Background To measure the aging process before a cancer diagnosis, we developed the first cancer-specific proteomic aging clock (CaPAC) and examined its association with cancer risk in the Atherosclerosis Risk in Communities (ARIC) and Multi-Ethnic Study of Atherosclerosis (MESA) studies. Methods Using the SomaScan assay, ARIC measured 4,712 proteins in plasma samples collected in 1990-92 from 3,347 participants who developed cancer over follow-up until 2015 and 7,487 who remained cancer-free, all aged 46-70. We constructed CaPAC0 using elastic net regression among two-thirds randomly selected cancer-free participants (N=4,991, training set) and calculated age acceleration for CaPAC0 (CaPAA0) as residuals of CaPAC0 on chronological age in all remaining ARIC participants. We used multivariable-adjusted Cox proportional hazards regression to calculate hazard ratios (HRs) for the risk of overall, obesity-related, smoking-related, and the most common cancers (prostate, lung, breast, colorectal) with CaPAA0 using a case-cohort design. We replicated the analysis in 3,893 MESA participants aged 46-70 at Exam 1 (456 incident cancer). Results CaPAC0 was correlated with chronological age in ARIC and MESA (r=0.82 and 0.86, respectively). In both ARIC and MESA, CaPAA0 was significantly (p<0.05) associated with the risk of overall [HRs per 5-years=1.08 and 1.23, respectively], smoking-related [HRs=1.30 and 1.54, respectively], and lung cancers [HRs=1.54 and 1.94, respectively]. CaPAA0 was also significantly associated with colorectal cancer risk in ARIC [HR=1.31], but not in MESA. CaPAA0 was not associated with obesity-related, breast, or prostate cancers. Conclusion CaPAA0 was associated with several types of cancer with the strongest association observed for lung cancer risk.

The authors have declared no competing interest.

This study was supported by the National Center for Advancing Translational Sciences grant UM1TR004405, and the National Cancer Institute grant R01CA267977. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). SomaLogic Inc. conducted the SomaScan assays in exchange for the use of ARIC data. This work was also supported in part by NHLBI grant R01 HL134320. Cancer data in ARIC are also supported by the National Cancer Institute (U01 CA164975). The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi-Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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The study used only publicly available ARIC and MESA data. The ARIC and MESA datasets are available through BioLINCC, with appropriate study approvals consistent with NIH policies. Data request forms through BioLINCC can be accessed at https://biolincc.nhlbi.nih.gov/studies/aric/ and https://biolincc.nhlbi.nih.gov/studies/mesa/.

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All data produced in the present study are available upon reasonable request to the authors.