Yang, Ping

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Lung cancer (LC) kills more people in the United States each year than any other cancer. While it is well known that a variety of environmental factors (particularly tobacco smoke) strongly increase the risk of LC, there are multiple associated genetic variants with small contributions to risk. High aggregation of LC within rare individual families suggest that there are high-risk genetic variants as well. However, these genetic risk factors for LC are under studied due to the rapid fatality of LC. We studied 28 highly aggregated extended high-risk familial lung cancer (HRFLC) families collected from eight different sites across the US. Whole exome sequencing was performed on 290 individuals from these families to identify potential risk variants for HRFLC using genetic linkage analysis. Quality control was performed on the sequence data, filtering on parameters such as read depth, genotype quality, missingness, and Mendelian inconsistencies. Identity-by-descent (IBD) values were also calculated to verify correct familial relationships. Quality control procedures left approximately 400,000 SNVs and indels for analysis.Parametric two-point linkage analysis was performed assuming an autosomal dominant mode of inheritance. Disease allele frequency was set to 1% with a penetrance of 80% for carriers and 1% phenocopy rate. While we did not identify any genome-wide significant variants across the 28 families, multiple suggestive variants were identified. The largest cluster of suggestive variants was located at 14q32 in the CATSPERB gene. Given the likely locus heterogeneity in LC (combined with the lack of power in some families), it is not surprising that none of the variants were significant across the families; looking at the individual family results proved more informative. Long haplotypes linked to LC risk were identified in multiple families. These long runs of positive linkages, which have little to no negative linkage evidence across them, are characteristic of true linkage signals in these types of analysis. Two of the most interesting linked regions were at 7p36.1 and 4q21.23-28.23. The 7p signal (observed in a single family) was genome-wide suggestive and located within the SSPO gene. SSPO has been implicated in breast and skin cancer (melanoma); it is a novel lung cancer signal. The 4q linkage (again observed in a single family) covers a large chunk of 4q and contains multiple potential candidate genes, however, the best candidate gene is PTPN13, a gene implicated in lung cancer but never in familial lung cancer. We are currently evaluating the individual family results of several other pedigrees and plan to perform additional analyses to confirm these linkages. Citation Format: Anthony Musolf, Haiming Sun, Bilal A. Moiz, Claudio W. Pikielny, Mariza de Andrade, Diptasri Mandal, Colette Gaba, Ping Yang, Yafang Li, Ming You, Richard K. Wilson, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Ramaswamy Govindan, Joan E. Bailey-Wilson. Familial lung cancer exhibits multiple novel linked haplotypes within pedigrees [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4176.