Identification of germline variants in cancer susceptibility genes in patients with multiple primary cancers

Abstract 4663

 The occurrence of multiple primary (MP) cancers in a patient suggests a genetic predisposition to tumor formation. Multiplex panel testing may be an efficient way of evaluating MP patients for the presence of germline mutations in cancer susceptibility genes. However the spectrum of mutations in many cancer susceptibility genes in the MP patient population is largely unknown. We performed massively parallel sequencing using targeted capture of 15 genes with well-established risks of breast and/or other cancers, specifically TP53, CDH1, PTEN, STK11, ATM, CHEK2, MRE11A, NBN, RAD50, PALB2, MLH1, MSH2, MSH6, PMS2, and MUTYH. Our patient cohort consisted of 221 BRCA1/2 negative patients diagnosed with breast cancer and at least one other primary cancer, excluding non-melanoma skin cancer. Patients diagnosed with contralateral breast cancer were included.


Thirty patients (14%) were found to have at least one deleterious variant in these 15 genes. Deleterious variants were found in CHEK2 (16 patients, 7.2%), TP53 (4, 1.8%), MSH6 (3, 1.4%), ATM (2, 0.9%) and one patient each had deleterious variants in CDKN2A, PTEN, PMS2, PALB2, BRIP1 and NBN. In addition, six patients (2.7%) were found to be heterozygous carriers of a MUTYH mutation. In comparison, deleterious variants were identified in 9% of 341 patients with breast cancer only, indicating a small but nonsignificant increase in the rate of deleterious variants in MP patients. The rate of MUTYH heterozygous mutations was also non-significantly different in patients with breast cancer only (1.2%). There was a significant increase in the rate of CHEK2 and MSH6 mutations in the MP versus breast-only patients (7.2% vs 3.5%, p = 0.04 for CHEK2 and 1.4% vs 0%, p = 0.05 for MSH6). As a corollary study, a subset of MP patients (n = 165) were assayed on a panel including TET2. Deleterious TET2 mutations were identified in 2 of 165 patients (1.2%) at allele frequencies of 0.17 and 0.36. These patients blood samples were ascertained at ages 77 and 72, respectively.

These preliminary data show that in our cohort of patients with multiple primary cancers, over 16% of patients were found to have deleterious variants in 15 cancer susceptibility genes. In addition, approximately 1% of MP patients have deleterious variants in TET2 that may be due to age-related clonal hematopoiesis, although it is unknown if these mutations are related to the development of the tumors in these individuals.

Further analysis of variants in less well-characterized cancer susceptibility genes and unclassified variants is ongoing. Discovery of clinically relevant mutations can potentially guide future treatment practices for those with similar diagnoses to our patients.