bims-lifras 2021-05-02 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–05–02
fourteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development.
Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.
A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome: Case Presentation and Review of the Literature.
The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals.
Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing.
Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence.
Benign Tumors in Long-Term Survivors of Retinoblastoma.
Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review.
Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis.
Clinical and Pathologic Spectrum of DDX41-Mutated Hematolymphoid Neoplasms.
Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli-Leydig Cell Tumor.
Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients.
Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities.
Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers.

Cancers (Basel). 2021 Apr 07. pii: 1762. [Epub ahead of print]13(8):

Tumor Signature Analysis Implicates Hereditary Cancer Genes in Endometrial Cancer Development.

Olga Kondrashova, Jannah Shamsani, Tracy A O'Mara, Felicity Newell, Amy E McCart Reed, Sunil R Lakhani, Judy Kirk, John V Pearson, Nicola Waddell, Amanda B Spurdle.

  Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas (n = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set (n = 59,095). Ancestry-matched case-control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted ATM, PALB2, RAD51C, MUTYH and NBN as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination (BRCA1, PALB2, RAD51C) or base excision (NTHL1, MUTYH) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases.

Keywords:  endometrial cancer; familial cancer; genomic sequencing; hereditary cancer genes; mismatch repair; tumor mutational signatures

DOI:  https://doi.org/10.3390/cancers13081762
Cancer Sci. 2021 May 01.

Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.

Michinori Funato, Yukiko Tsunematsu, Fumito Yamazaki, Chieko Tamura, Tadashi Kumamoto, Masatoshi Takagi, Shunsuke Kato, Haruhiko Sugimura, Kazuo Tamura.

  Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large-scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA-binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison to those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.

Keywords:  Japan; Li-Fraumeni syndrome; TP53 germline pathogenic variant; phenocopy; stomach cancer

DOI:  https://doi.org/10.1111/cas.14919
Neurol Int. 2021 Apr 22. 13(2): 175-183

A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome: Case Presentation and Review of the Literature.

Raffaella Messina, Gerardo Cazzato, Teresa Perillo, Vita Stagno, Valeria Blè, Mariachiara Resta, Francesco De Leonardis, Nicola Santoro, Francesco Signorelli, Giuseppe Ingravallo.

  Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms "Li-Fraumeni" AND "pediatric high-grade glioma (HGG)", identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.

Keywords:  Li-Fraumeni syndrome; NTRK genes; embryonal rhabdomyosarcoma; high-grade bithalamic glioma; p53 protein

DOI:  https://doi.org/10.3390/neurolint13020017
Int J Mol Sci. 2021 Apr 28. pii: 4629. [Epub ahead of print]22(9):

The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals.

Cristina Carrato, Carolina Sanz, Ana María Muñoz-Mármol, Ignacio Blanco, Marta Pineda, Jesús Del Valle, Estela Dámaso, Manel Esteller, Eva Musulen.

  Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.

Keywords:  MMR gene expression; MSH6 gene; constitutional mismatch repair deficiency syndrome; immunohistochemistry

DOI:  https://doi.org/10.3390/ijms22094629
J Ovarian Res. 2021 Apr 29. 14(1): 61

Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing.

Shelly Cummings, Susana San Roman, Jennifer Saam, Ryan Bernhisel, Krystal Brown, Johnathan M Lancaster, Lydia Usha.

   BACKGROUND: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N = 631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2.
RESULTS: PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~ 3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~ 2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years for BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D.
CONCLUSIONS: These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly until age 50-55 in BRIP and RAD51C PV carriers.

Keywords:  Genetic testing; Hereditary ovarian cancer; Ovarian cancer; Pan-cancer panel

DOI:  https://doi.org/10.1186/s13048-021-00809-w
Front Oncol. 2021 ;11 627217

Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence.

Judith Penkert, Andre Märtens, Martin Seifert, Bernd Auber, Katja Derlin, Ursula Hille-Betz, Philipp Hörmann, Norman Klopp, Jana Prokein, Lisa Schlicker, Frank Wacker, Hannah Wallaschek, Brigitte Schlegelberger, Karsten Hiller, Tim Ripperger, Thomas Illig.

  Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.

Keywords:  BRCA1 germline mutation; HIF1 alpha; NAD+ balance; aerobic glycolysis; breast cancer; energy metabolism; lactate; plasma metabolome

DOI:  https://doi.org/10.3389/fonc.2021.627217
Cancers (Basel). 2021 Apr 08. pii: 1773. [Epub ahead of print]13(8):

Benign Tumors in Long-Term Survivors of Retinoblastoma.

Milo van Hoefen Wijsard, Sara J Schonfeld, Flora E van Leeuwen, Annette C Moll, Armida W Fabius, David H Abramson, Johanna M Seddon, Jasmine H Francis, Margaret A Tucker, Ruth A Kleinerman, Lindsay M Morton.

  Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914-2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9-22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2-6.4%), corresponding to 4.9-fold (95%CI = 2.8-8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7-22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2-13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0-6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1-2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.

Keywords:  RB1; cumulative incidence; epidemiology; hereditary retinoblastoma; leiomyoma; lipoma; retinoblastoma; retinoblastoma survivor; subsequent benign tumor; subsequent malignant neoplasms

DOI:  https://doi.org/10.3390/cancers13081773
Fam Cancer. 2021 Apr 28.

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review.

Agata Pastorczak, Karolina Krajewska, Zuzanna Urbanska, Bartosz Szmyd, Elzbieta Salacinska-Los, Józef Kobos, Wojciech Mlynarski, Joanna Trelinska.

  Ovarian carcinoma is an extremely rare malignancy in children, often developing on the underlying inherited background. Female carriers of pathogenic germline mutations of SMARCA4 are at risk of an aggressive type of undifferentiated ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Regardless of age of the patient, stage of the disease, and oncological treatment, the prognosis for SCCOHT is poor. Therefore, early intervention with risk-reducing surgeries is recommended for these patients. In this study, we report genetic testing of a family with two children carrying pathogenic germline mutations of SMARCA4 and summarize the course of SCCOHT in all pediatric patients reported in the literature with constitutional defects identified within the SMARCA4 locus.

Keywords:  Children; Genetic predisposition; Ovarian carcinoma; SMARCA4

DOI:  https://doi.org/10.1007/s10689-021-00258-w
Cancers (Basel). 2021 Apr 14. pii: 1864. [Epub ahead of print]13(8):

Genetic Analysis Reveals Rare Variants in T-Cell Response Gene MR1 Associated with Poor Overall Survival after Urothelial Cancer Diagnosis.

Lisa Bang, Manu Shivakumar, Tullika Garg, Dokyoon Kim.

  Urothelial carcinoma of the bladder (UC) is the fifth most common cancer in the United States. Germline variants, especially rare germline variants, may account for a portion of the disparity seen among patients in terms of UC incidence, presentation, and outcomes. The objectives of this study were to identify rare germline variant associations in UC incidence and to determine its association with clinical outcomes. Using exome sequencing data from the DiscovEHR UC cohort (n = 446), a European-ancestry, North American population, the complex influence of germline variants on known clinical phenotypes were analyzed using dispersion and burden metrics with regression tests. Outcomes measured were derived from the electronic health record (EHR) and included UC incidence, age at diagnosis, and overall survival (OS). Consequently, key rare variant association genes were implicated in MR1 and ADGRL2. The Kaplan-Meier survival analysis reveals that individuals with MR1 germline variants had significantly worse OS than those without any (log-rank p-value = 3.46 × 10-7). Those with ADGRL2 variants were found to be slightly more likely to have UC compared to a matched control cohort (FDR q-value = 0.116). These associations highlight several candidate genes that have the potential to explain clinical disparities in UC and predict UC outcomes.

Keywords:  biobank; bladder cancer; electronic health record; rare variant analysis

DOI:  https://doi.org/10.3390/cancers13081864
Am J Clin Pathol. 2021 Apr 30. pii: aqab027. [Epub ahead of print]

Clinical and Pathologic Spectrum of DDX41-Mutated Hematolymphoid Neoplasms.

Tanu Goyal, Zheng Jin Tu, Zhen Wang, James R Cook.

   OBJECTIVES: This study seeks to further characterize the clinicopathologic spectrum of DDX41-mutated hematolymphoid malignancies.
METHODS: We identified DDX41 mutations from a cohort of known or suspected hematologic disorders and reviewed the corresponding clinical, genetic, phenotypic, and morphologic findings.
RESULTS: DDX41 mutations were identified in 20 (1.4%) of 1,371 cases, including 8 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 2 cases of therapy-related MDS/AML, 1 case of primary myelofibrosis, 1 case of chronic myeloid leukemia, 1 case of clonal cytopenia of uncertain significance (CCUS), 1 case of T-cell large granular lymphocytic leukemia (T-LGL), and 1 case of multiple myeloma. DDX41-mutated neoplasms were morphologically heterogeneous with a median cellularity of 20% (range, 10%-100%). Megakaryocyte dysplasia occurred in 7 (35%) of 20 cases and trilineage dysplasia in 1 (5%). Frequently comutated genes include a second, somatic DDX41 mutation (8/19, 42%) followed by mutations in TET2 (20%), DNMT3A (20%), ASXL1 (20%), and CUX1 (20%). Karyotypes were noncomplex in 17 (89%) of 19.
CONCLUSIONS: This report extends the spectrum of DDX41-mutated disorders to include CCUS, T-LGL, and plasma cell disorders. The morphologic features are heterogeneous and nonspecific, highlighting the importance of DDX41 testing during routine workup of hematolymphoid neoplasms.

Keywords:   DDX41 ; Germline predisposition; Hematolymphoid malignancies

DOI:  https://doi.org/10.1093/ajcp/aqab027
J Clin Med. 2021 Apr 23. pii: 1845. [Epub ahead of print]10(9):

Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli-Leydig Cell Tumor.

Elisa De Paolis, Rosa Maria Paragliola, Paola Concolino.

  Sertoli-Leydig Cell Tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms, which predominantly affect adolescents and young female adults. The SLCTs clinical diagnosis and treatment remains challenging due to the rarity and the varied presentation. A large majority of SLCTs are unilateral, but also bilateral neoplasms have been reported, sometimes in the context of DICER1 syndrome. In fact, the most significant discovery regarding the molecular genetics basis of SLCTs was the finding of somatic and germline pathogenic variants in the DICER1 gene. The DICER1 protein is a key component of the micro-RNA processing pathway. Germline DICER1 pathogenic variants are typically inherited in an autosomal dominant pattern and are most often loss-of-function variants dispersed along the length of the gene. Contrarily, DICER1-related tumors harbor a characteristic missense "RNase IIIb hotspot" mutation occurring in trans, or, less frequently, loss of heterozygosity (LOH) event involving the wild-type allele. While DICER1 mutations have been identified in approximately 60% of SLCTs, especially in the moderately or poorly differentiated types, there are only a few case reports of ovarian SLCT with underlying germline DICER1 mutations. In this review, we focus on the molecular genetic features of SLCT, performing an extensive survey of all germline pathogenic variants modifying the whole sequence of the DICER1 gene. We point out that DICER1 genetic testing, coupled with an accurate variants classification and timely counseling, is of crucial importance in the clinical management of ovarian SLCT-affected patients.

Keywords:  DICER1; Sertoli–Leydig Cell Tumors; molecular diagnosis

DOI:  https://doi.org/10.3390/jcm10091845
Sci Rep. 2021 Apr 26. 11(1): 8893

Recurrent somatic mutations and low germline predisposition mutations in Korean ALL patients.

Sang-Yong Shin, Hyeonah Lee, Seung-Tae Lee, Jong Rak Choi, Chul Won Jung, Hong Hoe Koo, Sun-Hee Kim.

In addition to somatic mutations, germline genetic predisposition to hematologic malignancies is currently emerging as an area attracting high research interest. In this study, we investigated genetic alterations in Korean acute lymphoblastic leukemia/lymphoma (ALL) patients using targeted gene panel sequencing. To this end, a gene panel consisting of 81 genes that are known to be associated with 23 predisposition syndromes was investigated. In addition to sequence variants, gene-level copy number variations (CNVs) were investigated as well. We identified 197 somatic sequence variants and 223 somatic CNVs. The IKZF1 alteration was found to have an adverse effect on overall survival (OS) and relapse-free survival (RFS) in childhood ALL. We found recurrent somatic alterations in Korean ALL patients similar to previous studies on both prevalence and prognostic impact. Six patients were found to be carriers of variants in six genes associated with primary immunodeficiency disorder (PID). Of the 81 genes associated with 23 predisposition syndromes, this study found only one predisposition germline mutation (TP53) (1.1%). Altogether, our study demonstrated a low probability of germline mutation predisposition to ALL in Korean ALL patients.

DOI: https://doi.org/10.1038/s41598-021-88449-4
Am Soc Clin Oncol Educ Book. 2021 Mar;41 1-13

Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities.

Michael S Lee, Shubham Pant.

Performing germline and somatic sequencing in locally advanced and metastatic pancreatic cancer can identify potentially targetable genomic aberrations that impact current standard treatment options or eligibility for biomarker-targeted clinical trials. Testing for deleterious germline mutations in BRCA1/2 impacts patient selection for platinum-based chemotherapy regimens and selection of patients who are candidates to receive maintenance therapy with olaparib. Additional germline mutations also similarly introduce potential vulnerabilities to the cancers that arise and may be targeted by clinical trials. Somatic mutation testing also provides opportunities for optimal selection of patients for biomarker-driven clinical trials. Although KRAS mutations are found in 90% to 93% of pancreatic cancers, there are increasing opportunities for therapies against particular mutant KRAS isoforms, especially with the advent of KRAS G12C-specific small molecule inhibitors, and KRAS targeting trials will increasingly require identification of the specific KRAS mutation present. There are also a range of tumor site-agnostic molecular features, such as microsatellite instability and NTRK fusions that, although rarely found in pancreatic cancers, impact selection of patients who have the potential for dramatic benefit with immune checkpoint inhibitors such as pembrolizumab or TRK inhibitors such as larotrectinib or entrectinib, respectively, and thus motivate broader somatic mutation and fusion testing for patients with locally advanced and metastatic pancreatic cancers. Multiple other rare actionable aberrations, particularly gene fusions in the 8% to 10% of KRAS wild-type pancreatic cancers, are also known, and enrollment in basket trials for these rare patient cohorts is highly encouraged.

DOI: https://doi.org/10.1200/EDBK_321255
Genes (Basel). 2021 Apr 21. pii: 616. [Epub ahead of print]12(5):

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers.

Angela Toss, Elena Tenedini, Claudia Piombino, Marta Venturelli, Isabella Marchi, Elisa Gasparini, Elena Barbieri, Elisabetta Razzaboni, Federica Domati, Federica Caggia, Giovanni Grandi, Francesca Combi, Giovanni Tazzioli, Massimo Dominici, Enrico Tagliafico, Laura Cortesi.

  The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

Keywords:  ATM; CHEK2; bilateral tumor; breast cancer; genetic testing; mastectomy

DOI:  https://doi.org/10.3390/genes12050616