by common lymphoma subtypes and multiple myeloma. The study population included newly diagnosed LM cases (N = 6990) and unrelated controls (N = 42,632), excluding individuals with a history of hematologic malignancy. Whole exome sequencing was performed on DNA from whole blood. PV were defined as loss-of-function (i.e., nonsense, frameshift, consensus splice sites) or identified as “pathogenic” or “likely pathogenic” in the ClinVar database. A total of 1816 (3.7%) individuals had a PV across the 19 genes, higher in cases (4.7%) than controls (3.5%). In controls, CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the highest prevalence. ATM (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.36–2.49), CHEK2 (OR = 1.74, 95% CI: 1.42–2.13) and TP53 (OR = 9.07, 95% CI: 4.51–18.87) were associated with increased risk of LM overall and were further validated in the UK Biobank. We observed heterogeneity in associations by LM subtype. These results demonstrate that several commonly tested cancer predisposition genes are associated with an increased risk of LM.