bims-lifras 2021-10-24 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–10–24
twenty-six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Choroid Plexus Carcinomas With TP53 Germline Mutations: Management and Outcome.
Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants.
Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma - a case report.
Lung cancer is also a hereditary disease.
Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges.
Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.
Current Testing Guidelines: A Retrospective Analysis of a Community-Based Hereditary Cancer Program.
The Prevalence of Pathogenic or Likely Pathogenic Germline Variants in a Nationwide Cohort of Young Colorectal Cancer Patients Using a Panel of 18 Genes Associated with Colorectal Cancer.
Hereditary Diffuse Gastric Cancer (HDGC). An overview.
Germline Testing in Prostate Cancer: When and Who to Test.
A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.
Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.
Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.
Reimagining prostate cancer screening: the IMPACT of germline mutations.
The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.
CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome.
NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.
The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome.
AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome.
Factors Affecting Genetic Consultation in Adolescent and Young Adult Patients With Sarcoma.
Identification of women at risk of hereditary breast-ovarian cancer among participants in a population-based breast cancer screening.
Fanconi Anaemia, Childhood Cancer and the BRCA Genes.
Acknowledging Disparities in Hereditary Cancer Testing.
Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene.
Biomarkers in Acute Myeloid Leukemia: Leveraging Next Generation Sequencing Data for Optimal Therapeutic Strategies.
Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review.

Front Oncol. 2021 ;11 751784

Choroid Plexus Carcinomas With TP53 Germline Mutations: Management and Outcome.

Yanong Li, Hailong Liu, Tandy Li, Jin Feng, Yanjiao He, Li Chen, Chunde Li, Xiaoguang Qiu.

   Background: Choroid plexus carcinomas (CPCs) are rare pediatric tumors commonly associated with Li-Fraumeni syndrome (LFS), which involves a germline mutation of the tumor suppressor gene TP53.
Materials and Methods: We retrospectively analyzed the corresponding information of 12 cases, including the effects of surgery and radiotherapy and TP53 germline mutations, to analyse the management strategies. Kaplan-Meier curves and the log-rank test were used to evaluate the progression-free survival (PFS).
Results: Twelve CPC patients were included, of which TP53 germline mutations were found in eight cases. All patients underwent surgical resection, and six patients received radiotherapy following with operation after initial diagnosis, one patient received radiotherapy following relapse. It was significantly different (P=0.012 and 0.028) that patients with TP53 germline mutation receiving the gross total resection (GTR) without radiotherapy showed survival advantages. Without TP53 germline mutations also showed survival advantages, but there is no statistical significance (P=0.063).
Conclusions: These findings provide evidence for the therapeutic strategy that radiotherapy should not be considered for patients with TP53 germline mutations.

Keywords:  Li-Fraumeni Syndrome (LFS); TP53 germline mutation; choroid plexus carcinoma; hereditary syndrome in pediatric; pediatric central nervous system tumors; radiotherapy

DOI:  https://doi.org/10.3389/fonc.2021.751784
Mol Cancer Res. 2021 Oct 21. pii: molcanres.MCR-21-0583-A.2021. [Epub ahead of print]

Clinical and Functional Significance of TP53 Exon 4-Intron 4 Splice Junction Variants.

Emilia M Pinto, Kara N Maxwell, Hadeel Halalsheh, Aaron Phillips, Jacquelyn Powers, Suzanne MacFarland, Michael F Walsh, Kelsey Breen, Maria N Formiga, Richard Kriwacki, Kim E Nichols, Roya Mostafavi, Jinling Wang, Michael R Clay, Carlos Rodriguez-Galindo, Raul C Ribeiro, Gerard P Zambetti.

Germline TP53 splicing variants are uncommon, and their clinical relevance is unknown. However, splice-altering variants at exon 4-intron 4 junctions are relatively enriched in pediatric adrenocortical tumors (ACTs). Nevertheless, family histories of cancer compatible with classic Li-Fraumeni syndrome are rarely seen in these patients. We used conventional and in-silico assays to determine protein stability, splicing, and transcriptional activity of ten TP53 variants at exon 4-intron 4 junctions and analyzed their clinical correlates. We reviewed public databases that report the impact of TP53 variants in human cancer and examined individual reports, focusing on family history of cancer. TP53 exon 4-intron 4 junctions germline variants were identified in 9 of 75 pediatric ACTs enrolled in the International Pediatric Adrenocortical Tumor Registry and Children's Oncology Group ARAR0332 study. An additional 8 independent TP53 variants involving exon 4 splicing were identified in the Pediatric Cancer Genome Project (n=5213). These variants resulted in improper expression due to ineffective splicing, protein instability, altered subcellular localization and loss of function. Clinical case review of carriers of TP53 exon 4-intron 4 junctions variants revealed a high incidence of pediatric ACTs and atypical tumor types not consistent with classic Li-Fraumeni Syndrome. Germline variants involving TP53 exon 4-intron 4 junctions are frequent in ACT and rare in other pediatric tumors. The collective impact of these germline TP53 variants on the fidelity of splicing, protein structure and function must be considered in evaluating cancer susceptibility. Implications: Taken together, the data indicate that splice variants at TP53 codon 125 and surrounding bases differentially impacted p53 gene expression and function.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0583
Hered Cancer Clin Pract. 2021 Oct 20. 19(1): 44

Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma - a case report.

Alexander Puzik, Markus Uhl, Juri Ruf, Tilmann Schumacher, Udo Kontny.

   BACKGROUND: Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research.
CASE PRESENTATION: We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH.
CONCLUSION: Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.

Keywords:  Copy number alterations; Genetics; Li-Fraumeni syndrome; Osteosarcoma

DOI:  https://doi.org/10.1186/s13053-021-00202-0
Eur Respir Rev. 2021 Dec 31. pii: 210045. [Epub ahead of print]30(162):

Lung cancer is also a hereditary disease.

Patrick R Benusiglio, Vincent Fallet, Mateo Sanchis-Borja, Florence Coulet, Jacques Cadranel.

Pathogenic genetic variants (formerly called mutations) present in the germline of some individuals are associated with a clinically relevant increased risk of developing lung cancer. These germline pathogenic variants are hereditary and are transmitted in an autosomal dominant fashion. There are two major lung cancer susceptibility syndromes, and both seem to be specifically associated with the adenocarcinoma subtype. Li-Fraumeni syndrome is caused by variants in the TP53 tumour-suppressor gene. Carriers are mainly at risk of early-onset breast cancer, sarcoma, glioma, leukaemia, adrenal cortical carcinoma and lung cancer. EGFR variants, T790M in particular, cause the EGFR susceptibility syndrome. Risk seems limited to lung cancer. Emerging data suggest that variants in ATM, the breast and pancreatic cancer susceptibility gene, also increase lung adenocarcinoma risk. As for inherited lung disease, cancer risk is increased in SFTPA1 and SFTPA2 variant carriers independently of the underlying fibrosis. In this review, we provide criteria warranting the referral of a lung cancer patient to the cancer genetics clinic. Pathogenic variants are first identified in patients with cancer, and then in a subset of their relatives. Lung cancer screening should be offered to asymptomatic carriers, with thoracic magnetic resonance imaging at its core.

DOI: https://doi.org/10.1183/16000617.0045-2021
Br J Haematol. 2021 Oct 18.

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges.

Kiran Tawana, Anna L Brown, Jane E Churpek.

  Over the last decade, the field of hereditary haematological malignancy syndromes (HHMSs) has gained increasing recognition among clinicians and scientists worldwide. Germline mutations now account for almost 10% of adult and paediatric myelodysplasia/acute myeloid leukaemia (MDS/AML). As our ability to diagnose HHMSs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients with MDS/AML and how to optimise management and surveillance of patients and asymptomatic carriers. Discoveries of novel syndromes combined with clinical, genetic and epigenetic profiling of tumour samples, have highlighted unique patterns of disease evolution across HHMSs. Despite these advances, causative lesions are detected in less than half of familial cases and evidence-based guidelines are often lacking, suggesting there is much still to learn. Future research efforts are needed to sustain current momentum within the field, led not only by advancing genetic technology but essential collaboration between clinical and academic communities.

Keywords:  acute myeloid leukaemia; familial; germline; malignancy; testing

DOI:  https://doi.org/10.1111/bjh.17855
Genes Chromosomes Cancer. 2021 Oct 23.

Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer.

Dianne E Sylvester, Yuyan Chen, Natalie Grima, Federica Saletta, Bhavna Padhye, Bruce Bennetts, Dale Wright, Michael Krivanek, Nicole Graf, Li Zhou, Daniel Catchpoole, Judy Kirk, Olivier Latchoumanin, Liang Qiao, Mandy Ballinger, David Thomas, Robyn Jamieson, Luciano Dalla-Pozza, Jennifer A Byrne.

Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs were investigated further by examining matched tumour samples, and the functional impact of AXIN1 variants was analysed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19/76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11/19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the paediatric oncology clinic. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/gcc.23006
J Adv Pract Oncol. 2021 Sep;12(7): 693-701

Current Testing Guidelines: A Retrospective Analysis of a Community-Based Hereditary Cancer Program.

Margaret Ward, Betty Elder, Maryon Habtemariam.

It is estimated that 5% to 10% of all cancers are related to a hereditary cancer syndrome. However, specific cancers, such as pancreatic and ovarian cancers, are related to hereditary cancer syndromes 15% to 20% of the time. Genetic testing guidelines for hereditary cancer syndromes are frequently reviewed and updated by the National Comprehensive Cancer Network (NCCN). The purpose of this retrospective analysis is to identify carriers of pathogenic variants or hereditary cancer syndrome who do not meet NCCN criteria for testing and compare the results with previous studies. The data obtained can be used to provide recommendations to assess current guidelines for testing and evaluate the benefit of comprehensive panel testing vs. standard testing for specific hereditary cancer syndromes. This project is a retrospective review of clinical histories of patients who had multigene panel testing between September 2015 and February 2019 through a cancer outreach and risk assessment (CORA) program. Frequencies analyses were performed to analyze results. A total of 233 individuals were included in the analysis: 171 met BRCA1/2 testing criteria, 66 met Lynch syndrome criteria, and 4 met polyposis criteria. Of the individuals meeting established criteria for testing, 39 were identified with pathogenic variants. However, only 10 of these individuals were identified with a pathogenic variant associated with the criteria for which they met. Genetic testing that is limited to only those patients with genes associated with hereditary cancer syndromes may lead to exclusion of other potentially actionable genes, which may impair a patient's ability to receive additional screening or preventative measures.

DOI: https://doi.org/10.6004/jadpro.2021.12.7.3
Cancers (Basel). 2021 Oct 12. pii: 5094. [Epub ahead of print]13(20):

The Prevalence of Pathogenic or Likely Pathogenic Germline Variants in a Nationwide Cohort of Young Colorectal Cancer Patients Using a Panel of 18 Genes Associated with Colorectal Cancer.

Erik Frostberg, Annabeth Høgh Petersen, Anders Bojesen, Hans Bjarke Rahr, Jan Lindebjerg, Karina Rønlund.

   INTRODUCTION: The prevalence of pathogenic or likely pathogenic germline variants (PGV) in colorectal cancer (CRC) in young patients is seen in approximately one in five patients, with the majority of cases having gene variants associated with Lynch syndrome (LS). The primary aim was to describe the prevalence of 18 genes, all associated with hereditary polyposis and CRC, in a nationwide population of young CRC (yCRC) patients, and outline disease characteristics in patients with or without germline variants.
METHODS: We screened 98 patients aged 18-40 with CRC diagnosed in 2010-2013 for variants in MSH2, MSH6, MLH1, PMS2, EPCAM, APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN, POLE, POLD1, NTHL1, AXIN2, MSH3, GREM1 and RNF43 using Next Generation Sequencing. Comparisons between patients' characteristics in patients with PGV, and patients without germline variants (NPGV) were analyzed.
RESULTS: PGV were detected in twenty-four patients (24.5%), and twenty-one patients (21.1%) had variants in the mismatch repair (MMR) genes associated with LS. Variants in the APC and MUTYH genes were detected in 1% and 4%, respectively. Patients with NPGV had more advanced disease with adverse histopathological features.
CONCLUSION: PGV was detected in one in four yCRC patients, and one in five yCRC patients had disease causing variants in the mismatch repair genes associated with LS.

Keywords:  Lynch syndrome; colorectal cancer; germline mutation; germline variants; nationwide; young

DOI:  https://doi.org/10.3390/cancers13205094
Clin Res Hepatol Gastroenterol. 2021 Oct 14. pii: S2210-7401(21)00198-4. [Epub ahead of print] 101820

Hereditary Diffuse Gastric Cancer (HDGC). An overview.

L Taja-Chayeb, S Vidal-Millán, C Trejo-Becerril, E Pérez-Cárdenas, A Chávez-Blanco, G Domínguez-Gómez, A González-Fierro, A Romo-Pérez, A Dueñas-González.

  It is estimated that up to 10% of gastric carcinomas show familial aggregation. In contrast, around 1-3 % (approximately 33,000 yearly) are genuinely hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 and CTNNA1 genes encoding the adhesion molecules E-cadherin and α-catenin, respectively. The multifocal nature of the disease and the difficulty of visualizing precursor lesions by endoscopy underscore the need to be aware of this malignancy as surgical prevention can be fully protective. Here, we provide an overview of the main epidemiological, clinical, genetic, and pathological features of HDGC, as well as updated guidelines for its diagnosis, genetic testing, counseling, surveillance, and management. We conclude that HDGC is a rare, highly penetrant disease that is difficult to diagnose and manage, so it is necessary to correctly identify it to offer patients and their families' adequate management following the recommendations of the IGCL. A critical point is identifying a mutation in HDGC families to determine whether unaffected relatives are at risk for cancer.

Keywords:  CDH1; CTNNA1; Diffuse gastric cancer; Gastric Cancer; Germline mutations; Hereditary Cancer

DOI:  https://doi.org/10.1016/j.clinre.2021.101820
Oncology (Williston Park). 2021 Oct 20. 35(10): 645-653

Germline Testing in Prostate Cancer: When and Who to Test.

Alexandra Sokolova, Heather Cheng.

  The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.

Keywords:  BRCA; DNA repair; PARPi; biomarker; genetic testing; germline; prostate cancer

DOI:  https://doi.org/10.46883/ONC.2021.3510.0645
Lancet Oncol. 2021 Oct 19. pii: S1470-2045(21)00522-2. [Epub ahead of print]

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

IMPACT Study Collaborators

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.
METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.
FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0).
INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.
FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

DOI: https://doi.org/10.1016/S1470-2045(21)00522-2
J Clin Oncol. 2021 Oct 21. JCO2100640

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

Siddhartha Yadav, Chunling Hu, Katherine L Nathanson, Jeffrey N Weitzel, David E Goldgar, Peter Kraft, Rohan D Gnanaolivu, Jie Na, Hongyan Huang, Nicholas J Boddicker, Nicole Larson, Chi Gao, Song Yao, Clarice Weinberg, Celine M Vachon, Amy Trentham-Dietz, Jack A Taylor, Dale R Sandler, Alpa Patel, Julie R Palmer, Janet E Olson, Susan Neuhausen, Elena Martinez, Sara Lindstrom, James V Lacey, Allison W Kurian, Esther M John, Christopher Haiman, Leslie Bernstein, Paul W Auer, Hoda Anton-Culver, Christine B Ambrosone, Rachid Karam, Elizabeth Chao, Amal Yussuf, Tina Pesaran, Jill S Dolinsky, Steven N Hart, Holly LaDuca, Eric C Polley, Susan M Domchek, Fergus J Couch.

PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.
MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).
RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.
CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

DOI: https://doi.org/10.1200/JCO.21.00640
Prostate. 2021 Oct 21.

Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

Zhuqing Shi, Lucy Lu, William Kyle Resurreccion, Wancai Yang, Jun Wei, Qiang Wang, Valentina Engelmann, Siqun Lilly Zheng, Kathleen A Cooney, William B Isaacs, Brian T Helfand, Jim Lu, Jianfeng Xu.

   BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis.
METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models.
RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers.
CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

Keywords:  germline mutation; guidelines; progression; prostate cancer

DOI:  https://doi.org/10.1002/pros.24252
Lancet Oncol. 2021 Oct 19. pii: S1470-2045(21)00571-4. [Epub ahead of print]

Reimagining prostate cancer screening: the IMPACT of germline mutations.

Giorgio Gandaglia, Alberto Briganti, Francesco Montorsi.

DOI: https://doi.org/10.1016/S1470-2045(21)00571-4
BJOG. 2021 Oct 17.

The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

Bethan Frugtniet, Sian Morgan, Alex Murray, Sheila Palmer-Smith, Rhian White, Rachel Jones, Louise Hanna, Claire Fuller, Emma Hudson, Anna Mullard, Amy Elizabeth Quinton.

   OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing.
DESIGN: National retrospective audit.
SETTING: The All Wales Medical Genomics Service (AWMGS).
POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS.
METHODS: Analysis of NGS data from germline and/or tumour testing.
MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants.
RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone.
CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer.

Keywords:  BRCA; germline; mainstreamed; oncology-led; ovarian cancer; pathogenic variant; somatic

DOI:  https://doi.org/10.1111/1471-0528.16975
Cancers (Basel). 2021 Oct 13. pii: 5139. [Epub ahead of print]13(20):

CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome.

Jessica Merkle, Markus Breunig, Maximilian Schmid, Chantal Allgöwer, Jana Krüger, Michael K Melzer, Susanne Bens, Reiner Siebert, Lukas Perkhofer, Ninel Azoitei, Thomas Seufferlein, Sandra Heller, Matthias Meier, Martin Müller, Alexander Kleger, Meike Hohwieler.

  Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.

Keywords:  CDKN2A; familial pancreatic cancer; induced pluripotent stem cells; pancreatic organoids

DOI:  https://doi.org/10.3390/cancers13205139
J Natl Compr Canc Netw. 2021 10 15. pii: jnccnglins1910. [Epub ahead of print]19(10): 1122-1132

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Jennifer M Weiss, Samir Gupta, Carol A Burke, Lisen Axell, Lee-May Chen, Daniel C Chung, Katherine M Clayback, Susan Dallas, Seth Felder, Olumide Gbolahan, Francis M Giardiello, William Grady, Michael J Hall, Heather Hampel, Rachel Hodan, Gregory Idos, Priyanka Kanth, Bryson Katona, Laura Lamps, Xavier Llor, Patrick M Lynch, Arnold J Markowitz, Sara Pirzadeh-Miller, Niloy Jewel Samadder, David Shibata, Benjamin J Swanson, Brittany M Szymaniak, Georgia L Wiesner, Andrew Wolf, Matthew B Yurgelun, Mae Zakhour, Susan D Darlow, Mary A Dwyer, Mallory Campbell.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

DOI: https://doi.org/10.1164/jnccn.2021.0048
Cells. 2021 Sep 29. pii: 2597. [Epub ahead of print]10(10):

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome.

Elena Masselli, Giulia Pozzi, Cecilia Carubbi, Marco Vitale.

  Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs.

Keywords:  GWAS; clonal hematopoiesis; germline predisposition; inflammation; myeloproliferative neoplasms; polymorphism

DOI:  https://doi.org/10.3390/cells10102597
Leukemia. 2021 Oct 20.

AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome.

Peng Li, Thomas White, Wei Xie, Wei Cui, Deniz Peker, Gang Zeng, Huan-You Wang, Jennie Vagher, Sara Brown, Margaret Williams, Tibor Kovacsovics, Jay L Patel.

Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

DOI: https://doi.org/10.1038/s41375-021-01404-0
J Natl Compr Canc Netw. 2021 Oct 19. pii: jnccn20581. [Epub ahead of print] 1-8

Factors Affecting Genetic Consultation in Adolescent and Young Adult Patients With Sarcoma.

Grace E McKay, Anna L Zakas, Fauzia Osman, Amanda Parkes.

BACKGROUND: Given a link between sarcomas and hereditary cancer predisposition syndromes, including Li-Fraumeni syndrome, the consideration for genetic counseling is recommended for all adolescent and young adult (AYA) patients diagnosed with sarcoma. The aim of this study was to evaluate factors influencing genetic consultations in AYA patients with sarcoma at the University of Wisconsin (UW).
METHODS: A retrospective chart review was performed on AYA patients diagnosed with sarcoma between the ages of 15 and 39 years who were seen at least once between 2015 to 2019 at UW. Our chart review identified discussions regarding genetics, referrals to genetics, genetic consultations, and results of genetic testing. Variables hypothesized to affect patient referrals for genetic consultation were identified a priori. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral.
RESULTS: We identified 87 AYA patients with sarcoma. Only 19 (22%) of these patients had documentation of a discussion about genetics, 15 (17%) of whom were subsequently referred for genetic consultation. Of these 15 patients, 9 (60%) were seen in consultation. All 9 patients seen by genetics underwent genetic testing, with 4 (44%) of these patients having identified heritable cancer predisposition syndromes. Likelihood for genetics referral was linked most strongly to documented genetics discussion with an oncology provider (P<.001).
CONCLUSIONS: Despite the recommendation for consideration for genetic counseling in AYA patients with sarcoma, <25% of such patients in our study had a documented discussion about genetics. Supporting this need, all referred patients met criteria for genetic testing, and 44% of tested patients were found to have a heritable cancer predisposition syndrome. These data support the initial conversation by a provider as critical to genetic referral and suggest the need for more specific national recommendations for the genetic evaluation of all AYA patients with sarcoma.

DOI: https://doi.org/10.6004/jnccn.2021.7034
Fam Cancer. 2021 Oct 20.

Identification of women at risk of hereditary breast-ovarian cancer among participants in a population-based breast cancer screening.

Luigina Bonelli, Ivana Valle, Ivana Rebora, Paola Ricci, Lidia Biocchi, Giovanna Bruschi, Sabrina Parodi, Carla Bruzzone, Liliana Varesco.

  Women attending mammography screening may benefit from family history (FH) assessment for the identification of Hereditary Breast Ovarian Cancer (HBOC). Few studies explored the efficacy of tailored educational interventions in driving the attention on FH-associated risk among these women. To compare the efficacy of two educational tools in increasing attention towards FH, 6.802 women with a negative mammography were randomized to receive a note on FH of breast/ovarian cancer (letter A, n = 3.402) or a note with details on possible implication of FH patterns (letter B, n = 3.200). Upon women's request, a brief questionnaire was administered on phone at the Screening Unit (S.U.) to select those eligible for an in-depth FH evaluation at the Genetic Unit (G.U.). Each affected relative was scored 1-3 according to type of cancer, age at diagnosis, gender, position in the family tree. In all, 401 women contacted the S.U.: 244 (6.6%) in group A and 177 (5.2%) in group B (adjOR 1.27; 95%CI 1.03-1.56). FH scored ≥ 3 for 164 women: 177 (47.5%) in group B and 224 (35.7%) in group A, (adjOR 1.59, 95%CI 1.06-2.38). The G.U. traced and interviewed 148 women, 65 (43.9%) were offered an in-person consultation: 38 attended and 30 were eligible for testing. A test was performed for 24 women: no BRCA pathogenic variant was found. Among mammographic screening attendees, educational material with a simple description of FH may improve self-referral of women deserving an in-depth evaluation for HBOC identification. Additional educational efforts are needed to enhance the efficiency of the intervention.

Keywords:  Genetic counselling/testing; Genetic literacy; Hereditary breast–ovarian cancer; Population-based breast cancer screening; Risk assessment; Women information

DOI:  https://doi.org/10.1007/s10689-021-00281-x
Genes (Basel). 2021 Sep 27. pii: 1520. [Epub ahead of print]12(10):

Fanconi Anaemia, Childhood Cancer and the BRCA Genes.

Emma R Woodward, Stefan Meyer.

  Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.

Keywords:  BRCA1; BRCA2; childhood cancer; fanconi anaemia

DOI:  https://doi.org/10.3390/genes12101520
J Clin Oncol. 2021 Oct 09. JCO2102287

Acknowledging Disparities in Hereditary Cancer Testing.

Sophie Sun, Karen A Gelmon.

DOI: https://doi.org/10.1200/JCO.21.02287
JTO Clin Res Rep. 2021 Oct;2(10): 100231

Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene.

Azam Ghafoor, Idrees Mian, Cathy Wagner, Yvonne Mallory, Maria Garcia Agra, Betsy Morrow, Jun S Wei, Javed Khan, Anish Thomas, Manjistha Sengupta, Seth M Steinberg, Raffit Hassan.

   Introduction: PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality.
Methods: A single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor.
Results: A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7-4.2 mo) and 8.7 months (95% CI: 4.7 mo-not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3-3.6 mo) versus 4.1 months (95% CI: 2.7-5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1-4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo-not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns.
Conclusions: Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

Keywords:  BAP1; MRE11A; Mesothelioma; Olaparib; PARPI

DOI:  https://doi.org/10.1016/j.jtocrr.2021.100231
Front Oncol. 2021 ;11 748250

Biomarkers in Acute Myeloid Leukemia: Leveraging Next Generation Sequencing Data for Optimal Therapeutic Strategies.

Hanadi El Achi, Rashmi Kanagal-Shamanna.

  Next generation sequencing (NGS) is routinely used for mutation profiling of acute myeloid leukemia. The extensive application of NGS in hematologic malignancies, and its significant association with the outcomes in multiple large cohorts constituted a proof of concept that AML phenotype is driven by underlying mutational signature and is amenable for targeted therapies. These findings urged incorporation of molecular results into the latest World Health Organization (WHO) sub-classification and integration into risk-stratification and treatment guidelines by the European Leukemia Net. NGS mutation profiling provides a large amount of information that guides diagnosis and management, dependent on the type and number of gene mutations, variant allele frequency and amenability to targeted therapeutics. Hence, molecular mutational profiling is an integral component for work-up of AML and multiple leukemic entities. In addition, there is a vast amount of informative data that can be obtained from routine clinical NGS sequencing beyond diagnosis, prognostication and therapeutic targeting. These include identification of evidence regarding the ontogeny of the disease, underlying germline predisposition and clonal hematopoiesis, serial monitoring to assess the effectiveness of therapy and resistance mutations, which have broader implications for management. In this review, using a few prototypic genes in AML, we will summarize the clinical applications of NGS generated data for optimal AML management, with emphasis on the recently described entities and Food and Drug Administration approved target therapies.

Keywords:  AML; FDA; actionable mutations; acute myeloid leukemia; next generation sequencing; targeted therapy

DOI:  https://doi.org/10.3389/fonc.2021.748250
Cancers (Basel). 2021 Oct 10. pii: 5064. [Epub ahead of print]13(20):

Possible Mechanisms of Subsequent Neoplasia Development in Childhood Cancer Survivors: A Review.

Jarmila Kruseova, Ales Vicha, Barbara Feriancikova, Tomas Eckschlager.

  Advances in medicine have improved outcomes in children diagnosed with cancer, with overall 5-year survival rates for these children now exceeding 80%. Two-thirds of childhood cancer survivors have at least one late effect of cancer therapy, with one-third having serious or even life-threatening effects. One of the most serious late effects is a development of subsequent malignant neoplasms (histologically different cancers, which appear after the treatment for primary cancer), which occur in about 3-10% of survivors and are associated with high mortality. In cancers with a very good prognosis, subsequent malignant neoplasms significantly affect long-term survival. Therefore, there is an effort to reduce particularly hazardous treatments. This review discusses the importance of individual factors (gender, genetic factors, cytostatic drugs, radiotherapy) in the development of subsequent malignant neoplasms and the possibilities of their prediction and prevention in the future.

Keywords:  cancer predisposition syndromes; chemotherapy; childhood cancer survivors; genetic factors; radiotherapy; subsequent malignant neoplasms

DOI:  https://doi.org/10.3390/cancers13205064