Abstract P3-08-07: ATM mutations contribution to hereditary breast-pancreatic cancer
Authors: Gordon OK , Childers K , McFarland R , Laduca H 
Published: March 2017

Abstract
BACKGROUND: Germline mutations in PALB2, BRCA2 and STK11 are well established as increasing risk of both breast and pancreatic cancer. More recently, ATM and BRCA1 mutations have also been associated with risk, but literature is limited. We investigated the prevalence of pathogenic mutations and likely pathogenic variants (“mutations”) in BRCA1/2, PALB2, STK11 and ATM, comparing mutation occurrence in individuals with diagnoses of breast cancer alone to those with both breast and pancreatic cancer primaries. Prevalence of CDKN2A (p16) mutations was also evaluated in the breast–pancreatic cohort because of its contribution to hereditary pancreatic cancer.
METHODS: Clinical histories and test results were reviewed for patients undergoing multi-gene panel testing at one clinical laboratory between April 2012 and June 2015. The study population was limited to women with breast cancer only (n=27,573) and women with both breast and pancreatic cancer (n=97) without other primaries. Patients underwent comprehensive analysis of 5-49 genes, depending on the panel ordered. Demographic and clinical information was provided by clinicians on test requisition forms and pedigrees/clinic notes if provided. Gene-specific mutation frequencies were compared between women with breast cancer only and women with breast and pancreatic cancer using Fisher's exact test.
RESULTS: Mutations were identified in BRCA1, BRCA2, PALB2 or ATM in 13 of the 97 breast - pancreatic cancer probands (13.4%) and 1,255 of the 27,573 breast cancer probands (4.6%). Gene-specific mutation frequencies and statistical comparisons may be found in Table 1. ATM mutations were significantly more likely to be identified in women with breast and pancreatic cancer compared to breast cancer alone (Table 1). Interestingly, no CDKN2A or STK11 mutations were identified in the breast plus pancreatic cohort, although this may have been limited by the small number of individuals tested for this gene. Of those 13 women with breast and pancreatic cancers who had identified mutations, 11 (85%) had diagnoses of breast cancer over age 50.
Table 1. Mutation FrequenciesGeneMutation Frequence n/N (%)Mutation Frequence n/N (%)pOR (95% PI) Breast & PancreaticBreast Only ATM6/89 (6.74%)209/17,570 (1.19%)0.000766.00(2.12,13.85)BRCA12/90 (2.22 %)429/26,336 (1.63%)0.661.37(0.16,5.14)BRCA24/90 (4.44%)442/26,336 (1.68%)0.0662.72 (0.72,7.28)CDKN2A0/54 (0.00%)13/3,965 (0.33%)10.00 (0, 24.70)PALB21/891.12% 175/17,570 (1%)0.591.13(0.03, 6.54)STK110/860.00% 0/16,931 (0.00)1Inf (0, Inf)
CONCLUSION: This exploratory study substantiates the association of deleterious germline ATM mutations with predisposition to both breast and pancreatic cancers. These results also suggest that mutations in ATM may account for a larger portion of inherited breast and pancreatic cancer kindreds than mutations in other well-described genes such as BRCA2, PALB2 and STK11. A personal history of breast and pancreatic cancer may warrant the expansion of current NCCN testing criteria as a single indicator for germline testing, and that pancreatic screening consortia (CAPS) consider inclusion of ATM mutations in screening recommendations.
Citation Format: Gordon OK, Childers K, McFarland R, Laduca H. ATM mutations contribution to hereditary breast-pancreatic cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-07.