Invasive breast carcinomas withATMgene variants of uncertain significance share distinct histopathologic features

Abstract

The increasing availability of next-generation sequencing for clinical research dramatically improved our understanding of breast cancer genetics and resulted in detection of new mutation variants. Cancer risk data relating to some of these variants are insufficient, prompting the designation of variants of uncertain significance (VUS). The histopathologic characteristics of these variants have not been previously described. We propose to depict these characteristics and determine if invasive carcinomas with similar VUS genes share similar histomorphologic features. In total, 28 invasive breast cancers with VUS were retrospectively identified. Tumor sections were reviewed and a predefined set of histopathologic characteristics were documented and compared. Nine of the 28 cases were variants in the ATM gene and were found to share similar histologic characteristics; all had tumor cells with low nuclear grade, absent tumor infiltrating lymphocytes, as well as a marked desmoplastic response. A subset of the above findings were identified in variants of other genes but none had all findings collectively. Furthermore, variants of ATM gene had smaller tumor size, lower pathologic T stage at presentation, and more favorable surrogate molecular subtype compared to variants of other genes. These findings could potentially be used to reclassify VUS and predict which patients may harbor ATM mutations, and hence could have implications in triaging toward ATM variant identification for potential future targeted therapy.

Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia–Telangiectasia Mutated Variant Carriers

“…Moreover, we did not observe an association between ATM variant status of the patient and clinical stage and histology criteria associated with aggressive tumors (for example, embolus, high mitotic index, triple-negative histological subtype), which is interesting in the discussion of the adjuvant RT treatment schedule of carriers of ATM PV or PPV who do not seem to have more aggressive histological characteristics than noncarrier patients. An exploration of a possible difference in histological subtypes of breast cancer in ATM variant carriers compared to other genes implicated in DNA double-strand break repair, such as BRCA1 and BRCA2, was conducted by Abdulrahman et al in 2018 and showed that tumors of ATM VUS carriers seem smaller, with lower pathologic T stages at diagnosis and greater surrogate molecular subtypes [37]. In a previous study, we performed a systematic pathology review of breast tumors from 21 ATM PV carriers from A-T families and 18 PV or predicted PV carriers from Hereditary Breast and Ovary Cancer families (including patients enrolled in CoF_AT2 and GENESIS), and we found that ATM-associated breast tumors belong mostly to the luminal B subtype in a retrospective tumor [38].…”

BRCA1/BRCA2 variants of uncertain significance in clinical practice: A case report

“…Variants of uncertain significance have also been identified in other genes such as: TP53 (15), ATM (16) or PALB2 (17). There are only few studies, which describe histopathologic characteristics of VUS (18).…”