bims-lifras 2023-05-07 papers

Nat Rev Cancer. 2023 May 02.

Clin Transl Oncol. 2023 May 03.

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022).

SEOM Hereditary Cancer Working Group and AEGH Hereditary Cancer Committee

Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype-phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals.

Keywords: Cancer; Li-Fraumeni syndrome; Pathogenic variants; TP53

DOI: https://doi.org/10.1007/s12094-023-03202-9

Cancer Discov. 2023 May 04. pii: CD-22-1315. [Epub ahead of print]

An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression.

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific, germline variant of TP53 in the DNA binding domain, Tyr107His (Y107H). NMR and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the non-natural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases, and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive, and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune checkpoint inhibitors.

DOI: https://doi.org/10.1158/2159-8290.CD-22-1315

Fam Cancer. 2023 Apr 29.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature.

Ketty Hu-Heimgartner, Noémie Lang, Aurélie Ayme, Chang Ming, Jean-Damien Combes, Victor N Chappuis, Carla Vazquez, Alex Friedlaender, Aurélie Vuilleumier, Alexandre Bodmer, Valeria Viassolo, José L Sandoval, Pierre O Chappuis, S Intidhar Labidi-Galy.

BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7-14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4-4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

Keywords: BRCA mutation; Breast cancer; Chemotherapy; Febrile neutropenia; Haploinsufficiency; Ovarian cancer; Therapy myeloid neoplasm; Toxicity

DOI: https://doi.org/10.1007/s10689-023-00331-6

Haematologica. 2023 May 04.

Germline loss of function BRCA1 and BRCA2 mutations and risk of de novo hematopoietic malignancies.

Ryan J Stubbins, Anase S Asom, Peng Wang, Angela M Lager, Alexander Gary, Lucy A Godley.

Not available.

DOI: https://doi.org/10.3324/haematol.2022.281580

Br J Haematol. 2023 May 05.

Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

Wanqiao Wang, Xin Li, Xia Qin, Yan Miao, Yingwen Zhang, Shanshan Li, Ruen Yao, Yi Yang, Lisha Yu, Hua Zhu, Lili Song, Shengqiao Mao, Xiumin Wang, Jing Chen, Haizhong Feng, Yanxin Li.

Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.

Keywords: NF1 ; JMML; differentiation; germline mutation; induced pluripotent stem cells

DOI: https://doi.org/10.1111/bjh.18851

Gastroenterology. 2023 May 02. pii: S0016-5085(23)00696-0. [Epub ahead of print]

Lynch syndrome: a single hereditary cancer syndrome or multiple syndromes defined by different mismatch repair genes?

Laura Valle.

DOI: https://doi.org/10.1053/j.gastro.2023.04.027

Cancer Res. 2023 May 02. OF1-OF12

BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.

Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as "benign." However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer.
SIGNIFICANCE: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2620

Breast Cancer Res Treat. 2023 May 02.

Clinical efficacy of PARP inhibitors in breast cancer.

Karan Pandya, Alyssa Scher, Coral Omene, Shridar Ganesan, Shicha Kumar, Nisha Ohri, Lindsay Potdevin, Bruce Haffty, Deborah L Toppmeyer, Mridula A George.

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

Keywords: Breast cancer; HRD breast cancer; Olaparib; PARP inhibitors; Talazoparib

DOI: https://doi.org/10.1007/s10549-023-06940-0