bims-lifras 2021-05-16 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒05‒16
thirteen papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Pediatric Head and Neck Tumors Associated with Li-Fraumeni Syndrome.
Endometrial Carcinoma as the Presenting Malignancy in a Teenager With a Pathogenic TP53 Germline Mutation: A Case Report and Literature Review.
Myelodysplastic syndrome with genetic predisposition.
Germline risk of clonal haematopoiesis.
CDH1 germline mutations in families with hereditary lobular breast cancer.
MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature.
Clinical Contribution of Next-Generation Sequencing Multigene Panel Testing for BRCA Negative High-Risk Patients With Breast Cancer.
A Validated Functional Analysis of PALB2 (Partner and Localizer of BRCA2) Missense Variants for Use in Clinical Variant Interpretation.
Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).
Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.
Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.
Zebrafish Cancer Predisposition Models.
BRCA and Breast Cancer-Related High-Penetrance Genes.

Ann Otol Rhinol Laryngol. 2021 May 10. 34894211014786

Pediatric Head and Neck Tumors Associated with Li-Fraumeni Syndrome.

Rodriguez KD, Schneider KW, Suttman A, Garrington T, Jellins T, Tholen K, Francom CR, Herrmann BW.

  INTRODUCTION: Cancer predisposition syndromes are germline pathogenic variants in genes that greatly raise the risk of developing neoplastic diseases. One of the most well-known is Li-Fraumeni syndrome (LFS), which is due to pathogenic variants in the TP53 gene. Children with LFS have higher risks for multiple malignancies before adulthood, often with rare and aggressive subtypes.OBJECTIVE: To examine head and neck manifestations of LFS in children treated at a tertiary children's hospital over a 20-year period.
METHODS: A retrospective review of LFS children with neoplastic disease presenting in traditional Otolaryngologic head and neck subsites from 2000 to 2019, with patient charts reviewed for relevant clinical, imaging, and operative data.
RESULTS: Of the 40 LFS patients initially identified, 27 neoplastic tumors were identified in 20 children within this cohort (20 primary, 7 second primary). Head and neck subsites aside from the brain or orbit were involved in 22% (6/27) of these tumors, representing 20% (4/20) of primary tumors and 29% (2/7) of second primary tumors. Both second primaries within the head and neck were within the radiation fields of the first primary tumor. The mean ages at primary and second primary diagnosis were 4.6 years (SD 3.5) and 12 years (SD 1.4), respectively. The male/female ratio was 1:6 among all patients with head and neck tumors. All 6 head and neck tumors were sarcomas. Rhabdomyosarcoma (N = 3, 50%) was the most common pathology, and the other 3 demonstrated rare tumor pathological subtypes (synovial cell sarcoma, pleomorphic myxoid liposarcoma, mandibular osteosarcoma). The neck was the most common subsite (75%) within this group for primary tumor presentation.
CONCLUSION: This study identifies a high potential for head and neck involvement in children with LFS, which has not been previously described in the literature. Otolaryngological care should be included in a multidisciplinary care team surveilling these patients.

Keywords:  Li-Fraumeni; cancer; genetic; head; neck; pediatric; predisposition; syndrome

DOI:  https://doi.org/10.1177/00034894211014786
Int J Gynecol Pathol. 2021 May 12.

Endometrial Carcinoma as the Presenting Malignancy in a Teenager With a Pathogenic TP53 Germline Mutation: A Case Report and Literature Review.

Irshaid L, Clark M, Fadare O, Finberg KE, Parkash V.

Patients with germline TP53 mutations are characterized by the occurrence of multiple early-onset malignancies. The characteristic syndrome is Li-Fraumeni syndrome (OMIM # 151623), an autosomal dominant disorder typified by premenopausal breast carcinoma, adrenal cortical tumors, bone and soft tissue sarcomas, leukemias, and tumors of the brain and spinal cord. Gynecologic malignancies are uncommonly reported in families harboring TP53 mutations, and the predominant tumor type reported is ovarian. Uterine carcinoma has been reported only a handful of times in patients with germline TP53 mutations, none as a presenting tumor in a teenager. We report on an 18-year-old patient who presented with grade 3, high-stage endometrioid endometrial carcinoma. Sequencing detected a single-nucleotide substitution in the TP53 gene (NM_000546.6:c.818G>A), encoding the missense substitution p.Arg273His (R273H) in both the tumor and normal tissue, consistent with a germline mutation. We discuss the biology of the TP53 gene and p53 protein, with emphasis on the R273H mutation. We also review the literature on endometrial carcinoma in patients with germline TP53 mutations.

DOI: https://doi.org/10.1097/PGP.0000000000000792
Blood Res. 2021 Apr 30. 56(S1): S34-S38

Myelodysplastic syndrome with genetic predisposition.

Park M.

  Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal blood disorders characterized by ineffective hematopoiesis, cytopenia, dysplasia, and an increased risk of acute myeloid leukemia (AML). A growing number of inherited genetic loci that contribute to MDS/AML development are rapidly being identified. As genetic sequencing has become increasingly integrated into clinical practice, clearly defined syndromes have emerged, known as the MDS/AML predisposition syndrome. With more patients and families being identified with predisposing conditions, knowledge of the approach of evaluating and managing MDS with genetic predisposition is increasingly essential. This article reviews MDS with genetic predisposition and the practical aspects of management in patients with predisposition syndrome.

Keywords:  Genetic predisposition; Myelodysplastic syndrome

DOI:  https://doi.org/10.5045/br.2021.2020327
Nat Rev Genet. 2021 May 13.

Germline risk of clonal haematopoiesis.

Silver AJ, Bick AG, Savona MR.

Clonal haematopoiesis (CH) is a common, age-related expansion of blood cells with somatic mutations that is associated with an increased risk of haematological malignancies, cardiovascular disease and all-cause mortality. CH may be caused by point mutations in genes associated with myeloid neoplasms, chromosomal copy number changes and loss of heterozygosity events. How inherited and environmental factors shape the incidence of CH is incompletely understood. Even though the several varieties of CH may have distinct phenotypic consequences, recent research points to an underlying genetic architecture that is highly overlapping. Moreover, there are numerous commonalities between the inherited variation associated with CH and that which has been linked to age-associated biomarkers and diseases. In this Review, we synthesize what is currently known about how inherited variation shapes the risk of CH and how this genetic architecture intersects with the biology of diseases that occur with ageing.

DOI: https://doi.org/10.1038/s41576-021-00356-6
Eur J Cancer Prev. 2021 May 07.

CDH1 germline mutations in families with hereditary lobular breast cancer.

Girardi A, Magnoni F, Vicini E, Kouloura A, La Vecchia C, Veronesi P, Corso G.

Pathogenic CDH1 germline mutations are associated with lobular breast cancer in the so-called hereditary lobular breast cancer (HLBC) syndrome, without apparent correlation with the classic hereditary diffuse gastric cancer (HDGC). Recent international guidelines recommend CDH1 screening also in absence of diffuse gastric cancer (DGC) history. Genomic characteristics underlying gastric and breast tumorigenesis in this varied population of patients is still unclear. In this review we revised all CDH1 germline mutations described in literature associated with lobular breast cancer (LBC). We distinguish two subgroups of CDH1 mutant carriers: (a) 'mixed' HDGC syndrome, showing both DGC plus LBC and (b) HLBC, in which DGC is absent and the LBC phenotype is predominant. A higher frequency of CDH1 mutations was identified in the HLBC syndrome with an early age at LBC diagnosis; it is possible that LBCs with CDH1 germline mutations are an independent inherited syndrome. This evidence allows us to gain biological insight into the pathophysiological mechanisms responsible for the different phenotypes of the disease and potentially tailor the prophylactic and screening procedures.

DOI: https://doi.org/10.1097/CEJ.0000000000000688
Genes Chromosomes Cancer. 2021 May 02.

MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature.

Zyla R, Graham T, Aronson M, Velsher L, Mrkonjic M, Turashvili G.

  Endometrial carcinoma is one of the prototypical malignancies associated with Lynch syndrome, an inherited cancer syndrome most commonly caused by germline mutations in DNA mismatch repair (MMR) genes, although rare alternative mechanisms also exist. In this report, we describe a patient first diagnosed with colorectal cancer at age 33, then vulvar squamous cell carcinoma, facial sebaceous adenoma/sebaceoma, and finally endometrial carcinoma at age 52. All tumors were MLH1/PMS2-deficient by immunohistochemistry, and MLH1 promoter methylation was identified in the endometrial cancer. Germline MLH1 testing was negative for pathogenic variants, but she was subsequently diagnosed with Lynch syndrome secondary to a germline monoallelic constitutional epimutation of the MLH1 promoter. Identification of patients displaying a Lynch syndrome phenotype but lacking germline MMR mutations is important to avoid delays in the diagnosis of Lynch syndrome as well as the initiation of appropriate cancer screening and genetic counseling.

Keywords:  Lynch syndrome; MLH1 promoter epimutation; colorectal cancer; endometrial cancer; sebaceous adenoma/sebaceoma; vulvar squamous cell carcinoma

DOI:  https://doi.org/10.1002/gcc.22957
Clin Breast Cancer. 2021 Apr 12. pii: S1526-8209(21)00070-7. [Epub ahead of print]

Clinical Contribution of Next-Generation Sequencing Multigene Panel Testing for BRCA Negative High-Risk Patients With Breast Cancer.

Ece Solmaz A, Yeniay L, Gökmen E, Zekioğlu O, Haydaroğlu A, Bilgen I, Özkınay F, Onay H.

  BACKGROUND: Breast cancer is the most common malignancy in women and thought to be hereditary in 10% of patients. Recent next-generation sequencing studies have increased the detection of pathogenic or likely pathogenic (P/LP) variants in genes other than BRCA1/2 in patients with breast cancer. This study evaluated pathogenic variants, likely pathogenic variants, and variants of unknown significance in 18 hereditary cancer susceptibility genes in patients with BRCA1/2-negative breast cancer.PATIENTS AND METHODS: This retrospective study included 188 high-risk BRCA1/2-negative patients with breast cancer tested with a multigene cancer panel using next-generation sequencing.
RESULTS: Among 188 proband cases, 18 variants in 21 patients (11.1%) were classified as P/LP in PALB2 (n = 6), CHEK2 (n = 5), MUTYH (n = 4), ATM (n = 3), TP53 (n = 2), BRIP1 (n = 1), and MSH2 (n = 1). Three novel P/LP variants were identified. An additional 28 variants were classified as variants of unknown significance and detected in 30 different patients (15.9%).
CONCLUSION: This is one of the largest study from Turkey to investigate the mutation spectrum in non-BRCA hereditary breast cancer susceptibility genes. A multigene panel test increased the likelihood of identifying a molecular diagnosis in patients with BRCA 1/2-negative breast cancer at risk for a hereditary breast cancer syndrome. More studies are needed to enable the clinical interpretation of these P/LP variants in hereditary patients with breast cancer.

Keywords:  BRCA1/2; Breast cancer; Hereditary cancer susceptibility genes; Multi-gene panel; NGS; Next-generation sequencing

DOI:  https://doi.org/10.1016/j.clbc.2021.04.002
J Mol Diagn. 2021 May 05. pii: S1525-1578(21)00119-7. [Epub ahead of print]

A Validated Functional Analysis of PALB2 (Partner and Localizer of BRCA2) Missense Variants for Use in Clinical Variant Interpretation.

Brnich SE, Arteaga EC, Wang Y, Tan X, Berg JS.

Clinical genetic testing readily detects germline genetic variants. Yet, the rarity of individual variants limits the evidence available for variant classification, leading to many variants of uncertain significance (VUS). VUS cannot guide clinical decisions, complicating counseling and management. In hereditary breast cancer gene PALB2 (Partner and Localizer of BRCA2), ∼50% of clinically-identified germline variants are VUS and ∼90% of VUS are missense. Truncating PALB2 variants have homologous recombination (HR) defects and rely on error-prone non-homologous end-joining (NHEJ) for DNA damage repair (DDR). Recent reports show some missense PALB2 variants may also be damaging, but most functional studies have lacked benchmarking controls required to have sufficient predictive power for clinical use. Variant-level DDR capacity in hereditary breast cancer genes was assessed using the Traffic Light Reporter (TLR) to quantify cellular HR/NHEJ with fluorescent markers. First, using BRCA2 missense variants of known significance as benchmarks, the TLR distinguished between normal/abnormal HR function. Then the TLR was validated for PALB2 and used to test 37 PALB2 variants. Based on the TLR's ability to correctly classify PALB2 validation controls, this functional data can be applied in subsequent germline variant interpretations at a moderate level of evidence towards a pathogenic interpretation (PS3_moderate) for 8 variants with abnormal DDR, or a supporting level of evidence towards a benign interpretation (BS3_supporting) for 13 variants with normal DDR.

DOI: https://doi.org/10.1016/j.jmoldx.2021.04.010
Genet Med. 2021 May 11.

Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Tischkowitz M, Balmaña J, Foulkes WD, James P, Ngeow J, Schmutzler R, Voian N, Wick MJ, Stewart DR, Pal T, .

PURPOSE: PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited.METHODS: A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors.
RESULTS: PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2.
CONCLUSION: This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.

DOI: https://doi.org/10.1038/s41436-021-01151-8
J Clin Oncol. 2021 May 10. JCO2100003

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2.

Reiss KA, Mick R, O'Hara MH, Teitelbaum U, Karasic TB, Schneider C, Cowden S, Southwell T, Romeo J, Izgur N, Hannan ZM, Tondon R, Nathanson K, Vonderheide RH, Wattenberg MM, Beatty G, Domchek SM.

PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved as maintenance therapy for patients with advanced pancreatic cancer (PC) and a germline BRCA1 or BRCA2 pathogenic variant (PV). This investigator-initiated, single-arm phase II study assessed the role of the PARPi rucaparib as maintenance therapy in advanced PC with germline or somatic PV in BRCA1, BRCA2, or PALB2.PATIENTS AND METHODS: Eligible patients had advanced PC; germline (g) or somatic (s) PVs in BRCA1, BRCA2, or PALB2, and received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance. Chemotherapy was discontinued and patients received rucaparib 600 mg orally twice a day until progression. The primary end point was the progression-free survival (PFS) rate at 6 months (PFS6). Secondary end points included safety, ORR, disease control rate, duration of response, and overall survival.
RESULTS: Of 46 enrolled patients, 42 were evaluable (27 gBRCA2, seven gBRCA1, six gPALB2, and two sBRCA2). PFS6 was 59.5% (95% CI, 44.6 to 74.4), median PFS was 13.1 months (95% CI, 4.4 to 21.8), and median overall survival was 23.5 months (95% CI, 20 to 27). The PFS at 12 months was 54.8%. ORR of the 36 patients with measurable disease was 41.7% (3 complete responses; 12 partial responses; 95% CI, 25.5 to 59.2), and disease control rate was 66.7% (95% CI, 49.0 to 81.4). Median duration of response was 17.3 months (95% CI, 8.8 to 25.8). Responses occurred in patients with gBRCA2 (41%, 11 out of 27), gPALB2 (50%, 3 out of 6), and sBRCA2 (50%, 1 out of 2). No new safety signals were noted.
CONCLUSION: Maintenance rucaparib is a safe and effective therapy for platinum-sensitive, advanced PC with a PV in BRCA1, BRCA2, or PALB2. The finding of efficacy in patients with gPALB2 and sBRCA2 PVs expands the population likely to benefit from PARPi beyond gBRCA1/2 PV carriers.

DOI: https://doi.org/10.1200/JCO.21.00003
NPJ Breast Cancer. 2021 May 12. 7(1): 52

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Li N, Zethoven M, McInerny S, Devereux L, Huang YK, Thio N, Cheasley D, Gutiérrez-Enríquez S, Moles-Fernández A, Diez O, Nguyen-Dumont T, Southey MC, Hopper JL, Simard J, Dumont M, Soucy P, Meindl A, Schmutzler R, Schmidt MK, Adank MA, Andrulis IL, Hahnen E, Engel C, Lesueur F, Girard E, Neuhausen SL, Ziv E, Allen J, Easton DF, Scott RJ, Gorringe KL, James PA, Campbell IG.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

DOI: https://doi.org/10.1038/s41523-021-00255-3
Front Cell Dev Biol. 2021 ;9 660069

Zebrafish Cancer Predisposition Models.

Kobar K, Collett K, Prykhozhij SV, Berman JN.

  Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5-10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment. In vivo models are needed to better understand tumor-driving mechanisms, tailor patient screening approaches and develop targeted therapies to improve patient care and disease prognosis. The zebrafish (Danio rerio) has emerged as a robust model for cancer research due to its high fecundity, time- and cost-efficient genetic manipulation and real-time high-resolution imaging. Tumors developing in zebrafish cancer models are histologically and molecularly similar to their human counterparts, confirming the validity of these models. The zebrafish platform supports both large-scale random mutagenesis screens to identify potential candidate/modifier genes and recently optimized genome editing strategies. These techniques have greatly increased our ability to investigate the impact of certain mutations and how these lesions impact tumorigenesis and disease phenotype. These unique characteristics position the zebrafish as a powerful in vivo tool to model cancer predisposition syndromes and as such, several have already been created, including those recapitulating Li-Fraumeni syndrome, familial adenomatous polyposis, RASopathies, inherited bone marrow failure syndromes, and several other pathogenic mutations in cancer predisposition genes. In addition, the zebrafish platform supports medium- to high-throughput preclinical drug screening to identify compounds that may represent novel treatment paradigms or even prevent cancer evolution. This review will highlight and synthesize the findings from zebrafish cancer predisposition models created to date. We will discuss emerging trends in how these zebrafish cancer models can improve our understanding of the genetic mechanisms driving cancer predisposition and their potential to discover therapeutic and/or preventative compounds that change the natural history of disease for these vulnerable children, youth and adults.

Keywords:  cancer; cancer predisposition; genetic models; model organism; p53; zebrafish

DOI:  https://doi.org/10.3389/fcell.2021.660069
Adv Exp Med Biol. 2021 ;1187 473-490

BRCA and Breast Cancer-Related High-Penetrance Genes.

Han SA, Kim SW.

  Genetic susceptibility explains 5-10% of all breast cancer cases. High-penetrance breast cancer susceptibility genes deliberate a greater than tenfold relative risk of breast cancer. BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer, and TP53, PTEN, and SKT11 (LKB1) are rarely present. The prevalence of BRCA1 and BRCA2 genetic alterations differ in various ethnic groups. The Korean Hereditary Breast Cancer (KOHBRA) Study, nationwide-scale study, was established to acquire evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea prospectively since 2007. In this chapter, we review previous research related to hereditary breast cancer and summarize the present concepts and research results centered on the Korean Hereditary Breast Cancer Research at this time.

Keywords:  BRCA1/2; Breast cancer; Genetic susceptibility; KOHBRA study; PTEN; STK11; TP53

DOI:  https://doi.org/10.1007/978-981-32-9620-6_25