Chanock, Stephen Jacob

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Summary 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 (HR 1‐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 (HR 1‐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.

Abstract Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.

Background and Aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses. Approach and Results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 −8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes. Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Abstract Background Breast cancer genome-wide association studies (GWAS) have identified more than 200 susceptibility loci, but most studies are dominated by European and East Asian populations. Methods We analyzed breast cancer GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR), and Hispanic/Latina (H/L) samples (159,297 cases and 212,102 controls). We estimated logit-scale SNP-based heritability, polygenicity, and cross-ancestry genetic correlation, partitioned heritability across functional annotations, and integrated GWAS results with the Tabula Sapiens single-cell atlas using scDRS+. Results The logit-scale heritability of breast cancer ranged from ℎ 2 =0.47 (SE = 0.07) in EAS to AFR ℎ 2 =0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The estimated number of susceptibility markers in a sparse normal-mixture effects model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS (𝜌 = 0.79, SE = 0.08) and weakest between AFR and H/L (𝜌 = 0.26, SE = 0.24). Regulatory annotations were enriched for breast cancer heritability across samples. Integration with single-cell expression profiles implicated ancestry-shared associations with innate immune, secretory epithelial, and stromal cell types. Conclusion These results indicate substantial cross-ancestry sharing of breast cancer polygenic architecture, highlight a consistent contribution of regulatory variation, and identify convergent cellular contexts that motivate functional follow-up and inform expectations for the transferability and attainable performance of common-variant risk prediction across populations.

Abstract Introduction: 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). Methods: 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 &lt; 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. Results: 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 &gt;= 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 &lt; 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. Conclusions: 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. Citation Format: 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.