bims-lifras 2022-12-18 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022‒12‒18
eight papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer.
Adolescent triple-negative breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes: A case report.
Two unique BAP1 pathogenic variants identified in the same family by panel cascade testing.
Germline findings in patients with advanced malignancies screened with paired blood-tumour testing for personalised treatment approaches.
Comprehensive genomic profiling of a unique liposarcoma arising in a patient with Li-Fraumeni syndrome and the novel detection of c-myc amplification: a case report.
Case report: Complete response to pembrolizumab in a liver metastatic colon adenocarcinoma patient with a novel likely pathogenic germline MSH2 mutation.
AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer.
Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study.

Cancers (Basel). 2022 Dec 02. pii: 5967. [Epub ahead of print]14(23):

Splicing-Disrupting Mutations in Inherited Predisposition to Solid Pediatric Cancer.

Piedad Alba-Pavón, Lide Alaña, Itziar Astigarraga, Olatz Villate.

  The prevalence of hereditary cancer in children was estimated to be very low until recent studies suggested that at least 10% of pediatric cancer patients carry a germline mutation in a cancer predisposition gene. A significant proportion of pathogenic variants associated with an increased risk of hereditary cancer are variants affecting splicing. RNA splicing is an essential process involved in different cellular processes such as proliferation, survival, and differentiation, and alterations in this pathway have been implicated in many human cancers. Hereditary cancer genes are highly susceptible to splicing mutations, and among them there are several genes that may contribute to pediatric solid tumors when mutated in the germline. In this review, we have focused on the analysis of germline splicing-disrupting mutations found in pediatric solid tumors, as the discovery of pathogenic splice variants in pediatric cancer is a growing field for the development of personalized therapies. Therapies developed to correct aberrant splicing in cancer are also discussed as well as the options to improve the diagnostic yield based on the increase in the knowledge in splicing.

Keywords:  alternative splicing; cancer predisposition syndromes; genes; hereditary cancer; mutations; pediatric cancer; solid tumors

DOI:  https://doi.org/10.3390/cancers14235967
Front Oncol. 2022 ;12 970641

Adolescent triple-negative breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes: A case report.

Dongmei Chen, Chenyang Zhang, Mengqi Yuan, Ying Zhang, Qing Liu, Donggui Wan.

  Almost 5-10% of breast cancer results from inherited genetic pathogenic variants. Patients with pathogenic variants in high-penetrance genes such as TP53, BRCA1 and BRCA2 are susceptible to breast cancer. Moreover, nearly 80% of BRCA pathogenic variants carriers are diagnosed with breast cancer at a young age before menopause. There is currently no report of early onset breast cancer with germline pathogenic variants in both BRCA1 and TP53 genes. Here, we report a case of a 14-years-old female diagnosed with triple-negative breast cancer with a family history of malignant tumors. The cancer metastasized to multiple lymph nodes 1 year and 4 months after surgery, and the progression-free survival after subsequent chemotherapy and surgery has been 2 years and 10 months. The patient's white blood cells were screened against a panel of 11 cancer-related genes, and both germline pathogenic variants in BRCA1 and TP53 were identified. Genetic tests of her family members revealed the same pathogenic variants in BRCA1 in her father and brother, but BRCA1 pathogenic variants wasn't shown in other family members. The case indicates that genetic testing needs be performed in early onset breast cancer to confirm inherited risk, and if a germline pathogenic variant is identified, tailored therapeutic interventions and preventive interventions should be taken and genetic testing is recommended for relatives.

Keywords:  BRCA1/2; TP53; gene mutation; triple-negative breast cancer; young breast cancer

DOI:  https://doi.org/10.3389/fonc.2022.970641
Fam Cancer. 2022 Dec 14.

Two unique BAP1 pathogenic variants identified in the same family by panel cascade testing.

Lindsey Byrne, Cana Ingalls, Aliya Ansari, Cassie Porteus, Talia R Donenberg, Daniel A Sussman, Colleen M Cebulla, Mohamed H Abdel-Rahman.

  Germline pathogenic variants in the tumor suppressor gene BAP1 are associated with the hereditary tumor predisposition syndrome with susceptibility to uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other cancers. Germline BAP1 pathogenic variants are rare in the non-cancer general population with an estimated carrier frequency of 1:19,898 but more common in cancer patients with a carrier frequency of 1:1299. In the following we present the first report of a family with two unique BAP1 pathogenic variants. Retrospective case report of a family with two unique pathogenic variants in BAP1. A male (proband) was referred to our ocular oncology clinic for second opinion for his multiple independent uveal melanomas at ages 65, 68 and 71. Given his personal history of squamous cell carcinoma at age 61, renal cell carcinoma at age 63, and family history of atypical meningioma, basal cell carcinoma, pancreatic and prostate cancers he was assessed for germline pathogenic variants in BAP1 through our ongoing research study. Sanger sequencing identified the American founder pathogenic variant, c.1717delC, pL573Wfs*3, that was confirmed in a clinical laboratory. Both the proband's brother and nephew tested negative for the familial variant through single site cascade genetic testing. However, based on the personal history of multiple basal cell carcinoma in the nephew and family history of pancreatic and laryngeal cancers (both not known to be associated with BAP1-TPDS), a large cancer panel testing was recommended for the nephew. His panel testing revealed a different BAP1 pathogenic variant, c.605G>A, p. Trp202*. This variant was not detected in the proband or the proband's brother. Based on the frequency of germline BAP1 variants in the cancer population, the chance of occurrence of two different BAP1 variants in a family with cancer history is 5.9 × 10-7. This case report provides support for the importance of offering large panel cascade genetic testing, rather than single site testing for only the family pathogenic variant, for all at risk family members especially when the family variant cannot explain all the cancers in the family.

Keywords:  BAP1; Case report; Familial cancer; Panel cascade genetic testing

DOI:  https://doi.org/10.1007/s10689-022-00321-0
Eur J Cancer. 2022 Nov 08. pii: S0959-8049(22)01338-7. [Epub ahead of print]179 48-55

Germline findings in patients with advanced malignancies screened with paired blood-tumour testing for personalised treatment approaches.

Cristiana Roggia, Sorin Armeanu-Ebinger, Axel Gschwind, Olga Seibel-Kelemen, Sonja Hertler, Ulrike Faust, Alexandra Liebmann, Tobias B Haack, Manuela Neumann, Irina Bonzheim, Andrea Forschner, Hans-Georg Kopp, Franziska Herster, Andreas Hartkopf, Michael Bitzer, Nisar P Malek, Ines B Brecht, Kristina Ruhm, Yvonne Möller, Hubert Löwenheim, Stephan Ossowski, Olaf H Rieß, Christopher Schroeder.

  BACKGROUND: Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour-normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families.METHODS: We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data.
RESULTS: We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases.
CONCLUSIONS: Tumour-normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour-normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families.

Keywords:  Cancer predisposition syndrome; Next-generation sequencing; Personalised medicine; Precision oncology; Tumour–normal testing

DOI:  https://doi.org/10.1016/j.ejca.2022.11.003
Diagn Pathol. 2022 Dec 13. 17(1): 93

Comprehensive genomic profiling of a unique liposarcoma arising in a patient with Li-Fraumeni syndrome and the novel detection of c-myc amplification: a case report.

Hirofumi Watanabe, Fumiyoshi Fujishima, Toru Motoi, Yayoi Aoyama, Tetsuya Niihori, Masanobu Takahashi, Sho Umegaki, Hisashi Oishi, Hiroshi Tada, Ryo Ichinohasama, Hironobu Sasano.

  BACKGROUND: Germline TP53 mutations have been frequently reported in patients with Li-Fraumeni syndrome (LFS), resulting in a predisposition to various malignancies. Mutations other than germline TP53 mutations can also cause LFS-associated malignancies, but their details remain unclear. We describe a novel c-myc amplification in a unique liposarcoma in a patient with LFS.CASE PRESENTATION: A female patient with LFS developed breast cancer twice at the age of thirty; both were invasive ductal carcinomas harboring HER2 amplifications. Computed tomography revealed an anterior mediastinal mass, which was surgically resected. Histological analysis revealed three different lesions corresponding to myxoid liposarcoma-, pleomorphic liposarcoma-, and well-differentiated liposarcoma-like lesions. Fluorescence in-situ hybridization (FISH) analysis did not detect MDM2 amplification, Rb1 deletion, break apart signals of EWS, FUS, DDIT3, or c-myc, or c-myc-IGH fusion signals, but it did detect more c-myc signals. Further FISH analysis and comprehensive genomic profiling revealed c-myc amplification. We considered two differential diagnoses, dedifferentiated liposarcoma lacking MDM2 amplification and myxoid pleomorphic liposarcoma (MPLPS), and determined that this case is most likely MPLPS. However, definite diagnosis could not be made because a clear-cut differentiation of the case from liposarcomas was not possible.
CONCLUSIONS: A previous study demonstrated that c-myc amplification could not be detected in various liposarcomas, but the present unique liposarcoma showed c-myc amplification, so the c-myc amplification may indicate that the present liposarcoma is an LFS-related tumor. The present case further clarifies the pathological features of MPLPS and LFS-related liposarcomas by broadening their histopathological and genetic diversities.

Keywords:  Cartilaginous differentiation; Li–Fraumeni syndrome; Myxoid pleomorphic liposarcoma; TP53 mutation; c-myc

DOI:  https://doi.org/10.1186/s13000-022-01264-x
Front Immunol. 2022 ;13 1064488

Case report: Complete response to pembrolizumab in a liver metastatic colon adenocarcinoma patient with a novel likely pathogenic germline MSH2 mutation.

Yanjie Xu, Qin Li, Jiemin Zhao, Xuefeng Ni, Ping Li, Wenwei Hu.

  Lynch syndrome (LS) is a genetic disorder mainly caused by germline mutations in mismatched repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2) or deletions of the epithelial cell adhesion molecule gene (EPCAM). A 43-year-old Chinese male patient underwent radical surgery and was pathologically confirmed to have stage IIIB colon adenocarcinoma. After four cycles of standard adjuvant chemotherapy, the tumor reoccurred in situ with intestinal obstruction. The patient received secondary colectomy. Immunohistochemistry analysis revealed a loss of MSH2 protein expression in the surgical specimen. Noticing that the patient's mother and grandfather all were diagnosed with LS-related cancers, we collected the patient's and his mother's peripheral blood for genetic testing, and the result showed a six-base deletion of MSH2. Thus, we concluded that our patient had LS. Subsequently, the patient accepted pembrolizumab as the first-line systemic therapy after liver metastases. He achieved clinical complete response (cCR) within 2 months and remained progression-free for more than 2 years. The case report showed that MSH2 mutation (c.489_494deTGGGTA) is a likely pathogenic mutation, and immunotherapy (pembrolizumab) is effective for this patient.

Keywords:  Lynch syndrome; MSH2; PD-1 inhibitors; colorectal cancer; germline mutation

DOI:  https://doi.org/10.3389/fimmu.2022.1064488
Genes Chromosomes Cancer. 2022 Dec 11.

AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer.

Julie Leclerc, Marie Beaumont, Roseline Vibert, Stéphane Pinson, Catherine Vermaut, Cathy Flament, Tonio Lovecchio, Lucie Delattre, Christophe Demay, Florence Coulet, Erell Guillerm, Nadim Hamzaoui, Patrick R Benusiglio, Afane Brahimi, François Cornelis, Hélène Delhomelle, Sandra Fert-Ferrer, Benjamin P J Fournier, Alain Hovnanian, Clémentine Legrand, Alain Lortholary, David Malka, Florence Petit, Jean-Christophe Saurin, Sophie Lejeune, Chrystelle Colas, Marie-Pierre Buisine.

  Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, ten different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3,322 patients, which represents a frequency of 0.24%. However loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (OR 11.89, 95% CI 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the β-catenin-binding domain. 91% of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. 40% of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidences for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer. This article is protected by copyright. All rights reserved.

Keywords:  Colorectal cancer susceptibility; Wnt signaling pathway; adenomatous polyposis; oligodontia

DOI:  https://doi.org/10.1002/gcc.23112
Lancet Oncol. 2022 Dec 09. pii: S1470-2045(22)00700-8. [Epub ahead of print]

Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study.

Colin Y C Lee, Adriaan Olivier, Judith Honing, Anne-Marie Lydon, Susan Richardson, Maria O'Donovan, Marc Tischkowitz, Rebecca C Fitzgerald, Massimiliano di Pietro.

BACKGROUND: Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions.METHODS: For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci.
FINDINGS: 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%.
INTERPRETATION: Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer.
FUNDING: UK Medical Research Council.

DOI: https://doi.org/10.1016/S1470-2045(22)00700-8