Background Radiation therapy is one of the most commonly used cancer therapeutics, but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure. Methods We analyzed 20,107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1,085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy. Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared to those harboring variants of unknown significance (VUS). All statistical tests were two-sided. Results Among 357 pan-cancer patients who received 727 courses of radiotherapy, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs VUS allele, respectively (HR: 0.51, 95% CI = 0.34-0.77, p= .001). The greatest clinical benefit was seen in tumors harboring bi-allelic ATM inactivation (HR = 0.19, 95% CI = 0.06-0.60, p=.005), with statistically significant benefit also observed in tumors with mono-allelic ATM inactivation (HR = 0.57, 95% CI = 0.35-0.92, p=.02). Notably, ATM LoF was highly predictive of outcome in TP53 wild type tumors, but not among TP53-mutant tumors. Conclusion We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following radiotherapy. The identification of a radiosensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically-guided radiotherapy.
Clinically silent double pituitary adenomas consisting of corticotroph and somatotroph cells are an exceedingly rare clinical finding. In this report, we present the case of a 28-year-old man with a 1-year history of recurrent headaches. Imaging revealed a 2.1 (anterior-posterior) × 2.2 (transverse) × 1.3 (craniocaudal) cm pituitary adenoma invading into the left cavernous sinus and encasing the left internal carotid artery. Endoscopic transnasal resection was performed without complications. Immunohistochemical staining revealed a double adenoma consisting of distinct sparsely granulated somatotroph and densely granulated corticotroph cells that were positive for growth hormone and adrenocorticotropic hormone, respectively. Ki-67 index labeling revealed a level of 6% within the corticotroph adenoma. No increase in serum growth hormone or adrenocorticotropic hormone was found, indicating a clinically silent double adenoma. While transsphenoidal surgery remains a first-line approach for silent adenomas presenting with mass effects, increased rates of proliferative markers, such as the Ki-67 index, provide useful insight into the clinical course of such tumors. Determining the Ki-67 index of silent pituitary adenomas could be valuable in predicting recurrence after initial surgical resection and identifying tumors that are at an increased risk of needing additional therapeutic interventions or more frequent surveillance imaging.
Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4–5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
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