Morphology and genomic hallmarks of breast tumours developed by ATM deleterious variant carriers

Abstract

BackgroundThe ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management.MethodsTo characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours. Morphology of ATM-associated tumours was compared with that of 599 patients with no BRCA1 and BRCA2 mutations from a hospital-based series, as well as with data from The Cancer Genome Atlas. Absolute copy number and loss of heterozygosity (LOH) profiles were obtained from the OncoScan SNP array. In addition, we performed whole-genome sequencing on four tumours from ATM loss-of-function variant carriers with available frozen material.ResultsWe found that ATM-associated tumours belong mostly to the luminal B subtype, are tetraploid and show LOH at the ATM locus at 11q22–23. Unlike tumours in which BRCA1 or BRCA2 is inactivated, tumours arising in ATM deleterious variant carriers are not associated with increased large-scale genomic instability as measured by the large-scale state transitions signature. Losses at 13q14.11-q14.3, 17p13.2-p12, 21p11.2-p11.1 and 22q11.23 were observed. Somatic alterations at these loci may therefore represent biomarkers for ATM testing and harbour driver mutations in potentially ‘druggable’ genes that would allow patients to be directed towards tailored therapeutic strategies.ConclusionsAlthough ATM is involved in the DNA damage response, ATM-associated tumours are distinct from BRCA1-associated tumours in terms of morphological characteristics and genomic alterations, and they are also distinguishable from sporadic breast tumours, thus opening up the possibility to identify ATM variant carriers outside the ataxia-telangiectasia disorder and direct them towards effective cancer risk management and therapeutic strategies.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0951-9) contains supplementary material, which is available to authorized users.

Pathogenicity assessment of variants for breast cancer susceptibility genes based on BRCAness of tumor sample

“…Whereas tumors with germline pathogenic variants with LOH or AST were enriched among BRCAness high tumors, ATM BAL tumors showed low BRCAness probability and were not identified as the triple‐negative subtype (Table B). This finding is indeed consistent with previous observations, in which ATM ‐mutated breast cancers showed low COSMIC signature #3, 18 low HRD‐LST, 16 and a luminal subtype 28,40 . Although ATM is a component of the HR repair pathway, ATM loss of function could exert a distinct tumorigenic program that differs from that of the other HBOC‐HR genes.…”

“…This finding is indeed consistent with previous observations, in which ATM-mutated breast cancers showed low COSMIC signature #3, 18 low HRD-LST, 16 and a luminal subtype. 28,40 Although…”

Tumor sequencing is useful to refine the analysis of germline variants in unexplained high-risk breast cancer families

“…Inactivation of both BRCA1 and BRCA2 alleles appears to be required for the HRD characteristic of BRCA-related HBOC [22]. Two-hit inactivation has also been described, in smaller case series, for PALB2-and ATM-related HBC, and BRIP1-related hereditary ovarian cancer [42][43][44].…”

Characterization of New ATM Deletion Associated with Hereditary Breast Cancer

“…In particular, families carrying heterozygous germ-line variants of ATM gene have a 5- to 9-fold risk of developing breast cancer, particularly in women younger than 50 years [ 6 ]. Approximately, 3% of the families affected by hereditary breast and ovarian cancer harbors a loss-of-function ATM mutation [ 7 ]. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients [ 8 ].…”