Patrick Glen Pilie, MD MD Anderson discusses an ASCO 2020 abstract entitled Identifying Functional Loss of ATM Gene In Patients With Advanced Cancer
Context:
In cancer, ATM is commonly mutated, and defects can serve as a putative predictive biomarker. However, most ATM variants are not well known for their functional effects. In this study , we examined the relationship between ATM variants and ATM protein expression in advanced cancer patients (pts) to better distinguish the ATM functional defects.
Approaches:
We retrospectively identified pts seen on CLIA-certified next generation sequencing (NGS) assays at MD Anderson Cancer Center that had ATM variants detected. ATM immunohistochemistry (IHC) has been conducted on the tumors available. On tumors from pts referred for DNA damage repair inhibitor (DDRi) trials, we then prospectively evaluated ATM IHC. The variants were functionally defined by means of reported in silico instruments and/or precision oncology decision support (PODS). An ATM protein loss (LOP) identified by an IHC cut-off of 100 percent loss in tumor cell nuclei.
Reviews:
Of the 1,394 retrospectively identified ATM-mutant tumors, ATM alterations were graded as 16% (N = 216) inactivating, 12% (N = 163) potentially inactivating, 71% (N = 993) variant of unknown significance (VUS), and 2% (N = 22) benign. Variants of coding were seen around the exonic structure / splice sites of the ATM, and 20 individual variants were shared at > 10 pts. There were interpretable IHC findings in 263/297 available retrospective tumor samples; 27 percent (N = 72) had ATM LOP. LOP was most common in tumors with inactivating ATM variants (39/100, 39 percent); however, significantly, LOP was seen in 20 percent (N = 33/162) of potentially inactivating / VUS, thus clarifying their functional effect better. 17 per cent (N = 37) had ATM LOP in the prospective cohort of 217 pt tumors. Of this cohort, 29 percent (N = 62/217) had ATM variants as well. In 48% of tumors with inactivating variants (N = 14/29), 25% of tumors with potential / VUS(N = 9/36), and 9% (N = 14/156) of tumors without known ATM variants, ATM LOP was seen. In colorectal (24 percent; N = 8/34), cholangiocarcinoma (20 percent; N = 6/30), prostate (16 percent; N = 16/104) and pancreatic (9 percent; N = 1/11) cancers, ATM LOP was most commonly found in this cohort of pts referred to for DDRi studies.
Findings:
Variants of ATM coding occurred across the genome, with some variants sharing across forms of tumor. The functional impact of most ATM variants was VUS, and in up to 25 per cent of these VUS, ATM LOP may help explain function. ATM LOP can also be seen in tumors with no known ATM variants, indicating epigenetic or post-translational loss. Future prospective studies evaluating paired DNA predictive capacity and protein-level ATM profiling are warranted.