bims-lifras 2020-12-20 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2020–12–20
fiveteen papers selected by
Joanna Zawacka-Pankau, University of Warsaw

Germline TP53 Testing in Breast Cancers: Why, When and How?
Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.
Advances in germline predisposition to acute leukaemias and myeloid neoplasms.
Population-based Screening for Hereditary Colorectal Cancer Variants in Japan.
Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.
Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer prone syndromes.
Multiple cancer susceptible genes sequencing in BRCA-negative breast cancer with high hereditary risk.
Germline Variation and Somatic Alterations in Ewing Sarcoma.
In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas.
Whole-exome sequencing identified a novel mutation of MLH1 in an extended family with lynch syndrome.
Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore.
Molecular Features and Clinical Management of Hereditary Gynecological Cancers.
Should the risk for uterine cancer influence decision making for prophylactic hysterectomy in BRCA1/2 mutated patients- a systematic review and meta-analysis.
Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.
BRCA testing delay during the COVID-19 pandemic: How to act?

Cancers (Basel). 2020 Dec 14. pii: E3762. [Epub ahead of print]12(12):

Germline TP53 Testing in Breast Cancers: Why, When and How?

D Gareth Evans, Emma R Woodward, Svetlana Bajalica-Lagercrantz, Carla Oliveira, Thierry Frebourg.

  Germline TP53 variants represent a main genetic cause of breast cancers before 31 years of age. Development of cancer multi-gene panels has resulted in an exponential increase of germline TP53 testing in breast cancer patients. Interpretation of TP53 variants, which are mostly missense, is complex and requires excluding clonal haematopoiesis and circulating tumour DNA. In breast cancer patients harbouring germline disease-causing TP53 variants, radiotherapy contributing to the development of subsequent tumours should be, if possible, avoided and, within families, annual follow-up including whole-body MRI should be offered to carriers. We consider that, in breast cancer patients, germline TP53 testing should be performed before treatment and offered systematically only to patients with: (i) invasive breast carcinoma or ductal carcinoma in situ (DCIS) before 31; or (ii) bilateral or multifocal or HER2+ invasive breast carcinoma/DCIS or phyllode tumour before 36; or (iii) invasive breast carcinoma before 46 and another TP53 core tumour (breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumour, adrenocortical carcinoma); or (iv) invasive breast carcinoma before 46 and one first- or second-degree relative with a TP53 core tumour before 56. In contrast, women presenting with breast cancer after 46, without suggestive personal or familial history, should not be tested for TP53.

Keywords:  Li-Fraumeni syndrome; TP53; breast cancer; gene panels; heritable TP53-related cancer syndrome; interpretation; variant

DOI:  https://doi.org/10.3390/cancers12123762
Cancer. 2020 Dec 15.

Psychosocial outcomes following germline multigene panel testing in an ethnically and economically diverse cohort of patients.

Julie O Culver, Charité N Ricker, Joseph Bonner, John Kidd, Duveen Sturgeon, Rachel Hodan, Kerry Kingham, Katrina Lowstuter, Nicolette M Chun, Alexandra P Lebensohn, Courtney Rowe-Teeter, Peter Levonian, Katlyn Partynski, Karlena Lara-Otero, Christine Hong, Jennifer Morales Pichardo, Meredith A Mills, Krystal Brown, Caryn Lerman, Uri Ladabaum, Kevin J McDonnell, James M Ford, Stephen B Gruber, Allison W Kurian, Gregory E Idos.

   BACKGROUND: Little is known about the psychological outcomes of germline multigene panel testing, particularly among diverse patients and those with moderate-risk pathogenic variants (PVs).
METHODS: Study participants (N = 1264) were counseled and tested with a 25- or 28-gene panel and completed a 3-month postresult survey including the Multidimensional Impact of Cancer Risk Assessment (MICRA).
RESULTS: The mean age was 52 years, 80% were female, and 70% had cancer; 45% were non-Hispanic White, 37% were Hispanic, 10% were Asian, 3% were Black, and 5% had another race/ethnicity. Approximately 28% had a high school education or less, and 23% were non-English-speaking. The genetic test results were as follows: 7% had a high-risk PV, 6% had a moderate-risk PV, 35% had a variant of uncertain significance (VUS), and 52% were negative. Most participants (92%) had a total MICRA score ≤ 38, which corresponded to a mean response of "never," "rarely," or only "sometimes" reacting negatively to results. A multivariate analysis found that mean total MICRA scores were significantly higher (more uncertainty/distress) among high- and moderate-risk PV carriers (29.7 and 24.8, respectively) than those with a VUS or negative results (17.4 and 16.1, respectively). Having cancer or less education was associated with a significantly higher total MICRA score; race/ethnicity was not associated with the total MICRA score. High- and moderate-risk PV carriers did not differ significantly from one another in the total MICRA score, uncertainty, distress, or positive experiences.
CONCLUSIONS: In a diverse population undergoing genetic counseling and multigene panel testing for hereditary cancer risk, the psychological response corresponded to test results and showed low distress and uncertainty. Further studies are needed to assess patient understanding and subsequent cancer screening among patients from diverse backgrounds.
LAY SUMMARY: Multigene panel tests for hereditary cancer have become widespread despite concerns about adverse psychological reactions among carriers of moderate-risk pathogenic variants (mutations) and among carriers of variants of uncertain significance. This large study of an ethnically and economically diverse cohort of patients undergoing panel testing found that 92% "never," "rarely," or only "sometimes" reacted negatively to results. Somewhat higher uncertainty and distress were identified among carriers of high- and moderate-risk pathogenic variants, and lower levels were identified among those with a variant of uncertain significance or a negative result. Although the psychological response corresponded to risk, reactions to testing were favorable, regardless of results.

Keywords:  genetic counseling; genetic techniques; genetic testing; hereditary neoplastic syndromes; psycho-oncology; psychosocial factors

DOI:  https://doi.org/10.1002/cncr.33357
Nat Rev Cancer. 2020 Dec 16.

Advances in germline predisposition to acute leukaemias and myeloid neoplasms.

Jeffery M Klco, Charles G Mullighan.

Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.

DOI: https://doi.org/10.1038/s41568-020-00315-z
Clin Gastroenterol Hepatol. 2020 Dec 10. pii: S1542-3565(20)31664-5. [Epub ahead of print]

Population-based Screening for Hereditary Colorectal Cancer Variants in Japan.

Masashi Fujita, Xiaoxi Liu, Yusuke Iwasaki, Chikashi Terao, Keijiro Mizukami, Eiryo Kawakami, Sadaaki Takata, Chihiro Inai, Tomomi Aoi, Misaki Mizukoshi, Kazuhiro Maejima, Makoto Hirata, Yoshinori Murakami, Yoichiro Kamatani, Michiaki Kubo, Kiwamu Akagi, Koichi Matsuda, Hidewaki Nakagawa, Yukihide Momozawa.

   BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most common cancers in the world. A small proportion of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes. To better understand cancer risk, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations.
METHODS: We analyzed the coding regions of 27 cancer-predisposing genes in 12,503 unselected Japanese CRC patients and 23,705 controls by target sequencing and genome-wide SNP chip. Their clinical significance was assessed using ClinVar and the guidelines by ACMG/AMP.
RESULTS: We identified 4,804 variants in the 27 genes and annotated them as pathogenic in 397, and benign variants in 941, of which 43.6% were novel. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant. The pathogenic variants of MSH2 (odds ratio (OR) =18.1), MLH1 (OR=8.6), MSH6 (OR=4.9), APC (OR=49.4), BRIP1 (OR=3.6), BRCA1 (OR=2.6), BRCA2 (OR=1.9), and TP53 (OR=1.7) were significantly associated with CRC development in the Japanese population (P-values<0.01, FDR<0.05). These pathogenic variants were significantly associated with diagnosis age and personal/family history of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes, indicating hereditary cancers.
CONCLUSIONS: This largest study of CRC heredity in Asia can contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs.

Keywords:  BRCA1/2; BRIP1; CNV; hereditary colorectal cancer; pathogenic variant

DOI:  https://doi.org/10.1016/j.cgh.2020.12.007
Hum Mutat. 2020 Dec 16.

Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer.

Paula S Felicio, Rebeca S Grasel, Natalia Campacci, Andre E de Paula, Henrique C R Galvão, Giovana T Torrezan, Cristina S Sabato, Gabriela C Fernandes, Cristiano P Souza, Rodrigo D Michelli, Carlos E Andrade, Bruna Durães de Figueiredo Barros, Marcus M Matsushita, Timothée Revil, Jiannis Ragoussis, Fergus J Couch, Steven N Hart, Rui M Reis, Matias E Melendez, Patricia N Tonin, Dirce M Carraro, Edenir I Palmero.

  The current study aimed to identify new breast and/or ovarian cancer predisposition genes. For that, whole-exome sequencing (WES) was performed in the germline DNA of 52 non-BRCA1/BRCA2/TP53 mutation carrier women at high-risk for hereditary breast and ovarian cancer (HBOC). All variants were classified using information from population and disease specific databases, in silico prediction tools and the American College of Medical Genetics and Genomics (ACMG) criteria. Loss of heterozygosity (LOH) of tumor samples and segregation analyses were performed whenever possible. The variants identified were investigated in a second, independent cohort of 17 BC cases. Pathogenic/Likely Pathogenic variants were identified in known cancer genes such as CHEK2, MUTYH, PMS2 and RAD51C. Rare and potentially pathogenic variants were identified in DNA repair genes (FAN1, POLQ, RAD54L) and other cancer-related genes such as DROSHA and SLC34A2. Interestingly, the variant c.149T>G in the FAN1 gene was identified in two unrelated families, and exhibited LOH in the tumor tissue of one of them. In conclusion, this is the largest Brazilian WES study involving families at high-risk for HBOC which has brought novel insights into the role of potentially new genetic risk factors for hereditary breast and ovarian cancer. This article is protected by copyright. All rights reserved.

Keywords:  BRCAX; breast cancer predisposition; hereditary breast and ovarian cancer predisposition syndrome; hereditary cancer; whole-exome sequencing

DOI:  https://doi.org/10.1002/humu.24158
PLoS Genet. 2020 Dec 17. 16(12): e1009231

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer prone syndromes.

Anna Byrjalsen, Thomas V O Hansen, Ulrik K Stoltze, Mana M Mehrjouy, Nanna Moeller Barnkob, Lisa L Hjalgrim, René Mathiasen, Charlotte K Lautrup, Pernille A Gregersen, Henrik Hasle, Peder S Wehner, Ruta Tuckuviene, Peter Wad Sackett, Adrian O Laspiur, Maria Rossing, Rasmus L Marvig, Niels Tommerup, Tina Elisabeth Olsen, David Scheie, Ramneek Gupta, Anne-Marie Gerdes, Kjeld Schmiegelow, Karin Wadt.

PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS.
METHODS: Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries.
RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene.
CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.

DOI: https://doi.org/10.1371/journal.pgen.1009231
Ann Transl Med. 2020 Nov;8(21): 1417

Multiple cancer susceptible genes sequencing in BRCA-negative breast cancer with high hereditary risk.

Guan-Tian Lang, Jin-Xiu Shi, Liang Huang, A-Yong Cao, Chen-Hui Zhang, Chuan-Gui Song, Zhi-Gang Zhuang, Xin Hu, Wei Huang, Zhi-Ming Shao.

   Background: Hereditary factors contributed to breast cancer susceptibility. Low BRCA mutation prevalence was demonstrated in previous BRCA mutation screening in Chinese breast cancer patients. Multiple-gene sequencing may assist in discovering detrimental germline mutation in.
BRCA: negative breast cancers.
Methods: A total of 384 Chinese subjects with any two of high-risk factors were recruited and screened by next-generation sequencing (NGS) for 30 cancer susceptible genes. Variants with a truncating, initiation codon or splice donor/acceptor effect, or with pathogenicity demonstrated in published literature were classified into pathogenic/likely-pathogenic mutations.
Results: In total, we acquired 39 (10.2%) patients with pathogenic/likely-pathogenic germline mutations, including one carrying two distinct mutations. Major mutant non-BRCA genes were MUTYH (n=11, 2.9%), PTCH1 (n=7, 1.8%), RET (n=6, 1.6%) and PALB2 (n=5, 1.3%). Other mutant genes included TP53 (n=3, 0.8%), RAD51D (n=2, 0.5%), CHEK2 (n=1, 0.3%), BRIP1 (n=1, 0.3%), CDH1 (n=1, 0.3%), MRE11 (n=1, 0.3%), RAD50 (n=1, 0.3%) and PALLD (n=1, 0.3%). A splicing germline mutation, MUTYH c.934-2A>G, was a hotspot (9/384, 2.3%) in Chinese breast cancer.
Conclusions: Among BRCA-negative breast cancer patients with high hereditary risk in China, 10.2% carried mutations in cancer associated susceptibility genes. MUTYH and PTCH1 had relatively high mutation rates (2.9% and 1.8%). Multigene testing contributes to understand genetic background of BRCA-negative breast cancer patients with high hereditary risk.

Keywords:  BRCA-negative; Germline mutation; hereditary breast cancer; multigene sequencing

DOI:  https://doi.org/10.21037/atm-20-2999
Methods Mol Biol. 2021 ;2226 3-14

Germline Variation and Somatic Alterations in Ewing Sarcoma.

Mitchell J Machiela, Thomas G P Grünewald.

  Ewing sarcoma (EwS) is a rare bone or soft tissue tumor that occurs early in life and as such genetic variation is a major contributor to EwS risk. To date, genetic investigations have identified key somatic mutations and germline variants of importance for EwS risk. While substantial progress is being made in uncovering the genetic etiology of EwS, considerable gaps in knowledge remain. Herein, we provide a summary of methodological approaches for future genomic investigations of EwS. We anticipate this recommended analytical framework for germline and somatic investigations, along with genomic data from growing EwS case series, will aid in accelerating new genomic discoveries in EwS and expand knowledge of the genetic architecture of EwS.

Keywords:  EWSR1-FLI1; Ewing sarcoma; Genetics; Germline variants; SNPs; Somatic mutations; Translocation

DOI:  https://doi.org/10.1007/978-1-0716-1020-6_1
Eur J Hum Genet. 2020 Dec 15.

In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas.

Diana Le Duc, Julia Hentschel, Sonja Neuser, Mathias Stiller, Carolin Meier, Elisabeth Jäger, Rami Abou Jamra, Konrad Platzer, Astrid Monecke, Mirjana Ziemer, Aleksander Markovic, Hendrik Bläker, Johannes R Lemke.

Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.

DOI: https://doi.org/10.1038/s41431-020-00781-x
Genes Dis. 2020 Dec;7(4): 614-619

Whole-exome sequencing identified a novel mutation of MLH1 in an extended family with lynch syndrome.

Hamid Ghaedi, Samira Molaei Ramsheh, Maryam Erfanian Omidvar, Afsaneh Labbaf, Elham Alehabib, Sanaz Akbari, Fatemeh Pourfatemi, Hossein Darvish.

  Hereditary nonpolyposis colorectal cancer or Lynch syndrome is autosomal dominant cancer predisposition syndrome characterized by early onset of colorectal cancer and neoplasia in other organs. This condition typically caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. To date, a considerable number of MLH1 gene mutations have been found to be associated with Lynch syndrome. We were aimed at identifying a genetic mutation in an extended Iranian family affected by Lynch syndrome-related cancers. Here, we applied whole-exome sequencing to identifying mutation in the proband. Furthermore, we applied Sanger sequencing to validate the candidate variant. We found a heterozygous novel single nucleotide deletion (c.206delG) in the exon two of the MLH1 gene in the proband. Also, Sanger sequencing analysis showed that this mutation has segregated in all affected family members. The mutation (c.206delG:p.R69fs) may create a premature stop codon followed by the formation of a truncated (p.R69fs) Mlh1 protein. Our findings expand the mutational spectra of MLH1 gene related Lynch syndrome which is vital for screening and genetic diagnosis of the disease.

Keywords:  Colorectal cancer; Lung cancer; MLH1; Mismatch repair

DOI:  https://doi.org/10.1016/j.gendis.2019.07.011
Hered Cancer Clin Pract. 2020 Dec 11. 18(1): 24

Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore.

Kay Reen Ting, Pei Yi Ong, Samuel Ow Guan Wei, Rajeev Parameswaran, Chin Meng Khoo, Doddabele Srinivasa Deepak, Soo-Chin Lee.

   BACKGROUND: Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients.
METHODS: We describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore.
RESULTS: Among 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers.
CONCLUSION: Hereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.

Keywords:  Chinese; Genetic testing; Hereditary paraganglioma; Pheochromocytoma; SDHB; SDHD

DOI:  https://doi.org/10.1186/s13053-020-00156-9
Int J Mol Sci. 2020 Dec 14. pii: E9504. [Epub ahead of print]21(24):

Molecular Features and Clinical Management of Hereditary Gynecological Cancers.

Arisa Ueki, Akira Hirasawa.

  Hereditary gynecological cancers are caused by several inherited genes. Tumors that arise in the female reproductive system, such as ovaries and the uterus, overlap with hereditary cancers. Several hereditary cancer-related genes are important because they might lead to therapeutic targets. Treatment of hereditary cancers should be updated in line with the advent of various new methods of evaluation. Next-generation sequencing has led to rapid, economical genetic analyses that have prompted a concomitant and significant paradigm shift with respect to hereditary cancers. Molecular tumor profiling is an epochal method for determining therapeutic targets. Clinical treatment strategies are now being designed based on biomarkers based on tumor profiling. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines significantly changed the genetic testing process in 2020 to initially consider multi-gene panel (MGP) evaluation. Here, we reviewed the molecular features and clinical management of hereditary gynecological malignancies, such as hereditary breast and ovarian cancer (HBOC), and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes. We also reviewed cancer-susceptible genes revealed by MGP tests.

Keywords:  Cowden; Li–Fraumeni; Lynch; Peutz–Jeghers; hereditary breast and ovarian cancer (HBOC); hereditary gynecological cancer; multi-gene testing; syndrome; tumor profiling

DOI:  https://doi.org/10.3390/ijms21249504
Gynecol Oncol. 2020 Dec 09. pii: S0090-8258(20)34162-7. [Epub ahead of print]

Should the risk for uterine cancer influence decision making for prophylactic hysterectomy in BRCA1/2 mutated patients- a systematic review and meta-analysis.

Chen Nahshon, Yakir Segev, Ofer Gemer, Tomer Bar Noy, Meirav Schmidt, Ludmila Ostrovsky, Ofer Lavie.

   OBJECTIVE: To study the possible association between uterine cancer and the BRCA1/2 associated cancer syndrome and discuss the implications of such an association on the clinical managment of patients with BRCA1/2 mutations.
METHODS: A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. Study protocol was prospectively registered at PROSPERO International prospective register of systematic reviews (registration number CRD42020193496). Considered for inclusion were studies providing the diagnosis rate of uterine cancer in patients with BRCA1/2 mutations by comparing observed and expected rate according to a known disease incidence. The results were measured by standardized incidence ratio (SIR). The primary outcome was defined as any uterine cancer diagnosis and subgroup analyses were conducted for uterine serous papillary cancer (USPC) specifically and for BRCA1 and BRCA2 mutations separately.
RESULTS: 4591 records were identified through database search; eight studies were finally included, comprising 13,098 patients with BRCA1/2 mutations. BRCA1/2 mutated patients were found to have a significantly higher risk for uterine cancer compared to the general population (SIR = 2.22, 95% CI 1.76-2.8, p < 0.001). A higher incidence of USPC was also found in patients with BRCA1/2 mutations (SIR = 17.97, 95% CI 9.89-32.66, p < 0.001), as well as in a separate analysis for BRCA1 (SIR = 2.81, 95% CI 2.09-3.79, p < 0.001) and BRCA2 (SIR = 1.75, 95% CI 1.09-2.80, p < 0.001) mutations.
CONCLUSION: Patients who carry a BRCA1/2 mutation are at a significantly higher risk of developing uterine cancer, specifically USPC, supporting that USPC may be a component of the BRCA1/2 syndrome. The decision to perform concurrent hysterectomy at the time of the risk reduction bilateral salpingo -oophorectomy surgery should be considered individually.

Keywords:  BRCA mutation; Endometrial cancer; Hereditary cancer; Prophylactic hysterectomy; Uterine cancer

DOI:  https://doi.org/10.1016/j.ygyno.2020.11.034
Crit Rev Oncol Hematol. 2020 Dec 14. pii: S1040-8428(20)30337-1. [Epub ahead of print] 103201

Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.

Petra Vuković, Fedro Alessandro Peccatori, Claudia Massarotti, Manuel Selvi Miralles, Lidija Beketić-Orešković, Matteo Lambertini.

  The detection of germline BRCA1/2 pathogenic variant has relevant implications for the patients and their family members. Family planning, prophylactic surgery and the possibility of preimplantation genetic testing for monogenic disorders (PGT-M) to avoid transmittance of pathogenic variant to the offspring are the most relevant topics. PGT-M is valuable option for BRCA carriers, but it remains a controversial and underdiscussed topic. Although the advances in PGT technologies have improved pregnancy rate, there are still several important challenges associated with its use. The purpose of this review is to report the current evidence on PGT-M for BRCA1/2 carriers, ethical concerns and controversy associated with its use, reproductive implications of BRCA pathogenic variants, underlying areas in which an educational effort would be beneficial as well as possibilities for future research efforts in the field.

Keywords:  BRCA1/2 pathogenic variants; Fertility preservation; Hereditary breast and ovarian cancer syndrome; Oocytes; Preimplantation genetic testing for monogenic disorders

DOI:  https://doi.org/10.1016/j.critrevonc.2020.103201
Mol Biol Rep. 2020 Dec 12.

BRCA testing delay during the COVID-19 pandemic: How to act?

Angelo Minucci, Giovanni Scambia, Maria De Bonis, Elisa De Paolis, Concetta Santonocito, Anna Fagotti, Ettore Capoluongo, Paola Concolino, Andrea Urbani.

  Recently, our lab, part of a referral center in Italy, reported its experience regarding the execution of germline BRCA1/2 (gBRCA) testing during the first months of the coronavirus disease-2019 (COVID-19) pandemic, which highlights a substantial reduction (about 60%) compared with the first 2 months of the current year. This evidence appeared to be a lockdown effect due to extraordinary restriction measures to slow down the spread of SARS-CoV-2. In this study, we aimed to evaluate the overall effects of the ongoing pandemic on gBRCA testing in our institution and to understand how COVID-19 has influenced testing after the complete lockdown (March 8-May 5, 2020). Additionally, we compared this year's trend with trends of the last 3 years to better monitor gBRCA testing progress. This detailed analysis highlights two important findings: (1) gBRCA testing did not increase significantly after the lockdown period (May-October 2020) compared with the lockdown period (March-April 2020), emphasizing that even after the lockdown period testing remained low. (2) Comparing the total tests per year (January-October 2017, 2018, 2019, with 2020), the impact of COVID-19 on gBRCA testing is apparent, with similarities of trends registered in 2017. These evidences reveal a gBRCA testing delay for cancer patients and healthy patients at this moment, and the new era of gBRCA testing in the management of ovarian, breast, pancreas and prostate cancer patients has been seriously questioned due to the COVID-19 pandemic. As consequence, we underline that measures to guarantee oncogenetic testing (e.g., gBRCA testing) along with new diagnostic/clinic strategies are mandatory. For these reasons, several proposals are presented in this study.

Keywords:  BRCA genes; COVID-19 pandemic in Italy; Coronavirus disease 2019; Germline BRCA testing; Tumor BRCA testing

DOI:  https://doi.org/10.1007/s11033-020-06060-8