bims-lifras 2022-01-23 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–01–23
seventeen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

TP53_PROF: a machine learning model to predict impact of missense mutations in TP53.
Characteristics of TP53 germline variants and their correlation with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients.
Challenges in Interpreting TP53 Pathogenic Variants With a Low Minor Allele Frequency in Germline Genetic Testing: A Case Report of a Patient With Mosaic Li-Fraumeni Syndrome.
Prevalence and Spectrum of Pathogenic Germline Variants in Japanese Patients With Early-Onset Colorectal, Breast, and Prostate Cancer.
Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition.
Precision Prevention: The Current State and Future of Genomically Guided Cancer Prevention.
Population-Based Newborn Screening for Germline TP53 Variants: Clinical Benefits, Cost-Effectiveness, and Value of Further Research.
Whole-Body MRI Surveillance-Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53).
Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy.
Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles.
A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias.
SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor.
No Evidence of Increased Risk of Breast Cancer in Women With Lynch Syndrome Identified by Multigene Panel Testing.
Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.
Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers.
A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma.
Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

Brief Bioinform. 2022 Jan 18. pii: bbab524. [Epub ahead of print]

TP53_PROF: a machine learning model to predict impact of missense mutations in TP53.

Gil Ben-Cohen, Flora Doffe, Michal Devir, Bernard Leroy, Thierry Soussi, Shai Rosenberg.

  Correctly identifying the true driver mutations in a patient's tumor is a major challenge in precision oncology. Most efforts address frequent mutations, leaving medium- and low-frequency variants mostly unaddressed. For TP53, this identification is crucial for both somatic and germline mutations, with the latter associated with the Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition. We present TP53_PROF (prediction of functionality), a gene specific machine learning model to predict the functional consequences of every possible missense mutation in TP53, integrating human cell- and yeast-based functional assays scores along with computational scores. Variants were labeled for the training set using well-defined criteria of prevalence in four cancer genomics databases. The model's predictions provided accuracy of 96.5%. They were validated experimentally, and were compared to population data, LFS datasets, ClinVar annotations and to TCGA survival data. Very high accuracy was shown through all methods of validation. TP53_PROF allows accurate classification of TP53 missense mutations applicable for clinical practice. Our gene specific approach integrated machine learning, highly reliable features and biological knowledge, to create an unprecedented, thoroughly validated and clinically oriented classification model. This approach currently addresses TP53 mutations and will be applied in the future to other important cancer genes.

Keywords:   TP53 ; Li-Fraumeni syndrome; genetic counseling; machine learning; personalized oncology; precision medicine

DOI:  https://doi.org/10.1093/bib/bbab524
J Genet Genomics. 2022 Jan 13. pii: S1673-8527(22)00003-0. [Epub ahead of print]

Characteristics of TP53 germline variants and their correlation with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome in Chinese tumor patients.

Panwen Tian, Xiaoyan Zhang, Sheng Yang, Yu Fang, Hongling Yuan, Wei Li, Honglin Zhu, Fangping Zhao, Jinlei Ding, Yunshu Zhu, Sizhen Wang, Guochen Sun, Hongbin Ni, Tonghui Ma, Ting Lei.

  Li-Fraumeni syndrome (LFS), a rare autosomal-dominant inheritance condition, is associated with a family cancer history as well as pathogenic/likely-pathogenic TP53 germline variants (P/LP TP53 GV). The current clinical methods for detecting LFS are limited. Here, we retrospectively investigate P/LP TP53 GV among Chinese cancer patients by next-generation sequencing and evaluate its relationship with a family cancer history. A total of 270 out of 19,226 cancer patients had TP53 GV, including 53 patients with P/LP TP53 GV. Patients with P/LP TP53 GV were mainly found in male with glioma, lung cancer or sarcoma. The median age of diagnosis for P/LP TP53 GV patients was significantly lower than that of non-P/LP TP53 GV patients (31-years vs. 53-years; P < 0.01). One LFS patient and three Li-Fraumeni-like syndrome (LFL) patients were among the 26 followed-up P/LP TP53 GV patients. Among 25 types of P/LP TP53 GV, the highest variant frequencies occurred at codon 175 and 248. p.M237I, p.R158H, p.C238Y and p.C275R, were firstly identified among the Chinese LFS/LFL patients. This is the first cohort report of (P/LP) TP53 GV characteristics of Chinese pan-cancer patients. These findings suggest analyzing the P/LP TP53 GV in cancer patients is an effective strategy for identifying cancer predisposition syndrome.

Keywords:  Li-Fraumeni Syndrome; TP53 germline variants

DOI:  https://doi.org/10.1016/j.jgg.2021.12.012
JCO Precis Oncol. 2020 Nov;4 91-95

Challenges in Interpreting TP53 Pathogenic Variants With a Low Minor Allele Frequency in Germline Genetic Testing: A Case Report of a Patient With Mosaic Li-Fraumeni Syndrome.

Ellie G Peacock, Lindsey M Grenon, Felipe Batalini, Nadine Tung.

DOI: https://doi.org/10.1200/PO.19.00279
JCO Precis Oncol. 2020 Nov;4 183-191

Prevalence and Spectrum of Pathogenic Germline Variants in Japanese Patients With Early-Onset Colorectal, Breast, and Prostate Cancer.

Xiaoxi Liu, Sadaaki Takata, Kyota Ashikawa, Tomomi Aoi, Shunichi Kosugi, Chikashi Terao, Nicholas F Parrish, Koichi Matsuda, Hidewaki Nakagawa, Yoichiro Kamatani, Michiaki Kubo, Yukihide Momozawa.

PUPOSE: We investigated the prevalence and spectrum of pathogenic germline variants in patients with early-onset colorectal cancer (CRC), breast cancer (BC), and prostate cancer (PCA) in the Japanese population. We also identified pathogenic variants in other cancer risk genes, giving consideration to future multigene testing panels for this population.
METHODS: We performed whole-genome sequencing for 1,037 Japanese individuals, including patients with early-onset CRC (n = 196), BC (n = 237), and PCA (n = 215) and controls (n = 389). We screened for pathogenic variants, including single nucleotide variants and copy number variants, among well-established first-tier cancer genes for each cancer type and examined an expended second-tier panel including cancer-predisposing genes from the Cancer Gene Census.
RESULTS: Proportions of patients with germline pathogenic variants differed by cancer subgroup, with the highest in BC (14.8%), followed by CRC (9.2%), and PCA (3.7%). In contrast, 2 of 389 control subjects (0.5%) carried a germline pathogenic variant. In comparison with controls, the proportion of patients with pathogenic variants in the second-tier panel was increased significantly for PCA (3.7% to 11.6%, P = 2.96 × 10-4), but not for CRC or BC, after multitesting adjustment. In patients with PCA, DNA repair pathway genes in the extended panel often contained pathogenic variants (P = .011).
CONCLUSION: Our analyses support the clinical usefulness of established cancer gene panels in the Japanese population for 3 major cancer types. Additional genes, especially those involved in DNA repair, might be considered for developing multipanel testing in Japanese patients with early-onset PCA.

DOI: https://doi.org/10.1200/PO.19.00224
Life (Basel). 2021 Dec 29. pii: 46. [Epub ahead of print]12(1):

Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition.

Juehua Gao, Yihua Chen, Madina Sukhanova.

  Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization's classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms-mainly acute myeloid leukemia and myelodysplastic syndrome. Although the incidence of myeloid neoplasms with germline predisposition remains poorly defined, these cases provide unique and important insights into the biology and molecular mechanisms of myeloid neoplasms. Knowledge of the regulation of the germline genes and their interactions with other genes, proteins, and the environment, the penetrance and clinical presentation of inherited mutations, and the longitudinal dynamics during the process of disease progression offer models and tools that can further our understanding of myeloid neoplasms. This knowledge will eventually translate to improved disease sub-classification, risk assessment, and development of more effective therapy. In this review, we will use examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms.

Keywords:  germline predisposition; myeloid neoplasm; pathways

DOI:  https://doi.org/10.3390/life12010046
JCO Precis Oncol. 2020 Nov;4 96-108

Precision Prevention: The Current State and Future of Genomically Guided Cancer Prevention.

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

The identification of cancer-predisposing germline variants has potentially substantial clinical impact for patients and their families. Although management guidelines have been proposed for some genes, guidelines for other genes are lacking. This review focuses on the current surveillance and management guidelines for the most common hereditary cancer syndromes and discusses some of the most pivotal studies supporting the available guidelines. We also highlight the gaps in the identification of germline carriers, the cascade testing of at-risk relatives, and the challenges impeding the proper follow-up and optimal management of pathogenic germline carriers. The anticipated surge in the number of identified germline carriers, deficient management guidelines, poor cascade testing uptake, and long-term follow-up necessitate the development of multidisciplinary clinics as an obligatory step toward the improvement of cancer prevention.

DOI: https://doi.org/10.1200/PO.19.00278
J Natl Cancer Inst. 2022 Jan 19. pii: djac013. [Epub ahead of print]

Population-Based Newborn Screening for Germline TP53 Variants: Clinical Benefits, Cost-Effectiveness, and Value of Further Research.

Natalia Kunst, Natasha K Stout, Grace O'Brien, Kurt D Christensen, Pamela M McMahon, Ann Chen Wu, Lisa Diller, Jennifer M Yeh.

BACKGROUND: Identification of children and infants with Li-Fraumeni syndrome (LFS) prompts tumor surveillance and allows potential early cancer detection. We assessed the clinical benefits and cost-effectiveness of population-wide newborn screening for TP53 variants (TP53-NBS).
METHODS: We simulated the impact of TP53-NBS using data regarding TP53-associated pediatric cancers and pathogenic or likely pathogenic (P/LP) TP53 variants from SEER, ClinVar and gnomAD and clinical studies. We simulated an annual US birth cohort under usual care and TP53-NBS and estimated clinical benefits, life years and costs associated with usual care and TP53-NBS.
RESULTS: Under usual care, out of 4 million newborns, 608 individuals (Uncertainty Interval [UI] = 581-636) would develop TP53-associated cancers before age 20 years. Under TP53-NBS, 894 individuals would have P/LP TP53 variants detected. These individuals would undergo routine surveillance after detection of P/LP TP53 variants decreasing the number of cancer-related deaths by 7.2% overall (UI = 4.0-12.1%) via early malignancy detection. Compared to usual care, TP53-NBS had an incremental cost-effectiveness ratio of $106,009 per life-year gained. Probabilistic analysis estimated a 40% probability that TP53-NBS would be cost-effective given a $100,000 per-life-year-gained willingness-to-pay threshold. Using this threshold, a value-of-information analysis found that additional research on the prevalence of TP53 variants among rhabdomyosarcoma cases would resolve most of the decision uncertainty, resulting in an expected benefit of 349 life-years gained (or $36.6 million).
CONCLUSIONS: While we found that TP53-NBS could be cost-effective, our findings suggest that further research is needed to reduce the uncertainty in the potential health outcomes and costs associated with TP53-NBS.

DOI: https://doi.org/10.1093/jnci/djac013
Cancers (Basel). 2022 Jan 13. pii: 380. [Epub ahead of print]14(2):

Whole-Body MRI Surveillance-Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53).

Meis Omran, Emma Tham, Yvonne Brandberg, Håkan Ahlström, Claudia Lundgren, Ylva Paulsson-Karlsson, Ekaterina Kuchinskaya, Gustav Silander, Anna Rosén, Fredrik Persson, Henrik Leonhardt, Marie Stenmark-Askmalm, Johanna Berg, Danielle van Westen, Svetlana Bajalica-Lagercrantz, Lennart Blomqvist, On Behalf Of The Swedish Clinical Tp Study Group SweClinTP.

  A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li-Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.

Keywords:  Li–Fraumeni; MRI screening; cancer; cancer prevention; clinically actionable TP53 variant; germline TP53; hTP53rc syndrome; hereditary breast cancer; hereditary cancer syndrome; surveillance program; whole-body MRI

DOI:  https://doi.org/10.3390/cancers14020380
JCO Precis Oncol. 2020 Nov;4 1109-1121

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy.

Bryan P Schneider, Leigh Anne Stout, Santosh Philips, Courtney Schroeder, Susanna F Scott, Cynthia Hunter, Nawal Kassem, Patrick J Kiel, Milan Radovich.

PURPOSE: Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action.
PATIENTS AND METHODS: A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters.
RESULTS: Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity.
CONCLUSION: The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

DOI: https://doi.org/10.1200/PO.19.00354
J Transl Med. 2022 Jan 15. 20(1): 29

Incidental germline findings during molecular profiling of tumor tissues for precision oncology: molecular survey and methodological obstacles.

Alexandra Lebedeva, Yulia Shaykhutdinova, Daria Seriak, Ekaterina Ignatova, Ekaterina Rozhavskaya, Divyasphoorthi Vardhan, Sofia Manicka, Margarita Sharova, Tatiana Grigoreva, Ancha Baranova, Vladislav Mileyko, Maxim Ivanov.

BACKGROUND: A fraction of patients referred for complex molecular profiling of biopsied tumors may harbor germline variants in genes associated with the development of hereditary cancer syndromes (HCS). Neither the bioinformatic analysis nor the reporting of such incidental germline findings are standardized.
METHODS: Data from Next-Generation Sequencing (NGS) of biopsied tumor samples referred for complex molecular profiling were analyzed for germline variants in HCS-associated genes. Analysis of variant origin was performed employing bioinformatic algorithms followed by manual curation. When possible, the origin of the variant was validated by Sanger sequencing of the sample of normal tissue. The variants' pathogenicity was assessed according to ACMG/AMP.
RESULTS: Tumors were sampled from 183 patients (Males: 75 [41.0%]; Females: 108 [59.0%]; mean [SD] age, 57.7 [13.3] years) and analysed by targeted NGS. The most common tumor types were colorectal (19%), pancreatic (13%), and lung cancer (10%). A total of 56 sequence variants in genes associated with HCS were detected in 40 patients. Of them, 17 variants found in 14 patients were predicted to be of germline origin, with 6 variants interpreted as pathogenic (PV) or likely pathogenic (LPV), and 9 as variants of uncertain significance (VUS). For the 41 out of 42 (97%) missense variants in HCS-associated genes, the results of computational prediction of variant origin were concordant with that of experimental examination. We estimate that Sanger sequencing of a sample of normal tissue would be required for ~ 1-7% of the total assessed cases with PV or LPV, when necessity to follow with genetic counselling referral in ~ 2-15% of total assessed cases (PV, LPV or VUS found in HCS genes).
CONCLUSION: Incidental findings of pathogenic germline variants are common in data from cancer patients referred for complex molecular profiling. We propose an algorithm for the management of patients with newly detected variants in genes associated with HCS.

DOI: https://doi.org/10.1186/s12967-022-03230-z
Genet Med. 2022 Jan 18. pii: S1098-3600(21)05467-8. [Epub ahead of print]

A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias.

Simone Feurstein, Christopher N Hahn, Nikita Mehta, Lucy A Godley.

   PURPOSE: The American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible.
METHODS: We have used a variety of methods such as calculations of minor allele frequencies, quasi-case-control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation.
RESULTS: We herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity.
CONCLUSION: These guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation.

Keywords:  ACMG/AMP criteria; Bone marrow failure; Cytopenia; Germline variant curation; Hematopoietic malignancies

DOI:  https://doi.org/10.1016/j.gim.2021.12.008
Front Oncol. 2021 ;11 778461

SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor.

Maria A Pantaleo, Milena Urbini, Angela Schipani, Margherita Nannini, Valentina Indio, Antonio De Leo, Bruno Vincenzi, Antonella Brunello, Giovanni Grignani, Mariaelena Casagrande, Elena Fumagalli, Elena Conca, Maristella Saponara, Elisa Gruppioni, Annalisa Altimari, Dario De Biase, Giovanni Tallini, Gloria Ravegnini, Daniela Turchetti, Marco Seri, Andrea Ardizzoni, Paola Secchiero, Annalisa Astolfi.

   Background: SDH-deficient gastrointestinal stromal tumors (GIST) account for 20-40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent. Here we sought to evaluate the presence and prevalence of SDHA variants in the germline lineage in a population of SDHA-deficient GIST.
Methods: Germline SDHA status was assessed by Sanger sequencing on a series of 14 patients with gastric SDHA-deficient GIST.
Results: All patients carried a germline SDHA pathogenic variant, ranging from truncating, missense, or splicing variants. The second hit was the loss of the wild-type allele or an additional somatic mutation. One-third of the patients were over 50 years old. GIST was the only disease presentation in all cases except one, with no personal or familial cancer history. Seven metastatic cases received a multimodal treatment integrating surgery, loco-regional and medical therapy. The mean follow-up time was of 10 years, confirming the indolent clinical course of the disease.
Conclusion: SDHA germline variants are highly frequent in SDHA-deficient GIST, and the disease may occur also in older adulthood. Genetic testing and surveillance of SDHA-mutation carriers and relatives should be performed.

Keywords:  CSS: Carney-Stratakis syndrome; CT: Carney Triad; SDH-deficient GIST; SDHA; SDHA germinal mutations; gastrointestinal stromal tumors

DOI:  https://doi.org/10.3389/fonc.2021.778461
JCO Precis Oncol. 2020 Nov;4 51-60

No Evidence of Increased Risk of Breast Cancer in Women With Lynch Syndrome Identified by Multigene Panel Testing.

Jessica Stoll, Eric Rosenthal, Shelly Cummings, Jamie Willmott, Ryan Bernhisel, Sonia S Kupfer.

PURPOSE: Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing.
METHODS: MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication.
RESULTS: In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30).
CONCLUSION: In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS.

DOI: https://doi.org/10.1200/PO.19.00271
Eur J Cancer. 2022 Jan 12. pii: S0959-8049(21)01304-6. [Epub ahead of print]163 44-54

Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment.

Marika Sculco, Marta La Vecchia, Anna Aspesi, Giulia Pinton, Michela G Clavenna, Elisabetta Casalone, Alessandra Allione, Federica Grosso, Roberta Libener, Alberto Muzio, Ottavio Rena, Guido Baietto, Sara Parini, Renzo Boldorini, Daniela Giachino, Mauro Papotti, Giorgio V Scagliotti, Enrica Migliore, Dario Mirabelli, Laura Moro, Corrado Magnani, Daniela Ferrante, Giuseppe Matullo, Irma Dianzani.

   INTRODUCTION: Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.
AIM: This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.
METHODS: NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.
RESULTS: We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).
CONCLUSIONS: Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.

Keywords:  DNA repair genes; Germline variants; Mesothelioma; Synthetic lethality; Tazemetostat

DOI:  https://doi.org/10.1016/j.ejca.2021.12.023
Cancers (Basel). 2022 Jan 12. pii: 365. [Epub ahead of print]14(2):

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers.

Antonella Turchiano, Daria Carmela Loconte, Rosalba De Nola, Francesca Arezzo, Giulia Chiarello, Antonino Pantaleo, Matteo Iacoviello, Rosanna Bagnulo, Annunziata De Luisi, Sonia Perrelli, Stefania Martino, Carlotta Ranieri, Antonella Garganese, Alessandro Stella, Cinzia Forleo, Vera Loizzi, Marco Marinaccio, Ettore Cicinelli, Gennaro Cormio, Nicoletta Resta.

   BACKGROUND: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice.
METHODS: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing.
RESULTS: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively.
CONCLUSION: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

Keywords:  BRCA1/2; HHR genes; PARPi; ovarian cancer; target resequencing

DOI:  https://doi.org/10.3390/cancers14020365
Hum Genome Var. 2022 Jan 17. 9(1): 3

A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma.

Yasuto Yagi, Naoko Abeto, Junichi Shiraishi, Chieko Miyata, Satomi Inoue, Haruka Murakami, Moeko Nakashima, Kokichi Sugano, Mineko Ushiama, Teruhiko Yoshida, Kazuki Yamazawa.

Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH, NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.

DOI: https://doi.org/10.1038/s41439-021-00180-8
Cancer Treat Rev. 2022 Jan 05. pii: S0305-7372(21)00185-7. [Epub ahead of print]104 102337

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

Shreya M Shah, Elena V Demidova, Randy W Lesh, Michael J Hall, Mary B Daly, Joshua E Meyer, Martin J Edelman, Sanjeevani Arora.

  DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.

Keywords:  DNA repair; Germline; Immune checkpoint inhibitors; PARP inhibitors; Precision oncology; Therapeutic response

DOI:  https://doi.org/10.1016/j.ctrv.2021.102337