Black, Mary Helen

Abstract Background: Polygenic risk scores (PRS) based on a large number of SNPs associated with breast cancer have recently been made available in combination with multigene panel testing for clinical management of breast cancer risk. Breast cancer risk assessment has historically been performed using various non-genetic risk models, which predict lifetime risk of breast cancer in unaffected women based on personal and family history information. While clinical use of PRS in combination with these models continues to increase, the predictive performance of a PRS combined with clinical information in real-world patient populations has not been thoroughly investigated. Methods: We assessed a 100-SNP breast cancer PRS in combination with the Tyrer-Cuzick model-estimated lifetime breast cancer risk in 5,374 Caucasian women from the case-control Mayo Clinic Breast Cancer Study (MCBCS), comprised of 3,373 breast cancer cases and 2,001 unaffected controls seen at Mayo Clinic from 2004 to 2016. Clinical, family history, and demographic information was collected on all MCBCS participants via questionnaires and medical record review. SNPs were selected for the PRS if they exceeded genome-wide significance in ≥2 large-scale breast cancer genome wide association studies (GWAS) in women of European descent. Selected SNPs were then used to construct a population standardized PRS, accounting for per-allele odds ratios reported in the largest GWAS to date and population-specific allele frequencies. PRS and Tyrer-Cuzick model associations with breast cancer and related clinical features were tested using multivariate logistic regression. Results: Among cases and controls, mean±SD age at diagnosis and study enrollment was 56.4±12.4 and 56.2±14.1, respectively. Approximately 36.9% of cases and 16.9% of controls had ≥1 first- or second-degree relative with breast or ovarian cancer, respectively. Among unaffected women, the median (IQR) estimated lifetime risk of breast cancer to age 85 based on Tyrer-Cuzick alone was 8.3% (6.9%), and 2.6% had a clinically actionable lifetime risk of ≥20%. The mean±SD sum of the risk alleles across 100 SNPs was significantly higher for cases vs. controls (94.8±6.3 vs. 92.7±6.2, p<0.001). Compared to women in the lowest quartile of PRS, those in the 2nd, 3rd and 4th quartiles were 1.47 (95% CI: 1.26-1.72), 1.87 (95% CI: 1.60-2.19), and 2.22 (95% CI: 1.89-2.61) times more likely to have breast cancer after adjustment for age and family history. The AUC was 0.59 (95% CI: 0.58-0.61) for PRS and 0.60 (95% CI: 0.58-0.61) for Tyrer-Cuzick model estimated risk alone; but when combined, the model achieved an AUC of 0.63 (95% CI: 0.62-0.65). Among unaffected women, 6.7% had ≥20% lifetime risk of breast cancer based on the combined PRS-clinical model. Conclusions: These findings suggest that the 100-SNP PRS significantly improves estimation of breast cancer risk based on non-genetic models, and can be used to further identify women at increased lifetime risk who would otherwise not be identified by clinical assessment alone. Citation Format: Mary Helen Black, Shuwei Li, Holly LaDuca, Sebastian Armasu, Eric C. Polley, Patrick Fitz-Gibbon, Chris G. Scott, Stacey J. Winham, Janet E. Olson, Kathryn J. Ruddy, Celine M. Vachon, Fergus J. Couch. Performance of a polygenic risk score combined with clinical assessment for breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-06.

Purpose The relevance of inherited pathogenic mutations in cancer predisposition genes in pancreatic cancer is not well understood. We aimed to assess the characteristics of patients with pancreatic cancer referred for hereditary cancer genetic testing and to estimate the risk of pancreatic cancer associated with mutations in panel-based cancer predisposition genes in this high-risk population. Methods Patients with pancreatic cancer (N = 1,652) were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes between March 2012 and June 2016. Gene-level mutation frequencies relative to Exome Aggregation Consortium and Genome Aggregation Database reference controls were assessed. Results The frequency of germline cancer predisposition gene mutations among patients with pancreatic cancer was 20.73%. Mutations in ATM, BRCA2, CDKN2A, MSH2, MSH6, PALB2, and TP53 were associated with high pancreatic cancer risk (odds ratio, > 5), and mutations in BRCA1 were associated with moderate risk (odds ratio, > 2). In a logistic regression model adjusted for age at diagnosis and family history of cancer, ATM and BRCA2 mutations were associated with personal history of breast or pancreatic cancer, whereas PALB2 mutations were associated with family history of breast or pancreatic cancer. Conclusion These findings provide insight into the spectrum of mutations expected in patients with pancreatic cancer referred for cancer predisposition testing. Mutations in eight genes confer high or moderate risk of pancreatic cancer and may prove useful for risk assessment for pancreatic and other cancers. Family and personal histories of breast cancer are strong predictors of germline mutations.

Abstract Purpose: The relevance of inherited pathogenic variants in cancer predisposition genes to pancreatic cancer (PC) is not well understood. Several small studies have identified pathogenic variants in 4% to 14% of unselected PC patients using multigene panels of predisposition genes, but only BRCA2, ATM, and PALB2 have been clearly implicated in this disease. We aimed to assess the clinical and molecular characteristics of PC patients referred for hereditary cancer genetic testing, and to estimate the risk of PC associated with pathogenic variants in panel-based cancer predisposition genes. Methods: PC patients (n=1,819) were ascertained from a large cohort of over 140,000 patients undergoing multigene panel testing (MGPT) of predisposition genes between March 2012 and June 2016 at a single diagnostic laboratory. Clinical histories and molecular results were reviewed and summarized. Gene-level variant frequencies among PC cases were compared to those from the Exome Aggregation Consortium (ExAC) to calculate gene-specific pancreatic cancer risk ratios. Results: PC patients were predominantly Caucasian (76.5%) and female (58.9%), with a median age at diagnosis of 61 years (51.7). Of these, 33.5% reported additional cancer primaries, and 44.8% reported a family history of PC. Overall, 15.4% of PC patients were found to have at least one pathogenic/likely pathogenic variant in panel-based predisposition genes. Genes with the highest frequencies of pathogenic/likely pathogenic variants included BRCA2 (3.9%), ATM (3.6%), CHEK2 (excluding p.Ile157Thr) (2.0%), PALB2 (1.5%), VHL (1.4%), CDKN2A (1.2%), BRCA1 (0.8%), and MSH6 (0.8%). 21.8% of BRCA1 and BRCA2 carriers did not meet BRCA1/2 testing criteria and 61.5% of MSH6 carriers did not meet Lynch syndrome testing criteria. No CDKN2A families met diagnostic criteria for familial atypical multiple mole melanoma syndrome, and 44% did not report any personal or family history of melanoma. To estimate associations between pathogenic variants and pancreatic cancer, Caucasian PC cases were compared to non-Finnish European, non-TCGA ExAC reference controls. Pathogenic variants in ATM, BRCA2, CDKN2A, MSH6, and PALB2 were significantly associated with high PC risks. Pathogenic variants in BRCA1 were associated with a moderate risk of PC (RR=2.7). Conclusions: These findings shed light on the spectrum of mutations that can be expected for PC patients referred for cancer predisposition testing. The results confirm the associations of CDKN2A and BRCA2 variants with PC, and expand on the phenotypic spectrum associated with these variants. Furthermore, these results suggest that ATM, PALB2, and MSH6 may be high-risk PC genes, warranting further investigation in case-control and family-based studies. Citation Format: Holly LaDuca, Chunling Hu, Hermela Shimelis, Eric Polley, Jenna Lilyquist, Mary Helen Black, Brigette Tippin Davis, David E. Goldgar, Jill Dolinsky, Fergus J. Couch. What have we learned from pancreatic cancer patients undergoing multigene panel testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4286. doi:10.1158/1538-7445.AM2017-4286