Abstract Background: Advances in cancer treatment and surveillance have increased survivorship, consequently elevating the risk of multiple primary cancers (MPC). However, distinguishing single primaries (SP) and MPC from recurrences or metastases remains a key barrier to studying gene and environmental drivers of second malignancies at scale. Methods: We developed an automated algorithm to classify tumors as distinct primaries versus recurrences/metastases using IARC criteria, curated exceptions, and clinical and molecular data from Memorial Sloan Kettering’s Cancer Data Science Initiative in 91,906 cancer patients. The classifier was validated against an expert-adjudicated dataset. Standardized incidence ratios (SIRs) were computed using age and sex-adjusted SEER-21 reference rates. To assess therapy-related risk, MPCs were stratified by exposure and analyzed for latency and survival. Inherited etiology based on rare germline pathogenic variants (PV) and cancer-specific polygenic risk scores (PRS) was assessed. Results: The classifier achieved 93% concordance in distinguishing MPC from SP tumors. Applied to 91,906 patients in the MSK-IMPACT cohort, the algorithm identified 16,990 (18.5%) with MPC. Among metachronous cases, the median latency to a second primary was 8.2 years. Twenty-one cancer pairs showed elevated SIRs, including four matching known hereditary syndromes. Excess risk persisted in non-carriers of PV, suggesting polygenic or exposure-related causes. Treatment-related pairs included ovary-leukemia (SIR=5.7), breast-leukemia (SIR=4.0), breast-lung (SIR=2.9), breast-uterus (SIR=2.7), and male bladder-lung (SIR=3.3). Therapy exposure significantly modified risk and latency. Tamoxifen exposure conferred a 3.5-fold higher uterine cancer hazard with earlier onset yet improved survival. Among radiotherapy-exposed breast cancer survivors (n=3,482), higher chest irradiation correlated with a 4-fold secondary lung cancer hazard. Platinum exposure for ovarian cancer (n=2,811) increased Acute Myeloid leukemia (AML) hazard by 4.4-fold while alkylating agents for breast cancer (n=9,497) conferred a 2.9-fold AML risk, with shorter latency supporting treatment-related mechanisms. In male bladder cancer survivors, smokers had 9.1-fold increased hazard of subsequent lung cancer (n=1,316). Among smokers, older age at bladder cancer diagnosis predicted shorter latency to lung cancer. Increased SIR persisted in several cancer pairs, even after accounting for rare PV and PRS, suggesting undiscovered genetic and environmental factors and interactions. Conclusions: Automated classification of MPC reveals genetic and exposure-related patterns in secondary cancer risk, timing, and survival. Ongoing work is integrating tumor genomics as well as polygenic risk scores to identify inherited and therapy-related drivers of cancer development and aggressiveness. (Supported by MSK Niehaus Center and BCRF). Citation Format: Johnathan Amsalem, Ying Liu, Aliya Khurram, Yelena Kemel, Andrew Marderstein, Mitul Waghmare, Semanti Mukherjee, Michael Conry, Vignesh Ravichandran, Saibaba Magunta, Ritika Kundra, Matthew Buas, Christopher Fong, Justin Jee, Michael Berger, Jian Carrot-Zhang, Zsofia Stadler, Venkatraman Seshan, Nikolaus Schultz, Kenneth Offit, Vijai Joseph. Multifactorial risks for multiple primary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5222.

Evidence for an association between insulin-like growth factors (IGF) and multiple myeloma (MM) is inconsistent. We examined total IGF-I concentrations and risk of MM by combining baseline serological data among UK Biobank participants (n = 444 187; 732 incident MM) with a two-sample Mendelian randomisation (MR) analysis using identified genetic variants associated with circulating total IGF-I and IGF-binding protein 3 (IGFBP-3) in the InterLymph consortium (2434 MM and their 2567 controls). Finally, additional lymphoid neoplasm (LN) subtypes were included for comparison with the main hypothesis. Circulating IGF-I level was positively associated with MM risk Hazard ratio-HR-per one standard deviation-SD-increase (HR1-SD = 1.11, 95% confidence interval [CI]: 1.01-1.22; p-value = 0.03), especially closer to diagnosis. Genetically inferred IGF-I levels were associated with increased MM risk (odds ratio [OR] = 1.27, 95% CI: 1.05-1.54) but not with any other LNs. Genetically inferred IGFBP-3 levels showed no associations with any LN evaluated. Corroborating previous findings, in a secondary analysis, IGF-I levels were associated with the risk of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in males with higher body mass index (HR1-SD in obese male = 1.36, 95% CI: 1.14-1.61). Our serological and MR analyses suggest a contributing role of IGF-I in the susceptibility of MM; the CLL/SLL findings warrant further investigation considering sex-specific adiposity.

DNA damage response genes (DDRG), implicated in several cancers as both predisposing risk factors as well as biomarkers for aggressiveness, have not been fully explored in multiple myeloma (MM). Herein, we analyzed disease associations of pathogenic variations in nine putative candidate genes using 3 446 MM cases and 323 233 cancer-free controls. Increased MM risk was found to be associated with inherited rare pathogenic mutations in TP53, ATM, CHEK2, KDM1A, and ARID1A, with an enrichment of these variants among individuals with early onset or family history of MM. Individuals with TP53 or ATM germline mutations are also likely to have worse overall survival. Our results suggest expansion of the phenotypic spectrum of some of these DDRG to include MM. The identification of these germline predisposition genes opens the avenue for targeted screening of higher risk individuals especially those with young-onset or a family history of plasma cell gammopathies.

Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size (β) and Nagelkerke's R2, and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.

Improvements in cancer survival have increased the burden of subsequent primary malignancies. We developed and validated a programmatic classifier of multiple primary cancers (MPC) to derive second cancer phenotypes at scale. Among 81,175 cancer patients, we identified 56 first-second cancer pairs, 22 of which exceeded SEER primary cancer incidence rates. Even after accounting for various known risk factors, substantial elevated risk persisted, even in established hereditary cancer pairs (breast-ovary, breast-pancreas, prostate-pancreas), suggesting that current screening protocols do not adequately account for MPC susceptibility. To address this limitation, we built machine-learning models integrating rare germline variants, polygenic risk scores, treatment exposures, and demographic features to predict site-specific second primaries in breast and prostate cancer survivors. These models accurately predicted second ovarian and pancreatic cancers across a long follow-up period (15-year time-dependent AUC 0.70). This is the first systematic, pan-cancer integration of clinicogenomic factors for early prediction of second-primary malignancies. Our framework enables individualized risk estimation, enhanced targeted surveillance, and cancer prevention amongst a growing population of cancer survivors. Statement of Significance:We identified second cancers that occurred more often than expected among survivors. Predictive models using genetic, lifestyle, and clinical factors accurately identified patients at higher risk of second hereditary cancers. Such predictions can enable cost-effective, selective surveillance in a growing population of cancer survivors, reducing cancer burden.

Loss-of-function variants in PALB2 give rise to defects in DNA damage repair by homologous recombination (HR), increasing the risk of breast cancer in female carriers. However, genetic testing frequently reveals missense variants of uncertain significance (VUS) for which the impact on protein function and cancer risk are unclear. Here we assay 84% of all possible missense variants in 11 out of 13 PALB2 exons using site-saturation functional screens with PARP inhibitor sensitivity as a readout for HR. These exons encode the coiled-coil and WD40 domains, which we identify as the minimal regions required for HR. Furthermore, we reveal the functional impact of 6718 missense variants, classifying 3904 variants as functional (58%), 2422 as intermediate (36%), and 392 as damaging (6%). A burden-type analysis shows that damaging missense variants in PALB2 are associated with a significantly increased risk of breast cancer, similar to that observed for truncating variants. These results will be valuable for the classification of PALB2 missense VUS and clinical management of carriers.

Abstract Urinary bladder cancer (BC) is the ninth most common malignancy worldwide. We conducted a meta-analysis of genome-wide association studies for BC risk in 32,470 cases and 1,753,462 controls, identifying 70 independent genome-wide significant loci, including 43 novel signals. A 70-marker polygenic risk score was strongly associated with BC risk (hazard ratio=1.61 (1.50-1.73) per standard deviation), substantially improving the area under the curve (AUC) when added to a model with age, sex, and smoking status (AUC=0.75 vs. 0.70, p=4.49E-20). BC risk variants (n=4,196 at p<5.0E-8) were enriched in regions of open chromatin in bladder tissue. Integrated germline, transcriptomic, and proteomic analyses nominated additional susceptibility genes and pathways, particularly related to xenobiotic metabolism. We detected a novel BC signal within a known smoking-related locus at 15q25.1 (rs7173514-C, OR=1.07, p=9.64E-10 for BC risk overall, ORNever-Smoker=1.00 and OREver-Smoker=1.14). This signal was primarily driven by an insertion/deletion variant within CHRNA3-3’UTR rs71581744/rs10637216 (A/ACCCC, r2=0.78 with rs7173514 in Europeans) linked with smoking cessation, with an additional contribution from a known lead variant for smoking intensity (rs16969968-G/A, D398N within CHRNA5). Further analyses revealed significant heterogeneity for rs71581744 by BC subtype (muscle-invasiveness), particularly among current smokers (ORMuscle Invasive=1.42 vs. ORNon-muscle Invasive=1.11, pheterogeneity=1.84E-02), consistent with epidemiologic observations that current smokers have a higher risk of muscle-invasive bladder cancer. Our in-vitro reporter assays for rs71581744-A/ACCCC demonstrated allele-specific effects on mRNA stability in several cell lines. Since neuronally expressed CHRNA5 and CHRNA3 encode subunits of the nicotinic acetylcholine receptors (nAChR) that regulate smoking behavior, we investigated their expression in normal brain tissues in GTEx. The BC risk signal colocalized with a top CHRNA3 eQTL in one brain area, with variable allelic expression imbalance for CHRNA3 in several brain areas from the same donors. Our results implicate rs71581744-A/ACCCC as a functional variant contributing to BC risk via regulation of CHRNA3 mRNA stability in specific brain areas, affecting nicotine reward/aversion circuits and possibly bladder function. Overall, our study provides new insights into BC genetics and etiology with relevant clinical implications. Citation Format: Ludmila Prokunina-Olsson, Oscar Florez-Vargas, Michael G. Levin, Diptavo Dutta, Charles Breeze, Lauren M. Hurwitz, Wusheng Yan, Philippe Lamy, Brenen Papenberg, Kevin Wang, Chia-Han Lee, Roger L. Milne, Jian Gu, Caroline Y. Um, Vijai Joseph, Helena Furberg, Florence Le Calvez-Kelm, Chikashi Terao, Koichi Matsuda, Francisco X. Real, Lambertus A. Kiemeney, Stephen J. Chanock, Núria Malats, Debra T. Silverman, Lars Dyrskjøt, Nathaniel Rothman, Scott M. Damrauer, Stella Koutros, Jeffrey S. Damrauer. Multi-population GWAS meta-analysis identifies novel bladder cancer susceptibility loci and highlights the genetic regulation of smoking-related risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3601.

Abstract Background: Nucleotide excision repair-deficient (NER-D) cancers comprise approximately 10% of bladder urinary tract and uterine cancers. Platinum-based chemotherapy is the current standard of care for NER-D cancers; however, its nephrotoxicity limits applicability in patients with compromised renal function. No druggable targets have been identified for NER-D tumors. Genome-wide CRISPR screening offers a powerful strategy to identify synthetic lethal interactions. We performed a genome-wide screen to identify potential synthetic lethal targets in NER-deficient cells. Methods: An RT112/84 ERCC4 knockout (ERCC4-/-) cell line was generated. ERCC4 status was examined by Sanger sequencing and Western blotting, and nucleotide excision repair activity was assessed using the Host Cell Reactivation Assay (HCRA). A genome-wide CRISPR screen was performed in RT112/84 wild-type (WT) and ERCC4-/- cells to identify candidate synthetic lethal targets. Colony formation assays validated candidate interactions, and SLC25A28 was further tested for synthetic lethality with ERCC2, ERCC3, and ERCC5. RNA sequencing was conducted to investigate the mechanism underlying SLC25A28-ERCC4 synthetic lethality. Results: Sanger sequencing and Western blot confirmed ERCC4 knockout in RT112/84 cells. HCRA demonstrated markedly reduced NER activity in ERCC4-/- cells. Genome-wide CRISPR screening identified SLC25A28 as a top synthetic lethal candidate with ERCC4. Colony assays validated the synthetic lethality between SLC25A28 and ERCC2, ERCC3, ERCC4 and ERCC5. Conclusions: Our findings identify SLC25A28 as a novel synthetic lethal target in NER-deficient cancers, suggesting that inhibition of SLC25A28 may represent a potential therapeutic strategy for tumors harboring NER pathway mutations. This study was supported by STTR 1 R41 CA275627-01, the Niehaus Center for Inherited Cancer Genomics, and the Breast Cancer Research Foundation. Citation Format: Nan Yang, Vijai Joseph, Lisa Hoeg, Xuechun Bai, Sizhi Gao, Ouathek Ouerfelli, David B. Solit, Jian Carrot-Zhang, Gopa Iyer, Daniel Durocher, Kent W. Mouw, Kenneth Offit, Steven M. Lipkin. SLC25A28 is a synthetic lethal target in nucleotide excision repair-deficient cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3093.

Abstract Background: Germline BRCA2 mutations substantially increase breast cancer risk, but penetrance varies, indicating a role for genetic modifiers. These modifiers can influence tumor initiation and progression even among individuals with the same BRCA2 variant, and their discovery and characterization can improve risk prediction and therapeutic stratification. For many GWAS-identified BRCA2 modifiers, the biological mechanisms are still unclear. We examined STARD13, a cytoskeletal regulator and putative tumor suppressor identified in prior BRCA2 GWAS signals, may intersect functionally with the Hippo pathway through effects on RhoA-actin dynamics that influence LATS2 activity, which in turn regulates YAP/TAZ-mediated proliferation and genomic stability. Because LATS2 supports genomic integrity and suppresses oncogenic signaling, we hypothesized that disruption of the STARD13 and LATS2 axis may modify BRCA2-associated phenotypes in breast epithelial cells. Methods: BRCA2 mutants were generated in breast epithelial cell lines using CRISPR/Cas9 genome editing. Allele-specific regulatory effects of the SNPs were assessed by luciferase reporter assays. To investigate STARD13 as a genetic modifier, siRNA- and shRNA-mediated knockdown was performed in wild-type and BRCA2 mutant cells. LATS2 expression was quantified by qRT-PCR. Functional assays measuring proliferation, apoptosis, and DNA damage sensitivity evaluated the impact of STARD13 knockdown in different BRCA2 contexts. Results: In wild-type BRCA2 cells, STARD13 knockdown upregulated LATS2 expression, indicating activation of a compensatory tumor suppressor pathway. In contrast, In BRCA2-mutant cells, loss of STARD13 fails to induce the compensatory increase in LATS2 seen in BRCA2-wild-type cells, identifying STARD13 as a modifier of the BRCA2-deficient state. These data implicate LATS2 as a modifier of BRCA2 via STARD13-dependent mechanisms. Ongoing experiments in BRCA2 mutant cell lines and organoids are examining effects on DNA damage, repair, colony formation, gene expression, and responses to PARP inhibitors using shRNA and CRISPR knockouts. Conclusions: Our findings support STARD13 as a potential genetic modifier of BRCA2, influencing the activity of LATS2 tumor suppressor and linking cytoskeletal signaling with DNA repair pathways. The differential regulation of LATS2 in wild-type versus BRCA2 mutant backgrounds suggests a novel axis that may underlie variation in BRCA2 penetrance and cancer risk. These studies aim to elucidate the STARD13-LATS2-BRCA2 interaction network as a determinant of BRCA2 penetrance, as a potential biomarker to allow targeting to decrease penetrance of hereditary breast cancer in affected kindreds. (Supported by Breast Cancer Research Foundation and Niehaus Center for Inherited Cancer Genomics). Citation Format: SHIV PRAKASH VERMA, Mitul Waghmare, Sanchari Bhattacharyya, Catherine Fanjoy, Shao Hong, Xu Zhang, Jonathan Amsalem, Yelena Kemel, Minna Lee, Matthew Buas, Zsofia Stadler, Pedram Razavi, Mark Robson, Sarat Chandarlapaty, Kenneth Offit, Vijai Joseph. STARD13-LATS2 Axis as a potential genetic modifier of BRCA2 in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6817.

Abstract Background: HLA-mediated immune surveillance involves classical, non-classical, and class I-like pathways. Because lymphoma and myeloma rely on different immune mechanisms, we evaluated HLA class I/II, non-classical, and class I-like loci across ancestries using allele-level amino acids(AA), heterozygosity (HET), evolutionary divergence (HED), IEDB-derived peptide-binding breadth (PBW; 9-mer binding entropy), and positional amino-acid heterozygosity (residue mismatch). Methods: Hodgkin lymphoma (HL), NHL and subtypes, and multiple myeloma (MM) in All of Us Cohort were identified using ICD/SNOMED; controls lacked hematologic malignancy. HIBAG-imputed allele with n>20 cases were analyzed in EUR, AFR, and AMR. Models adjusted for age, sex, PCs, and admixture proportions tested ORs, 95% CIs, and FDR<0.1. We used joint PRS-HLA models to test whether HLA metrics contributed risk information beyond the lymphoma PRS. Results: We replicated EUR HET and/or HED class I/II associations with NHL (N=1668), DLBCL (N=490), HL (N=393), and FL (N=435), and extended these patterns using PBW and AA-level metrics. In NHL, we confirmed that HET-C reduced risk (p=0.027) and found greater PBW was protective (OR=0.49; p=0.09). Similarly, in CLL, we replicated the HET-A association (p=0.027), identified PBW-A effect (OR=0.25; p=.03), and a positional signal at A-163 (OR=.83, p=0.015) that also appeared in NHL(p=.015). Neither locus showed HED effects.Novel MM associations with HET-B and -C (OR≈0.74; p<0.03), were supported by a positional hit at B-42 (OR=0.77; P=0.033) and a PBW-C effect (OR≈0.24; p=0.01), while HED remained null. In contrast, DLBCL showed protection across all class I metrics as well as at MICB (OR=0.75; p=0.006) and MHC-like HET (OR=0.73; p=0.084). In EUR DLBCL, A*01:01 (OR=1.23; p=0.076) and A26:01 (OR=1.56; p=0.051) showed risk effects consistent with some prior reports reinforced by multiple A-locus positional signals (P<0.02).Novel AFR-specific findings included A*68:02 in: HL (OR=2.88; p=1.8×10-5), mirrored by a positional hit at A-30 (OR≈3.0, p=.0004), NHL at B*07:02 (OR=1.69; p=0.018) and for C1-motif alleles C07:01 (OR=1.51, p=.04) and C*07:02 (OR= 2.02, p=.00017) consistent with a KIR-C1 mechanism.The DLBCL PRS replicated (which includes an HLA-B variant) in EUR (OR=1.25, 95% CI 1.15-1.36; p=7.3×10-7) and joint models showed HED (p=0.0028) and HET (OR=0.86, 95% CI 0.80-0.93, p=7.0×10-5) remained significant when combined with PRS. AIC identified HET + PRS with covariates as the best model. The PRS did not replicate in AFR or AMR. Conclusion: We replicated classical HLA associations and identified novel non-classical and functional HLA features that shape B-cell malignancy risk across ancestries. Furthermore, adding orthogonal HLA metrics provided substantial, independent information beyond the PRS. Citation Format: Lara Sucheston-Campbell, Saanika Tambe, Lian Zuo, Alyssa Clay-Gilmour, Vijai Joseph, Benjamin Tycko, Wendy Cozen. Functional Class I, Class II, and nonclassical HLA variation drives lymphoma and myeloma risk in the all of us research program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6266.

10511 Background: Pathogenic germline variants (PGV) in cancer-predisposition genes influence the development of many cancer types but our understanding of cancer risks in PGV carriers remains underexplored. This study aims to further characterize the spectrum of cancers associated with PGVs and factors contributing to the development of multiple primary cancers among PGV carriers. Methods: A case-control analysis of 61,453 cancer cases and 366,709 controls in the UK Biobank (UKBB) was performed to test for the associations between risks of 43 solid tumor types and PGVs in 237 cancer predisposition genes. We evaluated each association according to the ClinGen Gene-Disease Validity framework and categorized those with moderate or less evidence as novel. An independent validation cohort of 103,321 cases 340,786 controls from All of Us, Mass General Brigham Biobank, TCGA, Memorial Sloan Kettering IMPACT, and a case-control study of ovarian cancer was used to replicate novel associations. Results: We identified 51 novel associations between solid tumor development and PGVs in the UKBB. Out of these, 32 were also significantly associated (p<0.05) in our validation cohorts (Table 1). Among PGV carriers in the UKBB, 16% had one primary malignancy and 2% had two or more. Across most PGV carriers, we observed higher risks of multiple primary cancers compared to single primary cancers. Using cox proportional hazards models, we found that PGV carriers with a personal history of cancer showed a higher hazard ratio of second cancer compared to healthy controls, particularly among those diagnosed with the first cancer earlier in life. The association between PGVs and second cancer remained significant in case-only analysis limited to cancer survivors and adjusted for primary tumor type suggesting this was not explained by shared risk factors. Conclusions: These findings expand our understanding of spectrum of cancer risks associated with predisposition genes and highlight that PGV carriers are at high risk of developing multiple primary cancers. In addition to family history, personal history of cancer should be considered for tailored cancer screening in genetically predisposed individuals. Novel associations between PGV genes and selected cancers. Shown are the odds ratio estimates from the meta-analysis of replication cohorts. Cancer Genes Odds ratio (95% CI) Breast BAP1 4.68 (2.13-10.25) BRIP1 1.63 (1.18-2.26) LZTR1 2.01 (1.56-2.6) Colorectal ATM 1.43 (1.07-1.93) BARD1 2.33 (1.28-4.26) BRCA1 1.69 (1.2-2.37) BRCA2 1.69 (1.27-2.25) FLCN 2.6 (1.17-5.74) Melanoma BLM 1.68 (1.05-2.71) BRCA1 2.15 (1.29-3.58) Lung BRCA2 3.16 (2.36-4.23) NBN 1.94 (1.07-3.53) Endometrial BRCA1 8.05 (4.83-13.4) BRCA2 2.32 (1.19-4.54) MSH3 2.25 (1.07-4.72) Urinary ATM 1.71 (1.21-2.44) Renal MITF p.E318K 1.85 (1.16-2.97) WRN 2.71 (1.39-5.29) Head and neck CDKN2A 6.22 (3.31-11.7) FANCM 2.2 (1.38-3.52) Ovary DDX41 4.56 (1.56-13.36) PALB2 3.33 (1.98-5.61)

Excel file with all the supplementary tables (S1-S11) in separate tabs

Germline pathogenic variations (PV) increase heritable risk for cancer and are utilized to target tumor-specific prevention and early detection. However, inherited cancer associations may be pleomorphic, penetrance and expressivity may vary and may be modified by location of the PV, ancestry and polygenic or non-genetic factors. This study aims to determine the magnitude and spectrum of risk for specific tumor types and multiple primary cancer (MPC) for genes commonly tested in patients at familial risk for cancer or undergoing tumor-normal analysis for a cancer diagnosis. We conducted a retrospective cohort study of patients consenting to MSK-IMPACT, a matched tumor-normal sequencing assay, over a five-year period. We collected data on cancer onset, race, ethnicity, and, where consent was obtained, clinical information through cBioPortal and the MSKCC clinical databases. MPC were classified using IARC guidelines. Non-cancer control data was sourced from gnomAD. Clinically actionable pathogenic variants in cases and controls were identified using the automated variant curator PathoMAN and manual curation in a subset. Ancestry adjusted weighted generalized linear model was used to estimate risk for single primary (SP), MPC, and MPC-pairs. Biallelic losses were analyzed from paired tumors and normal. 28, 000 individuals across 22 cancer types were tested for 100 cancer predisposition genes (CPG). MPC had a higher rate of carrier frequency for germline PV in known or novel CPG compared to single primary (SP) cases (SP =15%, MPC=21%). In the analysis including MPC cases, we discovered or replicated novel associations including BRCA2 and biliary cancer (OR=4.5, CI=2.2-8), ATM (OR=4.8, CI=2.1-9.2) and BRCA2 and mesothelioma (OR=8, CI=3.1-16.6); NBN (OR=4.2, CI=2.3-6.9) and lung cancer, PALB2 and germ cell cancer (OR=7.8, CI=1.9-20.8). Novel associations were observed with RECQL4 and breast, bowel, cervix, lung cancers and uveal melanoma, and RECQL with breast, lung and bowel cancers. SLX4 was associated with prostate, soft tissue and ovarian cancers. PV in RECQL4, MSH2 and MLH1 were enriched in patients with two independent compared to single bowel tumors. In the MPC group, as expected, mismatch repair genes MSH2, MSH3 and MLH1 were associated with increased risks for stomach, bowel, and uterine cancer, and TP53 with multiple breast cancer primary tumors. The MPC cohort demonstrated pleiotropy of BRCA1/2, NF1, ATM, TP53 and RECQL4 with several tumor types, with biallelic losses in tumors supporting several of these associations. We did not replicate reported associations of PALB2 and ovarian cancer and CHEK2 and colon cancer. Ancestry adjusted risk estimates among a real-world case-cohort of primary and multiple primary cancer cases revealed several novel associations and did not confirm some prior associations with cancer phenotypes. Vignesh Ravichandran, Ying Liu, Irina Ostrovnaya, Kaitlyn Tkachuk, Aliya Khurram, Yelena Kemel, Alicia Latham, Diana Mandelker, Chaitanya Bandlamudi, Michael Conry, Saloni Sinhas, Syed Aijazuddin, Nikolaus Schultz, Michael Berger, Mark Robson, Zsofia Stadler, Kenneth Offit, Vijai Joseph. Germline susceptibility to single and multiple primary cancers utilizing an ancestry adjusted case-control analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7413.

Supplementary Figure S3. Rates of somatic loss of heterozygosity (LOH) stratified by cancer type. NSCLC: NonSmall Cell Lung Cancer, CRC: Colorectal Cancer.

Supplementary Data from Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer

To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis of 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline whole exome or genome sequencing data, and one cohort with imputed array data. At the gene level, our case-control collapsing analysis confirms associations between rare damaging variants in four genes and increased prostate cancer risk: SAMHD1, BRCA2 and ATM at the study-wide significance level (P < 1x10(-8)), and CHEK2 at the suggestive threshold (P < 2.6x10(-6)). Our case-only analysis, reveals that rare damaging variants in AOX1 are associated with more aggressive disease (OR = 2.60 [1.75-3.83], P = 1.35x10(-6)), as well as confirming the role of BRCA2 in determining disease severity. At the single-variant level, our study reveals that a rare missense variant in TERT is associated with substantially reduced prostate cancer risk (OR = 0.13 [0.07-0.25], P = 4.67x10(-10)), and confirms rare non-synonymous variants in a further three genes associated with reduced risk (ANO7, SPDL1, AR) and in three with increased risk (HOXB13, CHEK2, BIK). Altogether, this work provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity, with potential implications for clinical risk prediction and therapeutic strategies.

With over 80, 000 new cases of non-Hodgkin's lymphoma (NHL) diagnosed annually, modifiable risk factors remain unclear. Circadian disruption, linked to cancers like breast and prostate, affects immune cells (e.g., natural killer cells and T-helper cells) by altering their trafficking and proliferation. Some studies (PMID: 30566672, 27611440) suggest long sleep may increase overall NHL risk, including a Mendelian randomization (MR) study (PMID: 32895918). However, no research has examined the causal relationship between sleep traits, including long sleep, and NHL risk, by subtypes. We hypothesize that sleep traits are causally associated with NHL subtypes in European populations, testing this using MR with data from the International Lymphoma Epidemiology Consortium (InterLymph). We conducted two-sample MR using genome-wide association studies (GWAS) summary data for sleep traits and NHL subtypes. Only independent, genome-wide significant (p < 5×10-8) Single Nucleotide Polymorphisms (SNPs) were selected as valid instruments, sourced from the UK Biobank. Sleep traits included chronotype (153 SNPs), insomnia (48 SNPs), sleep duration (78 SNPs), excessive daytime sleepiness (37 SNPs), short sleep (27 SNPs), and long sleep (8 SNPs). NHL subtype data were from InterLymph: follicular lymphoma (6, 508 cases / 64, 183 controls), mantle cell lymphoma (1, 169 cases / 61, 603 controls), Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: 1, 697 cases / 59, 333 controls), and chronic lymphocytic leukemia (8, 522 cases / 67, 653 controls). The primary analysis used inverse-variance weighted (IVW) random-effects, with MR-Egger for pleiotropy adjustment. Using the IVW method, we did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes, but did yield several intriguing trends. Long sleep (sleep duration >= 9 h per night) showed a marginally increased NHL risk [Odds ratio (OR) range: 1.51 - 247.9] across each subtype. Short sleep (sleep duration < 7 h per night) showed a similar trend [OR range: 1.25 - 1.81], except for WM/LPL, where we noticed a negative trend. The confidence limit for long sleep was imprecise due to the small number of variants. We did not notice any significant directional horizontal pleiotropy or weak instrument bias. We found no conclusive evidence of a relationship between sleep traits and four NHL subtypes. However, we see suggestive trends of long and short sleep associated with higher risk of some NHL subtypes. These findings align with the previous studies, which showed long sleep was associated with higher risk of NHL overall. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses. Pankhil Shah, Brittany Crawford, Anwar Merchant, Brenda Birmann, Angelica Macauda, Michelle A. Hildebrandt, Aaron Norman, Neil E. Caporaso, Meredith Yeager, Michael Dean, Immaculata De Vivo, Lynn Goldin, Nicola J. Camp, Rosalie Griffin, Delphine Casabonne, Federico Canzian, Pelin Unal, Elad Ziv, Catherine R. Marinac, Alexandra Nieters, Stephen J. Chanock, Mitchell J. Machiela, Michael Conry, Charlie Zhong, Hanla A. Park, Simon Cheah, Jonathan N. Hofmann, Elizabeth E. Brown, Celine Vachon, Susan Slager, Sonja Berndt, Sophia S. Wang, Vijai Joseph, James McKay, Henrik Hjalgrim, Lara Sucheston-Campbell, Karl Smith-Byrne, Alyssa Clay-Gilmour. Association between sleep traits and risk of non-Hodgkin's lymphoma subtypes: a mendelian randomization study in the International Lymphoma Epidemiology (InterLymph) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7415.

BACKGROUND AND OBJECTIVE:In men with prostate cancer, one-third of deaths occur before the age of 75 yr. There remains a need to characterize heritable and environmental risk factors for these early deaths. This study aims to improve risk stratification for early lethal outcomes among prostate cancer patients with genetic factors beyond family history and with modifiable factors. METHODS:This study included 966 prostate cancer patients, enriched for high-risk localized disease and with germline genetic data, in two prospective cohorts. Three genetic factors (family history of prostate cancer, polygenic risk score [PRS] in the top 20%, and rare variants in DNA repair genes) and a lifestyle score were examined for their association with early lethal (metastases/prostate cancer death before the age of 75 yr) compared with nonlethal cases using logistic regression and by calculating 10-yr lethal disease risks. KEY FINDINGS AND LIMITATIONS:In total, 289 lethal, including 77 early lethal, cases were observed (median age at the end follow-up: 84.3 yr). Early lethal cases had higher percentages of men with a family history (23% vs 15%), a high PRS (47% vs 36%), and rare variants (14% vs 7.8%). Having two or more genetic factors was strongly associated with increased odds of early lethal disease (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8-7.0) and linked to higher 10-yr lethal disease risks in high-risk localized patients diagnosed before the age of 75 yr. Healthy men with none of the genetic factors had the lowest odds of early lethal disease (OR, 0.3: 95% CI, 0.1-0.7), compared with unhealthy men with any genetic factor. The pattterns were similar for early fatal disease. The study had limited data for more detailed analyses. CONCLUSIONS AND CLINICAL IMPLICATIONS:The combination of family history with rare variants, a PRS, and lifestyle factors may improve the identification of prostate cancer patients at risk of early lethal and fatal disease.

ABSTRACT:Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a type of T-cell lymphoma arising near textured breast implants. In a Dutch population, a higher prevalence of BRCA1/2 was found in BIA-ALCL. We analyzed the risk of BIA-ALCL occurrence related to BRCA in a large population of women with implants followed after breast cancer (BC) mastectomy. We compared the prevalence of BRCA1/2 between women from a large cohort of patients with BC who did and did not develop BIA-ALCL after reconstruction with textured implants. Hazard ratios (HRs) of developing BIA-ALCL were estimated using Cox regression. We also conducted a case-control study. Of 520 patients with BC tested for BRCA, the age-adjusted rate of developing BIA-ALCL for women with BRCA was 16 times the rate of BIA-ALCL among women without BRCA (95% confidence interval [CI], 3.6-76.1; P < .0003). Carrying bilateral implants (HR, 3.9; 95% CI, 0.4-32.7), chemotherapy (HR, 0.95; 95% CI, 0.2-4.2), and radiotherapy (HR, 0.37; 95% CI, 0.04-3.1) were not associated with BIA-ALCL. We also conducted a case-control study with 13 BIA-ALCL patients matched 1:3 with 39 controls. We used a complete enumeration of Bernoulli probability to rule out a nonassociation of BRCA with BIA-ALCL (P = .0002). In this study, we defined the role of BRCA1/2 mutations as a risk factor in developing BIA-ALCL in patients with BC. These results will help women undergoing breast reconstruction or with textured implants in place.