scholarly journals Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group

2021 ◽  
Author(s):  
M. C. Frühwald ◽  
K. Nemes ◽  
H. Boztug ◽  
M. C. A. Cornips ◽  
D. G. Evans ◽  
...  
Keyword(s):  
Working Group ◽  
Soft Part ◽  
Genetic Disorders ◽  
Panel Discussion ◽  
Rhabdoid Tumor ◽  
Host Genome ◽  
Cancer Surveillance ◽  
Malignant Neoplasms ◽  
Pathogenic Variants ◽  
Increased Risk

AbstractThe rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

scholarly journals The evolving role of germline genetic testing and management in prostate cancer: Report from the Princess Margaret Cancer Centre International Retreat

2021 ◽  
Vol 15 (12) ◽  
Author(s):  
Roderick Clark ◽  
Miran Kenk ◽  
Kristen McAlpine ◽  
Emily Thain ◽  
Kirsten M. Farncombe ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Genetic Risk ◽  
Genetic Disorders ◽  
Future Research ◽  
Policy Action ◽  
Cancer Centre ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
International Experts

Introduction: Prostate cancer is a significant cause of cancer mortality. It has been well-established that certain germline pathogenic variants confer both an increased risk of being diagnosed with prostate cancer and dying of prostate cancer.1 There are exciting developments in both the availability of genetic testing and opportunities for improved treatment of patients. On August 19, 2020, the Princess Margaret Cancer Centre in Toronto, Ontario, hosted a virtual retreat, bringing together international experts in urology, medical oncology, radiation oncology, medical genetics, and translational research, as well as a patient representative. We are pleased to provide this manuscript as a review of those proceedings for Canadian clinicians. Recommendations: We drafted several recommendations for future research and policy action based on this meeting: 1) Need for increased access to funding for germline testing for the common genetic disorders associated with increased risk of prostate cancer. 2) A need for increased research into identifying genetic factors influencing risk stratification, treatment response, and outcomes of prostate cancer within Canadian populations at increased genetic risk for prostate cancer. 3) Need for increased awareness about genetic risk factors among the Canadian public. 4) Need for research on patient perspectives and psychosocial outcomes in individuals identified to be at increased genetic risk of prostate cancer. 5) We support the creation of specialized multidisciplinary clinics that specialize in tailored care for patients at increased genetic risk of prostate cancer.

scholarly journals Primary Immunodeficiency with double strain break DNA (DSBs) and radiosensitvity: clinical, diagnostic and therapeutic implications

2018 ◽  
Vol 72 ◽  
pp. 449-460 ◽  
Author(s):  
Barbara Pietrucha ◽  
Hanna Gregorek ◽  
Edyta Heropolitańska-Pliszka ◽  
Ewa Bernatowska
Keyword(s):  
Dna Repair ◽  
Radiation Treatment ◽  
Genetic Disorders ◽  
Malignant Neoplasms ◽  
Dna Double Strand Breaks ◽  
Hematopoietic Stem ◽  
Therapeutic Implications ◽  
Treatment Regimens ◽  
Increased Risk ◽  
Immune Deficiencies

Primary Immunodeficiencies (PNO) are a group of about 300 genetic disorders which result from the absence or dysfunction of the major components of the immune system. Among them an important subgroup constitute deficiencies associated with defects in DNA double strand breaks (DSBs) recognition and repair. These are primarily radiation-sensitive severe combined immune deficiencies (SCIDs) and combined immune deficiencies (CIDs) associated with genetic defects in the DNA-repair genes, which encode proteins necessary for T-cell and B cell maturation/differentiation. Due to increased risk of developing malignant neoplasms, mainly from hematopoietic origin, and over-reaction to standard anticancer radiotherapy and chemotherapy, treatment of these patients is a real challenge for clinicians. Clinical and laboratory manifestations, which may indicate increased radiosensitivity include: microcephaly, telangiectasias, lymphopenia, and translocation of chromosomes 7 and 14 in karyotype. A basic test showing increased radiosensitivity of lymphoblastoid cells lines or skin fibroblasts is percentage evaluation of their survival after exposition to ionizing radiation. Treatment of patients with impaired DNA repair depends on the clinical picture, immunological findings and type of immunodeficiency. Patients with SCID require immediate hematopoietic stem cell transplantation (HSCT) using reduced intensity conditioning (RIC). In patients with CID, standard treatment regimens require modification and/or avoidance of radiotherapy and some radiomimetic agents.

scholarly journals No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

2021 ◽  
Vol 10 (13) ◽  
pp. 2856
Author(s):  
Mev Dominguez-Valentin ◽  
John-Paul Plazzer ◽  
Julian R. Sampson ◽  
Christoph Engel ◽  
Stefan Aretz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Urinary Tract ◽  
Lynch Syndrome ◽  
Cancer Surveillance ◽  
Aberrant Splicing ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Splicing Variants ◽  
Endometrial Cancers

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

scholarly journals Rhabdoid Tumor Predisposition Syndrome: From Clinical Suspicion to General Management

2021 ◽  
Vol 11 ◽  
Author(s):  
Giada Del Baldo ◽  
Roberto Carta ◽  
Iside Alessi ◽  
Pietro Merli ◽  
Emanuele Agolini ◽  
...  
Keyword(s):  
Soft Tissues ◽  
Rhabdoid Tumor ◽  
Primary Tumors ◽  
General Management ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Multiple Primary ◽  
The Central Nervous System ◽  
Rhabdoid Tumors ◽  
Infants And Young Children

Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the SMARCB1 gene, while RTPS2 has variants in SMARCA4. Interestingly, germline variants of SMARCB1 and SMARCA4 have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.

scholarly journals Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

2021 ◽  
Author(s):  
L. Guerrini-Rousseau ◽  
M. J. Smith ◽  
C. P. Kratz ◽  
B. Doergeloh ◽  
S. Hirsch ◽  
...  
Keyword(s):  
Working Group ◽  
Malignant Tumors ◽  
Brain Mri ◽  
Host Genome ◽  
Cancer Surveillance ◽  
Gorlin Syndrome ◽  
Causative Gene ◽  
Cancer Predisposition Syndrome ◽  
Evaluation Of Evidence ◽  
Tumor Types

AbstractGorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

scholarly journals Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1495
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Robert J. MacInnis ◽  
Jason A. Steen ◽  
Moeen Riaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Prediction Models ◽  
Aggressive Prostate Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Rare Genetic Variants

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

scholarly journals Extended gene panel testing in lobular breast cancer

2021 ◽  
Author(s):  
Elke M. van Veen ◽  
D. Gareth Evans ◽  
Elaine F. Harkness ◽  
Helen J. Byers ◽  
Jamie M. Ellingford ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Detection Rate ◽  
Gene Panel ◽  
Lobular Breast Cancer ◽  
Germline Variants ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
Increased Risk

AbstractPurpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

scholarly journals ATRT-04. INHERITED RHABDOID PREDISPOSITION SYNDROME: A CASE OF CHOROID PLEXUS CARCINOMA AND ATYPICAL TERATOID RHABDOID TUMOR IN SIBLINGS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii276-iii276
Author(s):  
Alexis Judd ◽  
Erin Wright ◽  
Sarah Rush
Keyword(s):  
Overall Survival ◽  
Choroid Plexus ◽  
Disease Recurrence ◽  
Genetic Alterations ◽  
Rhabdoid Tumor ◽  
Choroid Plexus Carcinoma ◽  
High Dose ◽  
Atypical Teratoid Rhabdoid Tumor ◽  
Increased Risk ◽  
Atypical Teratoid

Abstract Choroid plexus carcinoma (CPC) and Atypical teratoid/rhabdoid tumor (ATRT) are aggressive, malignant brain cancers most commonly arising in children less than 3 years of age. These tumors often have genetic alterations in the tumor suppressor gene SMARCB1/INI1. Rhabdoid predisposition syndrome (RTPS) categorizes patients with germline mutations in SMARCB1 or SMARCA4, leading to a markedly increased risk of developing rhabdoid tumors. Both CPC and ATRT have been demonstrated in patients with these rhabdoid predisposition syndromes. In general, these tumors tend to have a poor prognosis. However, with the presence of a SMARCB1 mutation they may have improved overall survival. We present two interesting cases of siblings with maternally inherited SMARCB1 mutations: one a 21-month-old male who presented with an ATRT and another a 10 month old female who presented with a CPC. The ATRT was treated as per the Children’s Oncology Group study ACNS0333 with high dose chemotherapy and stem cell rescue as well as cranial radiation. The CPC was treated as per CPT-SIOP 2009 with etoposide, cyclophosphamide and vincristine. Unlike other patients with these aggressive tumors, both of these patients are alive without evidence of disease recurrence 8 and 7 years post therapy, respectively. Additional genomic testing on both tumors is currently pending in order to potentially identify other mutations that may impact survival. These cases further illustrate the similar profile of two very different tumors with improved overall survival that may be secondary to mutations in SMARCB1 in RTPS.

scholarly journals Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes

2021 ◽  
Author(s):  
Gema Ariceta ◽  
Fadi Fakhouri ◽  
Lisa Sartz ◽  
Benjamin Miller ◽  
Vasilis Nikolaou ◽  
...  
Keyword(s):  
Family History ◽  
Hemolytic Uremic Syndrome ◽  
Univariate Analysis ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Renal Response ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
History Of ◽  
Uremic Syndrome

ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: eGFR changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants, or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation. Conclusions Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

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