bims-lifras 2023-12-10 papers

Genet Med. 2023 Dec 03. pii: S1098-3600(23)01053-5. [Epub ahead of print] 101037

Sequential tumor molecular profiling identifies likely germline variants.

Ira L Kraft, Hatice Basdag, Ashwin Koppayi, Courtnee V Rodgers, Caner Saygin, Yogameenakshi Haribabu, Pankhuri Wanjari, Nifang Niu, Soma Das, Jill L O de Jong, Jeremy Segal, Lucy A Godley.

PURPOSE: To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs).
METHODS: The coefficient of variance was calculated from variant allele frequency of next generation sequencing assays. Variants' likelihood of being germline was ranked on a 1-5 scale. Outcomes were examined in patients with such variants.
RESULTS: In a pilot set of 33 genes, 89% of grade 1, 77% of grade 2, 62% of grade 3, 52% of grade 4, and 21% of grade 5 variants were confirmed to be germline. Among those, 22% were pathogenic or likely pathogenic in genes recognized as conferring hereditary HM (HHM) risk, including BRCA1/2, CHEK2, CSF3R, and DDX41. To determine if this approach identified genes with known autosomal dominant inheritance, we analyzed sequential data from 1336 genes in 1135 HM patients. Among unique variants, 16% occurred in HHM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival two years following initial molecular testing (78% versus 88%, p=0.0037) and increased all-cause mortality compared to those without (HR 2.02, 95%CI 1.18-3.46, p=0.01).
CONCLUSION: Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared to those without.

Keywords: cancer risk; germline; hereditary hematopoietic malignancies; sequential tumor profiling

DOI: https://doi.org/10.1016/j.gim.2023.101037

Gynecol Oncol. 2023 Dec 01. pii: S0090-8258(23)01563-9. [Epub ahead of print]180 35-43

Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival.

OBJECTIVE: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
METHODS: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
RESULTS: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01).
CONCLUSIONS: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.

Keywords: BRCA1/2; Genetics; Homologous recombination; Ovarian cancer; Poly (ADP-ribose) polymerase; Survival

DOI: https://doi.org/10.1016/j.ygyno.2023.11.019

J Med Genet. 2023 Nov 30. pii: jmg-2023-109440. [Epub ahead of print]

Co-design of patient information leaflets for germline predisposition to cancer: recommendations for clinical practice from the UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar Programme and the Association of Genetic Nurse Counsellors (AGNC).

CanGene-CanVar Patient Reference Panel

BACKGROUND: Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation.
METHODS: Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions.
RESULTS: Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients.
CONCLUSIONS: Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios.

Keywords: Clinical Decision-Making; Genetics; Genomics; Information Science; Patient Care

DOI: https://doi.org/10.1136/jmg-2023-109440

Cold Spring Harb Mol Case Stud. 2023 Nov 29. pii: mcs.a006290. [Epub ahead of print]

Clinical and functional analysis of the germline TP53 p.K164E acetylation site variant.

Emilia Modolo Pinto, Enilze M S F Ribeiro, Jinling Wang, Aaron H Phillips, Richard W Kriwacki, Gerard P Zambetti.

TP53 plays a critical role as a tumor suppressor by controlling cell cycle progression, DNA repair, and apoptosis. Post-translational modifications such as acetylation of specific lysine residues in the DNA binding and C-terminus regulatory domains modulate its tumor suppressor activities. In this study we addressed the functional consequences of the germline TP53 p.K164E (NM_000546.5: c.490A>G) variant identified in a patient with early onset breast cancer and a significant family history of cancer. K164 is a conserved residue located in the L2 loop of the p53 DNA binding domain that is post-translationally modified by acetylation. In silico, in vitro, and in vivo analyses demonstrated that the glutamate substitution at K164 marginally destabilizes p53 protein structure, but significantly impairs sequence specific DNA binding, transactivation, and tumor cell growth inhibition. Although p.K164E is currently considered a variant of unknown significance by different clinical genetic testing laboratories, the clinical and lab-based findings presented here provide strong evidence to reclassify TP53 p.K164E as a likely pathogenic variant.

Keywords: Neoplasm of the breast

DOI: https://doi.org/10.1101/mcs.a006290

Acta Haematol. 2023 Dec 05.

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies and Future Considerations.

Jeremy DiGennaro, David A Sallman.

Background Acute Myeloid Leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (~10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis. Summary Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/- venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem cell transplantation. Recent developments geared towards the treatment of TP53-mutated MDS/AML have focused on immunotherapies. Key Messages Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy.

DOI: https://doi.org/10.1159/000535628