bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–02–19
sixteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53).
  2. Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies.
  3. Introduction to a review series on germline predisposition to hematologic malignancy: Time to consider germline testing.
  4. Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.
  5. Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.
  6. Fumarate Hydratase Variants and their Association with Paraganglioma/Pheochromocytoma.
  7. Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome.
  8. BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
  9. Clinical Factors Associated with Skin Neoplasms in Individuals with Lynch Syndrome in a Longitudinal Observational Cohort.
  10. The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.
  11. Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas.
  12. Two germline mutations can serve as genetic susceptibility screening makers for a lung adenocarcinoma family.
  13. Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
  14. European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.
  15. Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
  16. Cancer surveillance for patients with Li-Fraumeni Syndrome in Brazil: A cost-effectiveness analysis.
  1. Breast. 2023 Feb 07. pii: S0960-9776(23)00025-5. [Epub ahead of print]68 157-162
    A matched case-control study of the prognosis of early breast cancer in patients with Li-Fraumeni syndrome (BREAST TP53).
    Vanessa Petry, Renata Colombo Bonadio, Laura Testa, Daniela Jbh Cohn, Allyne Cagnacci, Roberta G Campos, Maria Cândida Bv Fragoso, Maria Del Pilar Estevez-Diz.
       INTRODUCTION: Breast cancer (BC) is the most common type of cancer in premenopausal women with germline TP53 pathogenic variants (mTP53) (Li Fraumeni syndrome - LFS). However, little is known about the BC prognosis in these patients. This study analyzed the BC-related oncologic outcomes of patients with LFS.
    METHODS: We evaluated a cohort of LFS patients with BC in comparison with a control cohort of BC patients with no pathogenic variant in a hereditary cancer panel. The primary endpoint was recurrence-free survival (RFS). Due to the risk of second malignancies in LFS, only locoregional and distant recurrences were considered events for RFS. Secondary endpoints included rates of contralateral BC, overall survival (OS), and breast cancer-specific survival (BCSS).
    RESULTS: Forty-one patients were evaluated in the mTP53 group and 82 in the control group. Median age at BC diagnosis was 40 and 41 years, respectively. The mTP53 group received less adjuvant radiotherapy than the control group (63.4% vs 93.9%, P < 0.001). Other relevant baseline characteristics and treatment received were similar between groups. 5y-RFS rates were 79.4% in the mTP53 versus 93.6% in the control group (HR 2.43, 95%CI 0.74-8.01, P = 0.143); and were not impacted by the use of adjuvant radiotherapy. 5y-BCSS rates were 92.2% and 98.6%, respectively (HR 1.87, IC95% 0.25-13.48, P = 0.534).
    CONCLUSIONS: Our results showed no statistically significant difference in BC-related RFS and BCSS between patients with mTP53 and a control group with no pathogenic variant. Larger multicentric studies are warranted to confirm these results.
    Keywords:  Breast cancer; Hereditary; Li Fraumeni syndrome; Phenotype; TP53
    DOI:  https://doi.org/10.1016/j.breast.2023.02.002
  2. Front Oncol. 2023 ;13 1084736
    Prioritization of patients for germline testing based on tumor profiling of hematopoietic malignancies.
    Lucy A Godley.
      Germline predisposition to hematopoietic malignancies is more common than previously appreciated, with several clinical guidelines advocating for cancer risk testing in an expanding pool of patients. As molecular profiling of tumor cells becomes a standard practice for prognostication and defining options for targeted therapies, recognition that germline variants are present in all cells and can be identified by such testing becomes paramount. Although not to be substituted for proper germline cancer risk testing, tumor-based profiling can help prioritize DNA variants likely to be of germline origin, especially when they are present on sequential samples and persist into remission. Performing germline genetic testing as early during patient work-up as possible allows time to plan allogeneic stem cell transplantation using appropriate donors and optimize post-transplant prophylaxis. Health care providers need to be attentive to the differences between molecular profiling of tumor cells and germline genetic testing regarding ideal sample types, platform designs, capabilities, and limitations, to allow testing data to be interpreted as comprehensively as possible. The myriad of mutation types and growing number of genes involved in germline predisposition to hematopoietic malignancies makes reliance on detection of deleterious alleles using tumor-based testing alone very difficult and makes understanding how to ensure adequate testing of appropriate patients paramount.
    Keywords:  cancer risk; germline predisposition; hematopoietic malignancies; molecular profiling; tumor profiling
    DOI:  https://doi.org/10.3389/fonc.2023.1084736
  3. Blood. 2023 Feb 14. pii: blood.2023019846. [Epub ahead of print]
    Introduction to a review series on germline predisposition to hematologic malignancy: Time to consider germline testing.
    Mario Cazzola.
      
    DOI:  https://doi.org/10.1182/blood.2023019846
  4. Clin Lung Cancer. 2023 Jan 26. pii: S1525-7304(23)00009-8. [Epub ahead of print]
    Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.
    Andrew S Rifkin, Ethan M Less, Jun Wei, Zhuqing Shi, Siqun Lilly Zheng, Brian T Helfand, Peter J Hulick, Seth B Krantz, Jianfeng Xu.
       INTRODUCTION/BACKGROUND: Published studies on association of germline monogenic genes and lung cancer risk were inconsistent. Our objective is to assess the validity of reported candidate monogenic genes for their association with lung cancer.
    MATERIALS AND METHODS: A systematic review of published papers prior to August 2022 was performed first to identify all genes where germline mutations were associated with lung cancer risk. We then performed a confirmation study in 2,050 lung cancer cases and 198,553 controls in the UK Biobank (UKB). Germline mutations of these genes were identified from sequencing data and annotated using The American College of Medical Genetics criteria. The robust SKAT-O, a gene-based analysis that properly controls for false positives due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, and genetic background.
    RESULTS: The systematic review identified 12 genes that were statistically significantly associated with lung cancer risk in at least one study (P < .05), including ATM, BLM, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, MSH6, PMS1, RAD51C, RAD51D, and TP53. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for ATM (P = 4.47E-4) at the study-wise significance level (P < .0042, Bonferroni correction for 12 tests). Suggestive evidence of association was found for 2 other genes, BRCA2 (P = .007) and TP53 (P = .03). Among these 3 genes, the lung cancer risks range from 1.95 (BRCA2) to 5.28 (TP53).
    CONCLUSION: This study provides statistical evidence for association of previously reported genes and lung cancer risk and has clinical utility for risk assessment and genetic counseling.
    Keywords:  Germline; Lung cancer; Monogenic gene; Pathogenic mutations; Risk
    DOI:  https://doi.org/10.1016/j.cllc.2023.01.005
  5. Gastro Hep Adv. 2023 ;2(2): 244-251
    Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.
    Monica Passi, Lauren A Gamble, Sarah G Samaranayake, Samuel A Schueler, Bryan F Curtin, Grace-Ann Fasaye, Cassidy Bowden, Sandeep Gurram, Martha Quezado, Markku Miettinen, Christopher Koh, Theo Heller, Jeremy L Davis.
       Background and Aims: Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown.
    Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated.
    Results: Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps.
    Conclusions: In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.
    Keywords:  CDH1; cancer screening; colon polyps; colorectal cancer; hereditary diffuse gastric cancer
    DOI:  https://doi.org/10.1016/j.gastha.2022.10.006
  6. Urology. 2023 Feb 09. pii: S0090-4295(23)00054-7. [Epub ahead of print]
    Fumarate Hydratase Variants and their Association with Paraganglioma/Pheochromocytoma.
    Shirin Zavoshi, Eric Lu, Paul C Boutros, Liying Zhang, Avital Harari, Kathryn E Hatchell, Sarah M Nielsen, Edward D Esplin, Karen Ouyang, Keith Nykamp, Blake Wilde, Heather Christofk, Brian Shuch.
       OBJECTIVE: To clarify the link between germline variants in fumarate hydratase (FH), hereditary leiomyomatosis and renal cell cancer (HLRCC), and paraganglioma (PGL) and pheochromocytoma (PCC) we utilize a well-annotated hereditary cancer testing database.
    METHODS: Records of 120,061 patients receiving germline testing were obtained. FH variants were classified into four categories: autosomal dominant (AD) HLRCC variants, autosomal recessive (AR) fumarase deficiency (FMRD), variants, previously reported as PGL/PCC FH variants, and variants of unknown significance (VUS) not previously associated with PGL/PCC (NPP-VUS). Rates of PGL/PCC were compared with those with negative genetic testing.
    RESULTS: 1.3% of individuals carried FH variants which were more common among individuals with PGL/PCC compared to those without (3.1% vs. 1.3%, p < 0.0001). PGL/PCC rates were higher among individuals with PGL/PCC FH variants compared to those with negative genetic testing (22.2% vs. 0.9%, p < 0.0001). Neither AD HLRCC variants (0.3% vs. 0.9%, p = 0.35) nor AR FMRD variants (1.4% vs. 0.9%, p=0.19) carried an increased prevalence of PGL/PCC. An increased prevalence of PGL/PCC was detected in those with NPP-VUS (2.0% vs. 0.9%, p =0.0023).
    CONCLUSIONS: Certain FH variants confer an increased risk of PGL/PCC, but not necessarily HLRCC. While universal screening for PGL/PCC among all individuals with FH variants does not appear warranted, it should be considered in select high-risk PGL/PCC FH variants.
    Keywords:  Fumarate Hydratase; Paraganglioma; Pheochromocytoma
    DOI:  https://doi.org/10.1016/j.urology.2022.11.053
  7. Front Oncol. 2023 ;13 1069467
    Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome.
    Shujuan Pan, Hannah Cox, Jamie Willmott, Erin Mundt, Heidi Gorringe, Michelle Landon, Karla R Bowles, Bradford Coffee, Benjamin B Roa, Debora Mancini-DiNardo.
       Background and Aims: Tumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC.
    Methods: We assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results.
    Results: The PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic.
    Conclusions: Among patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification.
    Keywords:  IHC – immunohistochemistry; cancer diagnosis; clinical genetic testing; hereditary cancer syndrome; universal tumor screening
    DOI:  https://doi.org/10.3389/fonc.2023.1069467
  8. bioRxiv. 2023 Feb 03. pii: 2023.01.31.525066. [Epub ahead of print]
    BARD1 germline variants induce haploinsufficiency and DNA repair defects in neuroblastoma.
    Michael P Randall, Laura E Egolf, Zalman Vaksman, Minu Samanta, Matthew Tsang, David Groff, J Perry Evans, Jo Lynne Rokita, Mehdi Layeghifard, Adam Shlien, John M Maris, Sharon J Diskin, Kristopher R Bosse.
       Importance: High-risk neuroblastoma is a complex genetic disease that is lethal in 50% of patients despite intense multimodal therapy. Our genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) within the BARD1 gene showing the most significant enrichment in neuroblastoma patients, and also discovered pathogenic (P) or likely pathogenic (LP) rare germline loss-of-function variants in this gene. The functional implications of these findings remain poorly understood.
    Objective: To define the functional relevance of BARD1 germline variation in children with neuroblastoma.
    Design: We correlated BARD1 genotype with BARD1 expression in normal and tumor cells and the cellular burden of DNA damage in tumors. To validate the functional consequences of rare germline P-LP BARD1 variants, we generated isogenic cellular models harboring heterozygous BARD1 loss-of-function (LOF) variants and conducted multiple complementary assays to measure the efficiency of DNA repair.
    Setting: (N/A).
    Participants: (N/A).
    Interventions/Exposures: (N/A).
    Main Outcomes and Measures: BARD1 expression, efficiency of DNA repair, and genome-wide burden of DNA damage in neuroblastoma tumors and cellular models harboring disease-associated BARD1 germline variants.
    Results: Both common and rare neuroblastoma associated BARD1 germline variants were significantly associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using neuroblastoma cellular models engineered to harbor disease-associated heterozygous BARD1 LOF variants, we functionally validated this association with inefficient DNA repair. These BARD1 LOF variant isogenic models exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA doublestrand break sites, and enhanced sensitivity to cisplatin and poly-ADP ribose polymerase (PARP) inhibition.
    Conclusions and Relevance: Considering that at least 1 in 10 children diagnosed with cancer carry a predicted pathogenic mutation in a cancer predisposition gene, it is critically important to understand their functional relevance. Here, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications, and these findings may also extend to other cancers harboring germline variants in genes essential for DNA damage repair.
    Key Points: Question: How do neuroblastoma patient BRCA1-associated RING domain 1 ( BARD1 ) germline variants impact DNA repair? Findings: Neuroblastoma-associated germline BARD1 variants disrupt DNA repair fidelity. Common risk variants correlate with decreased BARD1 expression and increased DNA double-strand breaks in neuroblastoma tumors and rare heterozygous loss-of-function variants induce BARD1 haploinsufficiency, resulting in defective DNA repair and genomic instability in neuroblastoma cellular models. Meaning: Germline variation in BARD1 contributes to neuroblastoma pathogenesis via dysregulation of critical cellular DNA repair functions, with implications for neuroblastoma treatment, risk stratification, and cancer predisposition.
    DOI:  https://doi.org/10.1101/2023.01.31.525066
  9. J Am Acad Dermatol. 2023 Feb 09. pii: S0190-9622(23)00173-1. [Epub ahead of print]
    Clinical Factors Associated with Skin Neoplasms in Individuals with Lynch Syndrome in a Longitudinal Observational Cohort.
    Connie S Zhong, Miki Horiguchi, Hajime Uno, Chinedu Ukaegbu, Anu Chittenden, Nicole R LeBoeuf, Sapna Syngal, Vinod E Nambudiri, Matthew B Yurgelun.
       BACKGROUND: Little is known about patient-specific risk factors for skin neoplasia in individuals with Lynch Syndrome (LS).
    OBJECTIVE: Identify clinical factors associated with development of skin neoplasms in LS.
    METHODS: Clinical data were systematically collected on a cohort of LS carriers (confirmed pathogenic germline variants [PGVs] in MLH1, MSH2, MSH6, PMS2, or EPCAM) age ≥18 undergoing clinical genetics care at Dana-Farber Cancer Institute from 1/2000-3/2020. Multivariable logistic regression was performed to evaluate clinical factors associated with skin neoplasia.
    RESULTS: Of 607 LS carriers, 9.2% had LS-associated skin neoplasia and 15.0% had non-LS-associated skin neoplasia. 58.2% (353/607) had documentation of prior dermatologic evaluation. 29.7% (38/128) with skin neoplasms lacked a history of visceral LS-associated malignancy. LS-associated skin neoplasms were significantly associated with male sex, age, race, MLH1 PGVs, MSH2/EPCAM PGVs, and personal history of non-LS skin neoplasms. Non-LS-associated skin neoplasms was significantly associated with age, number of first- and second-degree relatives with non-LS-associated skin neoplasms, and personal history of LS-associated skin neoplasms.
    LIMITATIONS: Single-institution observational study; demographic homogeneity.
    CONCLUSIONS: Skin neoplasms are common in individuals with LS. We identified clinical factors associated with LS- and non-LS-associated skin neoplasms. Regular dermatologic surveillance should be considered for all LS carriers.
    Keywords:  HNPCC; Muir-Torre syndrome; hereditary; keratoacanthoma; sebaceous
    DOI:  https://doi.org/10.1016/j.jaad.2023.01.035
  10. Am J Cancer Res. 2023 ;13(1): 236-244
    The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.
    Thomas Scharnitz, Mio Nakamura, Erika Koeppe, Marie-Louise Henry, Lori Lowe, Tobias Else, Kelly B Cha.
      Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.
    Keywords:  Hereditary leiomyomatosis and renal cell cancer; cutaneous leiomyoma; cutaneous leiomyosarcoma; fumarate hydratase; genetic variants; reed syndrome; renal cell cancer; uterine leiomyoma
  11. Am J Hum Genet. 2023 Feb 08. pii: S0002-9297(23)00009-5. [Epub ahead of print]
    Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas.
    Niko Välimäki, Vilja Jokinen, Tatiana Cajuso, Heli Kuisma, Aurora Taira, Olivia Dagnaud, Sini Ilves, Jaana Kaukomaa, Annukka Pasanen, Kimmo Palin, Oskari Heikinheimo, Ralf Bützow, Lauri A Aaltonen, Auli Karhu.
      Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.
    Keywords:  H2A.Z histone variant; SRCAP complex; UK Biobank; germline mutation; inherited mutation; medical genetics; next-generation sequencing; predisposition; tumor genetics; uterine leiomyoma
    DOI:  https://doi.org/10.1016/j.ajhg.2023.01.009
  12. J Cancer Res Clin Oncol. 2023 Feb 13.
    Two germline mutations can serve as genetic susceptibility screening makers for a lung adenocarcinoma family.
    Ning Xiao, Xiaoqing Cao, Zhidong Liu, Yi Han.
       OBJECTIVES: Lung cancer is the most common form of cancer and the leading cause of cancer death. For familial lung cancer, identification of causing genetic factors is essential for prevention and control of non-lung cancer in carriers.
    MATERIALS AND METHODS: We studied two generations of a family with suspected inherited lung cancer susceptibility. Four individuals in this family had lung adenocarcinoma. To identify the gene(s) that cause the lung cancer in this pedigree, we extracted DNA from the peripheral blood of four cancer individuals and blood from three cancer-free family members as the control and performed whole-genome sequencing. Our filtering strategy includes, assessment of allele frequency, functional affection on amino acids, mutation accumulation, phased blocks and evolution analysis towards the alterations.
    RESULTS: We identified two possible mutations, including PLEKHM2 (D134N) and MCC (R448Q) in all affected family members but did not found in the control group. Then, we performed a genetic susceptibility screening for 10 non-lung cancer relatives and found two individuals with PLEKHM2 (D134N) mutation, two with MCC (R448Q) mutation and one carrying both mutations. 3 carriers performed LDCT scan and 2 of them carried MCC (R448Q) also had ground-glass opacity (GGO) lesion in their lung.
    CONCLUSION: Our data suggested that WGS together with our filtering strategy was successful in identifying PLEKHM2 (D134N) and MCC (R448Q) as the possible driver mutations in this family. Genetic susceptibility screening of non-lung cancer carriers will be a useful approach to prevent and control lung cancer in families with high-risk for the disease.
    Keywords:  Genetic susceptibility; Germline mutations; Lung adenocarcinoma
    DOI:  https://doi.org/10.1007/s00432-023-04616-2
  13. Br J Haematol. 2023 Feb 14.
    Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Clinical Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
    Andrew Clark, Sally Thomas, Angela Hamblin, Polly Talley, Austin Kulasekararaj, Jacob Grinfeld, Beverley Speight, Katie Snape, Terri P McVeigh, John A Snowden.
      Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT).
    Keywords:  BMT; Leukaemia; germline cancer predisposition; transplant donor selection
    DOI:  https://doi.org/10.1111/bjh.18682
  14. Eur J Med Genet. 2023 Feb 10. pii: S1769-7212(23)00033-2. [Epub ahead of print] 104727
    European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.
    Alisa Förster, Claudia Davenport, Nicolas Duployez, Miriam Erlacher, Alina Ferster, Jude Fitzgibbon, Gudrun Göhring, Henrik Hasle, Marjolijn C Jongmans, Alexandra Kolenova, Geertruijte Kronnie, Tim Lammens, Cristina Mecucci, Wojciech Mlynarski, Charlotte M Niemeyer, Francesc Sole, Tomasz Szczepanski, Esmé Waanders, Andrea Biondi, Marcin Wlodarski, Brigitte Schlegelberger, Tim Ripperger.
      Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.
    Keywords:  Cancer predisposition; Familial leukemia; Genetic analyses; Genetic counseling; Germline variants; Patient care
    DOI:  https://doi.org/10.1016/j.ejmg.2023.104727
  15. bioRxiv. 2023 Jan 17. pii: 2023.01.17.524290. [Epub ahead of print]
    Genomic Landscape of Patients with Germline RUNX1 Variants and Familial Platelet Disorder with Myeloid Malignancy.
    Kai Yu, Natalie Deuitch, Matthew Merguerian, Lea Cunningham, Joie Davis, Erica Bresciani, Jamie Diemer, Elizabeth Andrews, Alice Young, Frank Donovan, Raman Sood, Kathleen Craft, Shawn Chong, Settara Chandrasekharappa, Jim Mullikin, Paul P Liu.
      Germline RUNX1 mutations lead to familial platelet disorder with associated myeloid malignancies (FPDMM), which is characterized by thrombocytopenia and a life-long risk (35-45%) of hematological malignancies. We recently launched a longitudinal natural history study for patients with FPDMM at the NIH Clinical Center. Among 29 families with research genomic data, 28 different germline RUNX1 variants were detected. Besides missense mutations enriched in Runt homology domain and loss-of-function mutations distributed throughout the gene, splice-region mutations and large deletions were detected in 6 and 7 families, respectively. In 24 of 54 (44.4%) non-malignant patients, somatic mutations were detected in at least one of the clonal hematopoiesis of indeterminate potential (CHIP) genes or acute myeloid leukemia (AML) driver genes. BCOR was the most frequently mutated gene (in 9 patients), and multiple BCOR mutations were identified in 4 patients. Mutations in 7 other CHIP or AML driver genes ( DNMT3A, TET2, NRAS, SETBP1, SF3B1, KMT2C , and LRP1B ) were also found in more than one non-malignant patient. Moreover, three unrelated patients (one with myeloid malignancy) carried somatic mutations in NFE2 , which regulates erythroid and megakaryocytic differentiation. Sequential sequencing data from 19 patients demonstrated dynamic changes of somatic mutations over time, and stable clones were more frequently found in elderly patients. In summary, there are diverse types of germline RUNX1 mutations and high frequency of somatic mutations related to clonal hematopoiesis in patients with FPDMM. Monitoring dynamic changes of somatic mutations prospectively will benefit patients’ clinical management and reveal mechanisms for progression to myeloid malignancies.
    Key Points: Comprehensive genomic profile of patients with FPDMM with germline RUNX1 mutations. Rising clonal hematopoiesis related secondary mutations that may lead to myeloid malignancies.
    DOI:  https://doi.org/10.1101/2023.01.17.524290
  16. Lancet Reg Health Am. 2022 Aug;12 100265
    Cancer surveillance for patients with Li-Fraumeni Syndrome in Brazil: A cost-effectiveness analysis.
    Isadora A Frankenthal, Mariana Cartaxo Alves, Casey Tak, Maria Isabel Achatz.
       Background: In Brazil, there is a higher prevalence of Li-Fraumeni Syndrome (LFS) compared to worldwide, due to the founder mutation in the TP53 gene p.R337H. However, a large portion of the population, that depends on National Health Care System, does not have access to effective screening through the Toronto Protocol guidelines that enables early diagnosis and improves overall survival. Population strategies for early cancer detection recommended in Brazil are limited and additional screening is not offered to patients at a high risk, leading to late diagnoses and higher cancer mortality. This study aims to assess the cost-effectiveness of introducing annual screening that follows the Toronto Protocol for patients diagnosed with LFS in Brazil.
    Methods: A Markov decision analytic model was developed to estimate cost-effectiveness of 1,000 LFS carriers under surveillance and non-surveillance strategies over a patient's lifetime. The main outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per additional life year gained, comparing surveillance and non-surveillance strategies in p.R337H TP53 carriers.
    Findings: For females, the model showed a mean cost of $2,222 and $14,640 and yielded 22 and 26·2 life years for non-surveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $2,982 per additional life year gained. For males, the model predicts mean lifetime costs of $1,165 and $12,883 and average life years of 23·5 and 26·3 for non-surveillance and surveillance strategies, respectively. This amounts to an ICER of $ 4,185 per additional life year. Surveillance had 64% and 45% probabilities of being the most cost-effective strategy for early cancer detection in female and male carriers, respectively.
    Interpretation: The adoption of surveillance for patients diagnosed with LFS by the Brazilian National Health Care System is cost-beneficial for both males and females.
    Funding: This research received no specific grant from any funding agency.
    Keywords:  Cancer surveillance; Cost-effectiveness; Li-fraumeni syndrome; TP53
    DOI:  https://doi.org/10.1016/j.lana.2022.100265
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