bims-lifras 2021-07-04 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–07–04
27 papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer.
Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.
Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome.
Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome.
Clinical Multigene Testing for Prostate Cancer.
Germline Predisposition to Prostate Cancer in Diverse Populations.
Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.
Germline Testing for Prostate Cancer Prognosis: Implications for Active Surveillance.
Reliability of Tumor Testing Compared to Germline Testing for Detecting BRCA1 and BRCA2 Mutations in Patients with Epithelial Ovarian Cancer.
Use of treatment focused tumor sequencing to screen for germline cancer predisposition.
Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population.
Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study.
Genetic Testing Guidelines and Education of Health Care Providers Involved in Prostate Cancer Care.
Genetically Informed Prostate Cancer Treatment for Metastatic Disease.
Genetic Counseling for Men with Prostate Cancer.
Genetic Contribution to Metastatic Prostate Cancer.
RB1 germline mutation spectrum and clinical features in patients with unilateral retinoblastomas.
Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis.
Germline Mutations Including the Rare Pathogenic Variant c.3206delC in the ATM Gene Cause Ataxia Teleangiectasia-Associated Primary Central Nervous System Lymphoma.
A Retrospective 5-Year Single Center Study Highlighting the Risk of Cancer Predisposition in Adolescents and Young Adults.
Prostate Cancer Predisposition.
Clinical Interpretation Challenges of Germline-Shared Somatic Variants in Cancer.
Identification of germline cancer predisposition variants during clinical ctDNA testing.
RASopathies: from germline mutations to somatic and multigenic diseases.
Likelihood of Germline Mutation With Solitary Unilateral Retinoblastoma Based on Patient Age at Presentation: Analysis of 482 Consecutive Patients.
Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer.
Precision Therapy for Brain Tumors in Hereditary Syndromes.

Int J Mol Sci. 2021 Jun 14. pii: 6345. [Epub ahead of print]22(12):

Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer.

Yaxuan Liu, Olga Axell, Tom van Leeuwen, Robert Konrat, Pedram Kharaziha, Catharina Larsson, Anthony P H Wright, Svetlana Bajalica-Lagercrantz.

  Rare germline pathogenic TP53 missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual TP53 variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (n = 24) or exclusively reported in HBC (n = 24) were included. LFS-variants were over-represented in residues tending to be buried in the core of the tertiary structure of TP53 (p = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78-0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline TP53 missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.

Keywords:  Li-Fraumeni syndrome; germline TP53 missense variants; hereditary breast cancer; protein conformation; quantitative prediction model

DOI:  https://doi.org/10.3390/ijms22126345
Cancers (Basel). 2021 Jun 29. pii: 3246. [Epub ahead of print]13(13):

Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.

Evan M Braunstein, Hang Chen, Felicia Juarez, Fanghan Yang, Lindsay Tao, Igor Makhlin, Donna M Williams, Shruti Chaturvedi, Aparna Pallavajjala, Theodoros Karantanos, Renan Martin, Elizabeth Wohler, Nara Sobreira, Christopher D Gocke, Alison R Moliterno.

  Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.

Keywords:  familial cancer; germline predisposition; myeloproliferative neoplasms

DOI:  https://doi.org/10.3390/cancers13133246
Oncogene. 2021 Jun 28.

Genetic modifiers regulating DNA replication and double-strand break repair are associated with differences in mammary tumors in mouse models of Li-Fraumeni syndrome.

Prabin Dhangada Majhi, Nicholas B Griner, Jacob A Mayfield, Shannon Compton, Jeffrey J Kane, Trevor A Baptiste, Karen A Dunphy, Amy L Roberts, Sallie S Schneider, Evan M Savage, Divyen Patel, Anneke C Blackburn, Kim Joana Maurus, Lisa Wiesmüller, D Joseph Jerry.

Breast cancer is the most common tumor among women with inherited variants in the TP53 tumor suppressor, but onset varies widely suggesting interactions with genetic or environmental factors. Rodent models haploinsufficent for Trp53 also develop a wide variety of malignancies associated with Li-Fraumeni syndrome, but BALB/c mice are uniquely susceptible to mammary tumors and is genetically linked to the Suprmam1 locus on chromosome 7. To define mechanisms that interact with deficiencies in p53 to alter susceptibility to mammary tumors, we fine mapped the Suprmam1 locus in females from an N2 backcross of BALB/cMed and C57BL/6J mice. A major modifier was localized within a 10 cM interval on chromosome 7. The effect of the locus on DNA damage responses was examined in the parental strains and mice that are congenic for C57BL/6J alleles on the BALB/cMed background (SM1-Trp53+/-). The mammary epithelium of C57BL/6J-Trp53+/- females exhibited little radiation-induced apoptosis compared to BALB/cMed-Trp53+/- and SM1-Trp53+/- females indicating that the Suprmam1B6/B6 alleles could not rescue repair of radiation-induced DNA double-strand breaks mostly relying on non-homologous end joining. In contrast, the Suprmam1B6/B6 alleles in SM1-Trp53+/- mice were sufficient to confer the C57BL/6J-Trp53+/- phenotypes in homology-directed repair and replication fork progression. The Suprmam1B6/B6 alleles in SM1-Trp53+/- mice appear to act in trans to regulate a panel of DNA repair and replication genes which lie outside the locus.

DOI: https://doi.org/10.1038/s41388-021-01892-5
Front Oncol. 2021 ;11 682445

Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome.

Daniele Fanale, Alessia Fiorino, Lorena Incorvaia, Alessandra Dimino, Clarissa Filorizzo, Marco Bono, Daniela Cancelliere, Valentina Calò, Chiara Brando, Lidia Rita Corsini, Roberta Sciacchitano, Luigi Magrin, Alessia Pivetti, Erika Pedone, Giorgio Madonia, Alessandra Cucinella, Giuseppe Badalamenti, Antonio Russo, Viviana Bazan.

  About 10-20% of breast/ovarian (BC/OC) cancer patients undergoing germline BRCA1/2 genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline BRCA1/2 VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk BRCA variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the "Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors" of University Hospital Policlinico "P. Giaccone" of Palermo, were genetically tested for germline BRCA1/2 variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were BRCA-w.t., whereas 67 (7.7%) were carriers of germline BRCA1/2 VUSs, and 168 (19.2%) harbored germline BRCA1/2 pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on BRCA1 gene, whereas 38 (64.4%) on BRCA2. We detected six alterations in BRCA1 and two in BRCA2 with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the BRCA1-c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline BRCA1/2 VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.

Keywords:  BRCA1; BRCA2; breast cancer; genetic testing; ovarian cancer; variants of uncertain significance (VUS)

DOI:  https://doi.org/10.3389/fonc.2021.682445
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00089-6. [Epub ahead of print]48(3): 297-309

Clinical Multigene Testing for Prostate Cancer.

Tala Berro, Elizabeth Barrett, Saud H AlDubayan.

  Germline genetic testing for prostate cancer (PC) is increasingly important as the clinical utility of germline variants in this patient population is understood better. To better characterize the clinical landscape of germline testing in PC, published clinical cohorts of PC who underwent clinical germline genetic analysis at point of care are reviewed. Limitations and heterogeneity of these cohorts are highlighted and pathogenic results with established or potential clinical utility in PC noted. The need for additional germline genetic studies is underscored, because the number of PC patients studied lags greatly behind the high prevalence of the disease.

Keywords:  Genetic counseling; Germline genetic testing; Multigene panel testing; Prostate cancer

DOI:  https://doi.org/10.1016/j.ucl.2021.03.002
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00095-1. [Epub ahead of print]48(3): 411-423

Germline Predisposition to Prostate Cancer in Diverse Populations.

Kelly K Bree, Patrick J Henley, Curtis A Pettaway.

  There remains a paucity of data related to germline genetic alterations predisposing patients to prostate cancer. Recent data suggest that African American, Hispanic, and Asian and Pacific Islander men exhibit genetic alterations in both highly penetrant germline genes, including BRCA1/2, ATM, and CHEK2, and the mismatch repair genes associated with Lynch syndrome, as well as low-penetrant single-nucleotide polymorphisms. However, cohort sizes remain small in many studies limiting the ability to determine clinical significance, appropriate risk stratification, and treatment implications in these diverse populations.

Keywords:  African American; Asian; Germline DNA testing; Prostate cancer; Single nucleotide polymorphisms

DOI:  https://doi.org/10.1016/j.ucl.2021.03.008
J Pers Med. 2021 Jun 12. pii: 548. [Epub ahead of print]11(6):

Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.

Maria Fonfria, Inmaculada de Juan Jiménez, Isabel Tena, Isabel Chirivella, Paula Richart-Aznar, Angel Segura, Ana Beatriz Sánchez-Heras, Eduardo Martinez-Dueñas.

  (1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

Keywords:  BRCA1 or BRCA2 negative; germline testing; hereditary breast and ovarian cancer; moderate penetrance genes; next-generation sequencing

DOI:  https://doi.org/10.3390/jpm11060548
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00955-1. [Epub ahead of print]48(3): 401-409

Germline Testing for Prostate Cancer Prognosis: Implications for Active Surveillance.

Brian T Helfand, Jianfeng Xu.

  Available evidence supports routine implementation of germline genetic testing for many aspects of prostate cancer (PCa) decision making. The purpose of obtaining genetic testing for newly diagnosed men would be focused on identifying mutations that predispose to aggressive PCa. Based on an evidence-based review, the authors review germline rare pathogenic mutations in several genes that are significantly associated with aggressiveness, metastases, and mortality. Then recent studies of these germline mutations in predicting tumor grade reclassification among patients undergoing active surveillance are discussed. Single nucleotide polymorphisms-based polygenic risk scores in differentiating PCa aggressiveness and prognosis are reviewed.

Keywords:  Active surveillance; Genetic risk score; Germline; Mutations; Polygenic risk score; Positive cores; Reclassification; Tumor upgrading

DOI:  https://doi.org/10.1016/j.ucl.2021.04.003
J Pers Med. 2021 Jun 24. pii: 593. [Epub ahead of print]11(7):

Reliability of Tumor Testing Compared to Germline Testing for Detecting BRCA1 and BRCA2 Mutations in Patients with Epithelial Ovarian Cancer.

Christine Bekos, Christoph Grimm, Marlene Kranawetter, Stephan Polterauer, Felicitas Oberndorfer, Yen Tan, Leonhard Müllauer, Christian F Singer.

   BACKGROUND: BRCA 1/2 mutation status has become one of the most important parameters for treatment decision in patients with epithelial ovarian cancer (EOC). The aim of this study was to compare tumor DNA with blood DNA sequencing to evaluate the reliability of BRCA tumor testing results.
METHODS: Patients who were treated for EOC between 2003 and 2019 at the Medical University of Vienna and underwent both germline (gBRCA) and tumor (tBRCA) testing for BRCA mutations were identified. We calculated the concordance rate and further analyzed discordant cases.
RESULTS: Out of 140 patients with EOC, gBRCA mutation was found in 47 (33.6%) and tBRCA mutation in 53 (37.9%) patients. Tumor testing identified an additional 9/140 (6.4%) patients with somatic BRCA mutation and negative germline testing. The comparison of germline testing with tumor testing revealed a concordance rate of 93.5% and a negative predictive value of tumor testing of 96.0%. After BRCA variants of uncertain significance were included in the analysis, concordance rate decreased to 90.9%.
CONCLUSION: Tumor testing identified the majority of pathogenic germline BRCA mutations but missed three (2.1%) patients. In contrast, nine (6.4%) patients harboring a somatic BRCA mutation would have been missed by gBRCA testing only.

Keywords:  BRCA mutations; germline testing; tumor testing; variants of uncertain significance

DOI:  https://doi.org/10.3390/jpm11070593
J Mol Diagn. 2021 Jun 28. pii: S1525-1578(21)00177-X. [Epub ahead of print]

Use of treatment focused tumor sequencing to screen for germline cancer predisposition.

Tammy T Y Lau, Christina M May, Zahra Jalali Sefid Dashti, Lucas Swanson, Elizabeth R Starks, Jeremy D K Parker, Richard A Moore, Tracy Tucker, Ian Bosdet, Sean S Young, Jennifer L Santos, Katie Compton, Nili Heidary, Lien Hoang, Kasmintan A Schrader, Sophie Sun, Janice S Kwon, Anna V Tinker, Aly Karsan.

Next generation sequencing assays are capable of identifying cancer patients eligible for targeted therapies and can also detect germline variants associated with increased cancer susceptibility. However, these capabilities have yet to be routinely harmonized in a single assay due to challenges with accurately identifying germline variants from tumor-only data. We have developed the Oncology and Hereditary Cancer Program (OncoHCP) targeted capture panel, which uses tumor tissue to simultaneously screen for both clinically actionable solid tumor variants and germline variants across 45 genes. Validation using 14 tumor specimens comprised of patient samples and cell lines analyzed in triplicate demonstrated high coverage with sensitive and specific identification of single nucleotide variants and small insertions and deletions. Average coverage across all targets remained above 2,000x in 198 additional patient tumor samples. Analysis of 55 formalin-fixed, paraffin-embedded tumor samples for the detection of known germline variants within a subset of cancer-predisposition genes, including one multi-exon deletion, yielded a 100% detection rate, demonstrating that germline variants can be reliably detected in tumor samples using a single panel. Combining targetable somatic and actionable germline variants into a single tumor tissue assay represents a streamlined approach that can inform treatment for patients with advanced cancers as well as identify those with potential germline variants who are eligible for confirmatory testing, but would not otherwise have been identified.

DOI: https://doi.org/10.1016/j.jmoldx.2021.06.006
Int J Clin Oncol. 2021 Jul 02.

Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population.

Makoto Kagawa, Satoru Kawakami, Azusa Yamamoto, Okihide Suzuki, Nao Kamae, Hidetaka Eguchi, Yasushi Okazaki, Gou Yamamoto, Kiwamu Akagi, Jun-Ichi Tamaru, Tatsuro Yamaguchi, Tomio Arai, Hideyuki Ishida.

BACKGROUND: The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated.
METHODS: Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor.
RESULTS: Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63-79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS.
CONCLUSIONS: The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.

DOI: https://doi.org/10.1007/s10147-021-01922-y
Cancers (Basel). 2021 Jun 23. pii: 3132. [Epub ahead of print]13(13):

Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study.

Anna Pocurull, Cristina Herrera-Pariente, Sabela Carballal, Joan Llach, Ariadna Sánchez, Laura Carot, Josep María Botargues, Miriam Cuatrecasas, Teresa Ocaña, Francesc Balaguer, Luis Bujanda, Leticia Moreira.

  Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

Keywords:  DNA mismatch repair; early onset cancer; familial cancer; gastric cancer; hereditary cancer

DOI:  https://doi.org/10.3390/cancers13133132
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00090-2. [Epub ahead of print]48(3): 311-322

Genetic Testing Guidelines and Education of Health Care Providers Involved in Prostate Cancer Care.

James Ryan Mark, Carey McDougall, Veda N Giri.

  Germline testing for prostate cancer (PCA) is revolutionizing PCA care. Two PARP inhibitors are FDA approved for men with metastatic, castration-resistant disease after progression on first-line therapies. In the screening setting, genetic test results may inform initiation and screening strategies. For men with early-stage disease, literature is emerging on the possible role of germline testing in active surveillance discussions. As such, urologists and oncologists must gain working knowledge of the principles and practice of germline testing and hereditary cancer implications for responsible implementation. Here the authors outline key learning areas and practice strategies for responsible dissemination of PCA germline testing.

Keywords:  Genetic education; Germline testing; Precision medicine; Prostate cancer

DOI:  https://doi.org/10.1016/j.ucl.2021.03.003
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00093-8. [Epub ahead of print]48(3): 365-371

Genetically Informed Prostate Cancer Treatment for Metastatic Disease.

Aisha L Siebert, Brittany M Szymaniak, Yazan Numan, Alicia K Morgans.

  Germline testing should be performed to support treatment selection for patients with metastatic prostate cancer, and should be identified in patients with high-risk localized disease. Patients with germline BRCA1/2 mutations should be educated regarding additional personal cancer risk, and risk for family members. Guidelines recommend that all men with metastatic prostate cancer should also undergo somatic tissue and germline testing for priority genes BRCA1/2, PALB2, ATM, and MSH2/6. The advent of high throughput sequencing enables patients to be tested for a more comprehensive panel of germline and somatic mutations.

Keywords:  DNA-damage repair; Metastatic prostate cancer; Mismatch repair; Targeted treatment

DOI:  https://doi.org/10.1016/j.ucl.2021.03.006
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00091-4. [Epub ahead of print]48(3): 323-337

Genetic Counseling for Men with Prostate Cancer.

Colette Hyatt, Carey McDougall, Susan Miller-Samuel, Jessica Russo.

  Germline genetic testing is becoming more prevalent in urology clinics because of precision medicine for prostate cancer treatment. Genetic testing results can also influence cancer screening discussions for patients and/or their families. An important part of germline genetic testing is genetic counseling. This article provides an overview of the historical aspects of genetic counseling, discusses the components needed to provide proper genetic counseling, summarizes genes related to hereditary prostate cancer risk, and reviews genetic privacy and genetic discrimination concerns related to germline genetic testing.

Keywords:  Genetic counseling; Genetic counselor; Genetic testing; Hereditary prostate cancer; Prostate cancer

DOI:  https://doi.org/10.1016/j.ucl.2021.03.004
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00092-6. [Epub ahead of print]48(3): 349-363

Genetic Contribution to Metastatic Prostate Cancer.

Alexandra O Sokolova, Elias I Obeid, Heather H Cheng.

  Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.

Keywords:  BRCA2; Genetic testing; Germline; Metastatic prostate cancer

DOI:  https://doi.org/10.1016/j.ucl.2021.03.005
Ophthalmic Genet. 2021 Jun 30. 1-7

RB1 germline mutation spectrum and clinical features in patients with unilateral retinoblastomas.

Xiaolian Fang, Jun Chen, Yizhuo Wang, Minchao Zhao, Xin Zhang, Lei Yang, Xin Ni, Junyang Zhao, Brenda L Gallie.

  Background: Retinoblastoma is the most common intraocular cancer in children in which above 90% of bilateral cases and 10-25% of unilateral cases have germline RB1 mutations. We summarized the spectrum of RB1 germline mutations and the clinical manifestations of unilateral retinoblastomas to guide clinical treatments.Methods: Two hundred and sixty-three unrelated patients with unilateral retinoblastoma and their parents were included between February 2014 and August 2020. Next-generation sequencing and Sanger sequencing analysis of the core promoter region and exons 1-27 including flanking intronic regions of the RB1 gene were performed. If a germline mutation was identified in a retinoblastoma patient, the parental blood sample was requested to test for the identified mutation.Results: RB1 germline mutations were identified in 39/263 (14.8%) unilateral retinoblastoma patients and 11 (28.2%) had a missense mutation, 10 (25.6%) had nonsense mutations, 2 (5.1%) had frameshifts, 1 (2.6%) had synonymous mutation, and 7 (17.9%) had a large deletion, 2 (5.1%) had splice site mutations, 6 (15.4%) had variant of uncertain significance. Moreover, 27 (69.2%) of 39 patients identified RB1 mutations were predicted to have pathogenic mutation. The median age at diagnosis of patients with identified RB1 pathogenic mutations was 16.9 months and the patients with the wild-type allele was 21.1 months (P = .323).Conclusion: The rate of germline RB1 mutations is 14.8% in our cohort of unilateral retinoblastomas. The high incidence of germline mutations indicates that genetic testing and counseling for families of unilateral retinoblastoma patients would be beneficial.

Keywords:  Children; genetic testing; germline mutation; next-generation sequencing; retinoblastoma

DOI:  https://doi.org/10.1080/13816810.2021.1946703
J Clin Oncol. 2021 Jul 01. JCO2003238

Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis.

Raffaella Casolino, Salvatore Paiella, Danila Azzolina, Philip A Beer, Vincenzo Corbo, Giulia Lorenzoni, Dario Gregori, Talia Golan, Chiara Braconi, Fieke E M Froeling, Michele Milella, Aldo Scarpa, Antonio Pea, Giuseppe Malleo, Roberto Salvia, Claudio Bassi, David K Chang, Andrew V Biankin.

PURPOSE: To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC).
MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813).
RESULTS: Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD).
CONCLUSION: Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.

DOI: https://doi.org/10.1200/JCO.20.03238
Children (Basel). 2021 Jun 02. pii: 469. [Epub ahead of print]8(6):

Germline Mutations Including the Rare Pathogenic Variant c.3206delC in the ATM Gene Cause Ataxia Teleangiectasia-Associated Primary Central Nervous System Lymphoma.

Jan R Dörr, Anne Thorwarth, Agnieszka Mizia-Malarz, Josefine Radke, Anna Tietze, Pablo Hernáiz-Driever, Denise Horn, Alexander Gratopp, Angelika Eggert, Hedwig E Deubzer.

  We here report the case of a 2-year-old patient with a primary central nervous system lymphoma of B-cell origin. Due to their past medical history of repeated respiratory tract infections and the marked chemotherapy-associated toxicity and infectious comorbidity, we suspected that the patient also suffered from an inherited immune deficiency disorder. Despite the lack of classical pathognomonic symptoms for ataxia teleangiectasia and missing evidence for a cancer predisposition syndrome in the family, genetic testing identified biallelic germline mutations, including the rare pathogenic variant c.3206delC (p.Pro1069Leufs*2), in the ataxia telangiectasia-mutated (ATM) gene. The case highlights the importance of searching for immune deficiency disorders associated with primary central nervous system lymphoma before treatment initiation and the urgent need to develop novel treatment strategies for cancer patients with underlying immunodeficiency syndromes.

Keywords:  cancer; cancer predisposition; chemotherapy tolerance; immune deficiency disorder; multiresistant bacteria

DOI:  https://doi.org/10.3390/children8060469
Cancers (Basel). 2021 Jun 17. pii: 3033. [Epub ahead of print]13(12):

A Retrospective 5-Year Single Center Study Highlighting the Risk of Cancer Predisposition in Adolescents and Young Adults.

Frank Jordan, Simon Huber, Sebastian Sommer, Gerhard Schenkirsch, Michael C Frühwald, Martin Trepel, Rainer Claus, Michaela Kuhlen.

  The knowledge of inherited cancer susceptibility opens a new field of cancer medicine. We conducted a retrospective single-center cohort study. Data of AYA cancer patients registered between January 2014 and December 2018 were analyzed. The median age at cancer diagnosis of 704 patients (343 males, 361 females) was 32 years (range, 15-39 years), median follow-up was 181 days (range, 1-1975 days). Solid tumors were diagnosed in 575 (81.7%) patients, hematologic malignancies in 129 (18.3%) patients. Multiple primary cancers were reported in 36 (5.1%) patients. Malignancies that may be indicators of inherited cancer susceptibility were diagnosed in 2.6% of patients with cancers of the endocrine system, in 73% of cancers of the gastrointestinal system, in 88% of tumors of the central nervous system, in 92% of cancers of the urinary tract, and in 59% of head and neck tumors. In addition, all patients with breast cancer, sarcoma, and peripheral nerve sheath tumor were in need of genetic counselling. In sum, at least 181 of 704 (25.7%) AYA cancer patients presented with malignancies suspicious of harboring pathogenic germline variants. Evaluation of AYA cancer patients for hereditary cancer predisposition needs to be integrated into daily practice.

Keywords:  adolescents; awareness; inherited cancer predisposition; suspicious findings; young adults

DOI:  https://doi.org/10.3390/cancers13123033
Urol Clin North Am. 2021 Aug;pii: S0094-0143(21)00088-4. [Epub ahead of print]48(3): 283-296

Prostate Cancer Predisposition.

Yasin Bhanji, William B Isaacs, Jianfeng Xu, Kathleen A Cooney.

  The identification and characterization of alterations in prostate cancer (PCa)-predisposing genes can help to inform screening strategies in undiagnosed men and treatment options in men in both the clinically localized and in the metastatic setting. This review provides an overview of the genetic basis underlying hereditary predisposition to PCa, the current role of genetics and PCa risk assessment, and how genetic risk factors affect aggressiveness and lethality of PCa.

Keywords:  Cancer susceptibility gene; Hereditary cancer syndrome; Polygenic risk score; Prostate cancer

DOI:  https://doi.org/10.1016/j.ucl.2021.03.001
Lab Med. 2021 Jun 29. pii: lmab020. [Epub ahead of print]

Clinical Interpretation Challenges of Germline-Shared Somatic Variants in Cancer.

Kyoung-Jin Park.

   OBJECTIVE: To investigate the interpretation differences of germline-shared somatic variants.
METHODS: A total of 123,302 COSMIC variants associated with hematologic malignant neoplasms were used. The pathogenicity and actionability of shared variants were analyzed based on the standardized guidelines.
RESULTS: The overall frequency of variants shared in ClinVar/HGMD and COSMIC was 10%. The pathogenicity of 54 shared variants was pathogenic/likely pathogenic (P/LP; n = 30), variants of unknown significance (n = 3), and benign/likely benign (n = 21). In total, 30 P/LP variants were reclassified to tier I/tier II (83%) and tier III (17%) variants.
CONCLUSIONS: This is the first study about different clinical interpretations of shared variants based on the current standard guidelines. This study takes a meaningful step in bridging the interpretation gap between the somatic and germline variants.

Keywords:  actionability; germline; interpretation; pathogenicity; somatic; variant

DOI:  https://doi.org/10.1093/labmed/lmab020
Sci Rep. 2021 Jul 01. 11(1): 13624

Identification of germline cancer predisposition variants during clinical ctDNA testing.

Leigh Anne Stout, Nawal Kassem, Cynthia Hunter, Santosh Philips, Milan Radovich, Bryan P Schneider.

Next-generation sequencing of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40-60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39-87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40 and 60% were found to be germline. Therefore, variants with a VAF between 40 and 60% should induce suspicion for germline status but should not be used as a replacement for germline testing.

DOI: https://doi.org/10.1038/s41598-021-93084-0
Biomed J. 2021 Jun 24. pii: S2319-4170(21)00070-6. [Epub ahead of print]

RASopathies: from germline mutations to somatic and multigenic diseases.

Quentin Riller, Frédéric Rieux-Laucat.

  The RAS-RAF-MEK-ERK signaling pathway is vital for different cellular mechanisms including cell proliferation, differentiation and apoptosis. This importance is highlighted by the high prevalence of mutations in RAS or related proteins of the pathway in cancers. More recently, development abnormalities have been linked to various germline mutations in this pathway and called RASopathies. Interestingly, rare disorders such as RAS-associated leukoproliferative diseases and histiocytosis have also been recently linked to multiple mutations in the same pathway, sometimes with the same mutation. This review will focus on germline RASopathies and rare somatic RASopathies and focus on how gain-of-function mutations in the same pathway can lead to various diseases.

Keywords:  RAS; germline; histiocytes; lymphoproliferation; monocytes; somatic

DOI:  https://doi.org/10.1016/j.bj.2021.06.004
J Pediatr Ophthalmol Strabismus. 2021 Jun 01. 1-10

Likelihood of Germline Mutation With Solitary Unilateral Retinoblastoma Based on Patient Age at Presentation: Analysis of 482 Consecutive Patients.

Carol L Shields, Philip Dockery, Megan Ruben, Antonio Yaghy, Madalyne A Sunday, Emily R Duffner, Hannah J Levin, Olivia S Taylor, Martin Calotti, Sara E Lally, Jerry A Shields.

PURPOSE: To evaluate the likelihood of germline retinoblastoma in patients presenting with solitary unilateral retinoblastoma, based on age at presentation.
METHODS: This retrospective case series of 482 consecutive patients presenting with solitary unilateral retinoblastoma analyzed the likelihood of germline retinoblastoma, defined as family history of retinoblastoma, germline retinoblastoma mutation documented on genetic testing, and/or development of bilateral disease and/or additional new tumors. This analysis was based on age at presentation (0 to 12 months vs older than 12 to 24 months vs older than 24 to 36 months vs older than 36 months) and a sub-study was conducted on infant age at presentation (0 to 3 months vs older than 3 to 6 months vs older than 6 to 9 months vs older than 9 to 12 months).
RESULTS: Of the overall group (482 consecutive patients) with solitary unilateral retinoblastoma, there were significantly different findings in the youngest age group (0 to 12 months old) with greater family history of retinoblastoma (10% vs 2% vs 1% vs 2%, P = .004), smaller median basal diameter (18.0 vs 20.0 vs 20.0 vs 20.0 mm, P = .014), smaller median tumor thickness (8.7 vs 10.0 vs 11.5 vs 10.0 mm, P = .002), greater macular tumor location (33% vs 16% vs 10% vs 8%, P < .001), and greatest likelihood of germline mutation (29% vs 17% vs 8% vs 9%, P = .001). By comparison, patients 1 year and younger (vs older than 1 year) demonstrated a 2.96 odds ratio (OR) (P = .001) for likelihood of germline retinoblastoma. For those classified as infants (1 year and younger) (n = 132 consecutive patients), the youngest patients (0 to 3 months old) demonstrated the greatest likelihood for germline mutation (61% vs 20% vs 24% vs 22%, P = .009) and greatest odds ratio (5.52, P = .002) compared to patients older than 3 to 12 months.
CONCLUSIONS: The youngest patients with solitary uni-lateral retinoblastoma showed the greatest likelihood of germline disease when evaluating all patients (1 year and younger vs older than 1 year of age) (OR = 2.96) and the sub-study of infants (3 years and younger vs older than 3 to 12 months old) (OR = 5.52). [J Pediatr Ophthalmol Strabismus. 20XX;X(X):XX-XX.].

DOI: https://doi.org/10.3928/01913913-20210414-02
Front Genet. 2021 ;12 681857

Prognostic Value of Germline Copy Number Variants and Environmental Exposures in Non-small Cell Lung Cancer.

Shizhen Chen, Liming Lu, Jianfeng Xian, Changhong Shi, Jinbin Chen, Boqi Rao, Fuman Qiu, Jiachun Lu, Lei Yang.

  Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16-1.74) and validation cohort (HR = 1.42, 95%CI: 1.13-1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664-0.693) and 0.686 (95%CI: 0.670-0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (P interaction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.

Keywords:  gene-environment interaction; germline copy number variant; nomogram; non-small cell lung cancer; overall survival

DOI:  https://doi.org/10.3389/fgene.2021.681857
Curr Treat Options Oncol. 2021 Jul 02. 22(9): 80

Precision Therapy for Brain Tumors in Hereditary Syndromes.

Gerald E Wallace, Madeleine Tjoelker, Kaitlyn Bartley, John W Henson.

   OPINION STATEMENT: Nervous system tumors arising in the setting of monogenic, hereditary cancer predisposition syndromes are unique in that the initiating genetic event in tumor formation is known. This knowledge provides a powerful treatment approach if the alteration or pathway can be targeted with a therapeutic agent. A reasonable argument can be made for the use of targeted agents in these tumor patients, even though many of them have FDA approval only for other tumor types. It is our practice to use and employ targeted therapy when standard treatments have failed or represent an unattractive option. Over time, however, targeted therapies will likely become first-line options.

Keywords:  Brain tumor; Genetic; Hereditary; Precision; Targeted

DOI:  https://doi.org/10.1007/s11864-021-00876-7