Ataxia telangiectasia mutated germline pathogenic variant in adrenocortical carcinoma

Open AccessPublished:March 24, 2021DOI:https://doi.org/10.1016/j.cancergen.2021.03.003

      Abstract

      Background

      : Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Here, we report the first case of ACC in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene.

      Patients and Methods

      : A 56-year-old Caucasian woman with biopsy proven ACC deemed unresectable and treated with etoposide, doxorubicin and cisplatin (EDP), and mitotane presented to our institution for evaluation. The tumor specimen was examined pathologically, and genetic analyses were performed on the tumor and germline using next-generation sequencing.

      Results

      : Pathologic evaluation revealed an 18.0 × 14.0 × 9.0 cm low-grade ACC with tumor free resection margins. Immunohistochemistry stained for inhibin, melan-A, and chromogranin. ClinOmics analysis revealed a germline pathogenic deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. Genomic analysis of the tumor showed loss of heterozygosity (LOH) of chromosome 11 on which the ATM resides.

      Conclusion

      : ACC is an aggressive malignancy for which surgical resection currently offers the only curative option. Here we report a heterozygous loss-of-function mutation in germline DNA and LOH of ATM in tumor in an ACC patient, a classic two-hit scenario in a well-known cancer suppresser gene, suggesting a pathogenic role of the ATM gene in certain ACC cases.

      Keywords

      Introduction

      Adrenocortical carcinomas (ACC) are exceedingly rare tumors that arise from the adrenal gland cortex. Despite its poor prognosis, with an incidence of only 0.5 to 2 cases per million per year [
      • Erickson L.A.
      • Rivera M.
      • Zhang J.
      Adrenocortical carcinoma: review and update.
      ,
      • Fassnacht M.
      • Kroiss M.
      • Allolio B.
      Update in adrenocortical carcinoma.
      ACC accounts for less than one percent of cancer related deaths in the United States [
      • del Rivero J.
      • Fojo T.
      Endocrine cancers.
      ]. ACC has a bimodal distribution with the first peak in children less than five years old and the second peak in adults in the fourth to fifth decade of life [
      • Fassnacht M.
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      Update in adrenocortical carcinoma.
      ,
      • Fassnacht M.
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      Epidemiology of adrenocortical carcinoma.
      . Regardless of the age at diagnosis, there are limited treatment options for ACC. Surgical resection with negative margins is the only curative therapeutic option but is only available for patients with localized disease. For those patients with advanced disease, systemic therapy with mitotane in combination with etoposide, doxorubicin and cisplatin (EDP) is the regimen with proven benefit to some patients [
      • Terzolo M.
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      ]. Given its rarity, often aggressive nature, and its biology frequently refractory to systemic therapy, ACC is difficult to treat and carries an extremely poor prognosis with median survival of all patients combined just over three years [
      • Ayala-Ramirez M.
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      Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center.
      ].
      Approximately 10% of ACC cases are associated with hereditary cancer syndromes including, Li-Fraumeni syndrome, multiple endocrine neoplasia type 1, Beckwith–Wiedemann syndrome, and Familial Adenomatous Polyposis [
      • Erickson L.A.
      • Rivera M.
      • Zhang J.
      Adrenocortical carcinoma: review and update.
      ,
      • del Rivero J.
      • Fojo T.
      Endocrine cancers.
      ,
      • Else T.
      Association of adrenocortical carcinoma with familial cancer susceptibility syndromes.
      , while the prevalence of Lynch Syndrome in patients with ACC has been reported at 3.2% [
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      Adrenocortical carcinoma is a lynch syndrome-associated cancer.
      . In addition, ACC has been reported in 4 patients with neurofibromatosis type 1 (NF1) [
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      ], and in at least four cases of hereditary nonpolyposis colorectal cancer (HNPCC) [
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      ,
      • Broaddus R.R.
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      Unusual tumors associated with the hereditary nonpolyposis colorectal cancer syndrome.
      ,
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      Adrenocortical carcinoma, an unusual extracolonic tumor associated with Lynch II syndrome.
      ]. Finally, ACC has also been reported in four patients with germline pathogenic variants in the SDHx genes [
      • Else T.
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      • Everett J.
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      • Mullane M.
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      Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series.
      ]. Although ACC is a rare disease, advances in next generation sequencing (NGS) can detect genomic alterations that can help guide targeted therapies in challenging diseases such as ACC. In this report, we describe to our knowledge the first patient with ACC found to have a heterozygous germline pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene.

      Methods and results

       Clinical summary

      A 56-year-old Caucasian woman with a past medical history of hypertension, descending aortic dissection, and chronic obstructive pulmonary disease (COPD) requiring home oxygen via nasal canula presented with right upper quadrant abdominal pain and shortness of breath. Magnetic Resonance Imaging (MRI) and CT scan of her abdomen and pelvis demonstrated a 16.4 × 11.6 × 13.3 cm heterogeneous right suprarenal mass with microcalcifications and effacement of the inferior vena cava ( Fig. 1A-E) concerning for ACC. Biochemical evaluation revealed an adrenocorticotropic hormone (ACTH) independent cortisol secreting adrenal mass. CT guided biopsy of the mass was performed which confirmed the diagnosis of ACC. She was treated with 3 cycles of systemic standard dose chemotherapy, EDP. She was transitioned to mitotane due to tumor progression to a size of 19 cm at greatest diameter. She sought a second opinion at our institute, where after careful review she underwent a right adrenalectomy with en-bloc partial hepatectomy of segments seven and eight, a right nephrectomy and right diaphragm removal followed by diaphragm repair. Her post-operative course was uncomplicated, and she was found to have no radiologic evidence of disease at her 3-month visit.
      Fig 1
      Fig. 1Multimodal imaging consistently demonstrating a 16.4 × 11.6 × 13.3 cm right sided adrenocortical carcinoma tumor. A. T1 weighted MRI of the abdomen B. Axial view of chest abdomen pelvis computed tomography (CT). C. Sagittal view of chest abdomen pelvis CT. D. Coronal view of chest abdomen pelvis CT. E. Coronal view of chest abdomen pelvis CT angiography. F. FDG PET scan of the chest abdomen pelvis.

       Pathology

      Gross evaluation of the mass revealed a 1.64 kg tumor measuring 18.0 × 14.0 × 9.0 cm ( Fig. 2A-B). Pathologic assessment confirmed the presence of a low-grade ACC with extensive necrosis, infiltrating but not penetrating the tumor capsule and tumor free margins. Ki-67 score was 3–4%, with 3 mitoses per 50 high-power fields ( Fig. 2B).
      Fig 2
      Fig. 2Gross and immunohistochemical (IHC) representations of excised right sided adrenocortical tumor specimen. A. Gross tumor specimen measuring 18 × 14 × 9 cm and weighing 1642.5 g. B. IHC staining of tumor sample for Ki67confirming a diagnosis of ACC.

       Genomic analysis

      ClinOmics(18) exome and panel sequencing of matched tumor and germline performed at the National Cancer Institute (NCI) revealed the patient had a heterozygous germline pathogenic mutation in the ATM gene, which was subsequently confirmed with an independent blood sample at GeneDx Laboratories. This deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. The variant allele frequency (VAF) was 0.486 in the blood and 0.851 in the tumor with a VAF ratio of 1.75 demonstrating loss of heterozygosity in the tumor ( Fig. 3). The deletion causes a frameshift, which changes an Asparagine to a Lysine at amino acid 405 and creates a premature stop codon at position 15 of the new reading frame. Additionally, the tumor showed loss-of-heterozygosity (LOH) of whole chromosome 11 where the ATM gene is located as a result of loss the normal copy while gain multiple mutant copies ( Fig. 3B), suggesting a pathogenic role of the ATM gene in this ACC case.
      Fig 3
      Fig. 3A. Integrative Genomics Viewer (IGV) image of the c.1215delT indel mutation (p.Asn405LysfsX15) in the ATM gene. This shows a variant allele frequency (VAF) of 0.486 in the germline (upper panel) indicating a heterozygous mutation, and loss of heterozygosity (LOH) in the tumor as evidenced by a lower coverage and a higher VAF of 0.851 (lower panel). B. Copy number alteration across all the autosome chromosomes shows extensive LOH including at chromosome 11 where ATM is located. Red bar represents the copy number of one chromosome and blue the other. Data analyzed using CNVkit (https://github.com/etal/cnvkit). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

      Discussion

      Adrenal cortical carcinoma (ACC) is a rare cancer with limited treatment options. As such, patients suspected of having ACC should be referred to an experienced treatment center and must undergo a comprehensive work-up to ensure precise diagnosis and staging. For patients with suspected ACC, radiographic work-up includes CT scan of the abdomen with intravenous (IV) contrast. MRI can provide additional characterization in the event that CT scan is unequivocal or unavailable. Additionally, biochemical evaluation is required and should include assessment of basal cortisol, ACTH, dexamethasone suppression test, urinary free cortisol, and serum metanephrine levels to exclude pheochromocytoma [
      • Dickson P.V.
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      • Patel D.
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      Evaluation, staging, and surgical management for adrenocortical carcinoma: an update from the SSO endocrine and head and neck disease site working group.
      ,
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      • Baudin E.
      • Berruti A.
      • de Krijger R.
      • et al.
      European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors.
      . There is a limited role for needle biopsy in the diagnosis of ACC as they are associated with low diagnostic accuracy, and carry high risk of violating the tumor capsule [
      • Fassnacht M.
      • Kroiss M.
      • Allolio B.
      Update in adrenocortical carcinoma.
      ,
      • Williams A.R.
      • Hammer G.D.
      • Else T.
      Transcutaneous biopsy of adrenocortical carcinoma is rarely helpful in diagnosis, potentially harmful, but does not affect patient outcome.
      . Currently, microscopically-negative margin (R0) resection is the only curative treatment for localized disease (stage I-III), while debulking surgery can be considered for metastatic disease. Systemic treatment with EDP and mitotane is warranted for high risk disease in the adjuvant setting or in the metastatic setting.
      Increased access to NGS has facilitated genomic sequencing of rare cancers including ACC. Previous studies have reported decreased expression, deletions, and gene alterations in the ATM gene with potential to contribute to malignancy [
      • Ye J.
      • Qi Y.
      • Wang W.
      • Sun F.
      • Wei Q.
      • Su T.
      • et al.
      Lower expression of ATM and gene deletion is more frequent in adrenocortical carcinomas than adrenocortical adenomas.
      ,
      • Ross J.S.
      • Wang K.
      • Rand J.V.
      • Gay L.
      • Presta M.J.
      • Sheehan C.E.
      • et al.
      Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.
      ,
      • De Martino M.C.
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      • Assié G.
      • Scoazec J.Y.
      • Leboulleux S.
      • et al.
      Molecular screening for a personalized treatment approach in advanced adrenocortical cancer.
      ]. De Martino et al. reported higher frequency of ATM variants than the general population, while additional studies have reported genomic alterations, and decreased copies of the ATM gene in ACC shedding light into potential alterations for targeted therapy [
      • Ye J.
      • Qi Y.
      • Wang W.
      • Sun F.
      • Wei Q.
      • Su T.
      • et al.
      Lower expression of ATM and gene deletion is more frequent in adrenocortical carcinomas than adrenocortical adenomas.
      ,
      • Ross J.S.
      • Wang K.
      • Rand J.V.
      • Gay L.
      • Presta M.J.
      • Sheehan C.E.
      • et al.
      Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies.
      ,
      • De Martino M.C.
      • Al Ghuzlan A.
      • Aubert S.
      • Assié G.
      • Scoazec J.Y.
      • Leboulleux S.
      • et al.
      Molecular screening for a personalized treatment approach in advanced adrenocortical cancer.
      ]. Here, we report the first case of a patient with ACC and a germline heterozygous pathogenic variant in the ATM gene. The loss of heterozygosity of the ATM gene (located on chromosome 11q22–23) is in keeping with a classical two-hits genomic alteration for the ATM gene in this ACC tumor, suggesting a pathogenic role of ATM in this cancer. The ATM gene encodes a PI3K-related serine/threonine protein kinase (PIKK) associated with maintaining genomic integrity and repair of double strand DNA breaks [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ]. ATM is most commonly associated with ataxia-telangiectasia syndrome (AT), an autosomal recessive syndrome associated with neurodegeneration, cerebellar ataxia, immunodeficiency, hypogammaglobulinemia, radio-sensitivity, adrenal atrophy, and gonadal dysgenesis [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ,
      • Teive H.A.
      • Moro A.
      • Moscovich M.
      • Arruda W.O.
      • Munhoz R.P.
      • Raskin S.
      • et al.
      Ataxia-telangiectasia - a historical review and a proposal for a new designation: ATM syndrome.
      ,
      • Dunn H.G.
      • Meuwissen H.
      • Livingstone C.S.
      • Pump KK.
      ATAXIA-TELANGIECTASIA.
      ]. Additionally, patients with AT have a higher risk up to 20% of developing hematologic and other epithelial cancers [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ,
      • Reiman A.
      • Srinivasan V.
      • Barone G.
      • Last J.I.
      • Wootton L.L.
      • Davies E.G.
      • et al.
      Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.
      . Furthermore, sensitivity and increased toxicity to radiotherapy has been reported in patients with AT. However, this has not been associated with the development of secondary cancers after radiotherapy in heterozygote germline pathogenic variant carriers [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ]. The ATM c.1215delT has been reported in an individual with triple negative breast cancer and an individual with male breast cancer [
      • Fostira F.
      • Saloustros E.
      • Apostolou P.
      • Vagena A.
      • Kalfakakou D.
      • Mauri D.
      • et al.
      Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.
      ,
      • Couch F.J.
      • Hart S.N.
      • Sharma P.
      • Toland A.E.
      • Wang X.
      • Miron P.
      • et al.
      Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
      . This variant was also observed in a patient with ataxia-telangiectasia syndrome (AT) who carried a second pathogenic variant in ATM
      • Nahas S.A.
      • Butch A.W.
      • Du L.
      • Gatti R.A.
      Rapid flow cytometry-based structural maintenance of chromosomes 1 (SMC1) phosphorylation assay for identification of ataxia-telangiectasia homozygotes and heterozygotes.
      ].
      Approximately 1% of the U.S. white population are reported to have germline ATM heterozygosity [
      • Swift M.
      • Morrell D.
      • Massey R.B.
      • Chase C.L.
      Incidence of cancer in 161 families affected by ataxia-telangiectasia.
      ,
      • Broeks A.
      • Urbanus J.H.
      • Floore A.N.
      • Dahler E.C.
      • Klijn J.G.
      • Rutgers E.J.
      • et al.
      ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
      ,
      • Swift M.
      • Morrell D.
      • Cromartie E.
      • Chamberlin A.R.
      • Skolnick M.H.
      • Bishop D.T.
      The incidence and gene frequency of ataxia-telangiectasia in the United States.
      ]. Patients with germline heterozygous ATM pathogenic variants have a 2–3-fold risk of breast cancer compared to the general population [
      • Swift M.
      • Morrell D.
      • Massey R.B.
      • Chase C.L.
      Incidence of cancer in 161 families affected by ataxia-telangiectasia.
      ,
      • Peterson R.D.
      • Funkhouser J.D.
      • Tuck-Muller C.M.
      • Gatti R.A.
      Cancer susceptibility in ataxia-telangiectasia.
      ,

      Jerzak K.J., Mancuso T., Eisen A. Ataxia-telangiectasia gene Curr Oncol. 2018;25(2):e176–e80. Epub 2018/04/30. doi: 10.3747/co.25.3707. PubMed PMID: 29719442; PubMed Central PMCID: PMCPMC5927797.

      . Furthermore, Easton reported a 1.9 relative risk of non-breast cancer in heterozygous carriers [
      • Easton D.F.
      Cancer risks in A-T heterozygotes.
      ]. Additional studies have associated germline pathogenic variants in the ATM gene with an increased risk of melanoma, oropharyngeal, thyroid, lung, prostate, and pancreatic cancer [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ]. Although not validated in large studies, the ATM S49C germline variant has been associated with increased incidences of melanoma, prostate cancer and oropharyngeal cancer; while the S707P germline variant has been associated with increased risk of thyroid and endocrine cancer [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ]. The presence of a germline ATM pathogenic variant warrants increased cancer screening for patients who are carriers [
      • Broeks A.
      • Urbanus J.H.
      • Floore A.N.
      • Dahler E.C.
      • Klijn J.G.
      • Rutgers E.J.
      • et al.
      ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
      ,
      • Stredrick D.L.
      • Garcia-Closas M.
      • Pineda M.A.
      • Bhatti P.
      • Alexander B.H.
      • Doody M.M.
      • et al.
      The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer.
      ,
      • Dombernowsky S.L.
      • Weischer M.
      • Allin K.H.
      • Bojesen S.E.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Risk of cancer by ATM missense mutations in the general population.
      ,
      • Liu J.
      • Wang X.
      • Ren Y.
      • Li X.
      • Zhang X.
      • Zhou B.
      Effect of single nucleotide polymorphism Rs189037 in ATM gene on risk of lung cancer in Chinese: a case-control study.
      ,
      • Shen L.
      • Yin Z.H.
      • Wan Y.
      • Zhang Y.
      • Li K.
      • Zhou B.S.
      Association between ATM polymorphisms and cancer risk: a meta-analysis.
      ,
      • Grant R.C.
      • Al-Sukhni W.
      • Borgida A.E.
      • Holter S.
      • Kanji Z.S.
      • McPherson T.
      • et al.
      Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer.
      ,
      • Roberts N.J.
      • Jiao Y.
      • Yu J.
      • Kopelovich L.
      • Petersen G.M.
      • Bondy M.L.
      • et al.
      ATM mutations in patients with hereditary pancreatic cancer.
      . Current National Comprehensive Cancer Network (NCCN) recommendations include high-risk screening with annual mammography and consideration of annual breast MRI for women by a least 40 years of age [

      Jerzak K.J., Mancuso T., Eisen A. Ataxia-telangiectasia gene Curr Oncol. 2018;25(2):e176–e80. Epub 2018/04/30. doi: 10.3747/co.25.3707. PubMed PMID: 29719442; PubMed Central PMCID: PMCPMC5927797.

      ,
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN Guidelines Insights: genetic/Familial High-Risk Assessment: breast, Ovarian, and Pancreatic, Version 1.2020.
      . Beginning at age 50, NCCN recommends annual pancreatic cancer screening using MRI/MRCP and/or EUS in ATM carriers with a family history of pancreatic cancer. There is currently no data that supports early screening for other ATM associated cancers [

      Jerzak K.J., Mancuso T., Eisen A. Ataxia-telangiectasia gene Curr Oncol. 2018;25(2):e176–e80. Epub 2018/04/30. doi: 10.3747/co.25.3707. PubMed PMID: 29719442; PubMed Central PMCID: PMCPMC5927797.

      ], however, research is underway to determine optimal surveillance strategies for prostate cancer [
      • Dahut W.L.
      • Couvillon A.
      • Pinto P.A.
      • Turkbey B.
      • Karzai F.
      Natural history and imaging in men with high genetic risk for developing prostate cancer.
      ].
      The presence of a somatic ATM pathogenic variant in patients with ACC offers the prospect for additional therapies. For example, ATM-deficient cancers have been reported to have increased sensitivity to platinum-based chemotherapeutic agents and ionizing radiation [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ,

      Jerzak K.J., Mancuso T., Eisen A. Ataxia-telangiectasia gene Curr Oncol. 2018;25(2):e176–e80. Epub 2018/04/30. doi: 10.3747/co.25.3707. PubMed PMID: 29719442; PubMed Central PMCID: PMCPMC5927797.

      . Additionally, PARP inhibitors are approved for the treatment of ATM deficient gastric cancer and are likely to offer an option in ATM deficient ACC [
      • Weston V.J.
      • Oldreive C.E.
      • Skowronska A.
      • Oscier D.G.
      • Pratt G.
      • Dyer M.J.
      • et al.
      The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo.
      ,
      • Kubota E.
      • Williamson C.T.
      • Ye R.
      • Elegbede A.
      • Peterson L.
      • Lees-Miller S.P.
      • et al.
      Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines.
      ,
      • Williamson C.T.
      • Kubota E.
      • Hamill J.D.
      • Klimowicz A.
      • Ye R.
      • Muzik H.
      • et al.
      Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53.
      ,
      • Bang Y.J.
      • Im S.A.
      • Lee K.W.
      • Cho J.Y.
      • Song E.K.
      • Lee K.H.
      • et al.
      Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.
      ]. Additional agents in pre-clinical and early clinical trials include ATR inhibitors and CHK1 inhibitors which demonstrate promising results in cancers lacking double-strand DNA repair [
      • Choi M.
      • Kipps T.
      • Kurzrock R.
      ATM Mutations in Cancer: therapeutic Implications.
      ].
      Lastly, the importance of genetic counseling cannot be understated in patients identified with germline pathogenic variants in ATM. Genetic counseling involves discussing associated cancer risks in context to the personal and family history of cancer and reviewing recommended medical management options. Genetic counseling should also include encouraging patients to inform their at-risk relatives about ATM and the availability of genetic testing to determine whether they inherited the pathogenic variant. Potential health benefits for relatives identified as ATM heterozygotes include identifying cancers at early stages with intensive screening. ATM heterozygotes of childbearing age should also be counseled about the risk of AT in offspring and partners should be offered carrier genetic testing. Identifying relatives who are ATM carriers has the potential to identify cancers at their earliest stages thereby increasing life expectancy and reducing healthcare costs by averting expensive cancer treatments.
      Our results should be interpreted with caution as this is the first report of a patient with ACC and a germline heterozygous pathogenic variant in the ATM gene. Although the loss of heterozygosity would suggest a pathogenic role in the development of ACC in this patient, this has not been confirmed and further research is needed. ACC remains a rare cancer with limited therapy options that carry high toxicity with limited targeted therapies. Surgical resection should be considered when feasible at experienced centers, while sequencing of all resected tumors should be considered to identify potential actionable mutations.

      Declaration of Competing Interests

      The authors have no conflicts of interest to disclose.

      Acknowledgements/Funding

      This research was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute.

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