bims-lifras 2022-07-10 papers

Pancreatology. 2022 May 27. pii: S1424-3903(22)00172-7. [Epub ahead of print]

Identification of high-risk germline variants for the development of pancreatic cancer: Common characteristics and potential guidance to screening guidelines.

Cade Bennett, Mike Suguitan, John Abad, Akhil Chawla.

Pancreatic cancer (PC) is a product of a variety of environmental and genetic factors. Recent work has highlighted the influence of hereditary syndromes on pancreatic cancer incidence. The purpose of this review is to identify the high-risk syndromes, common variants, and risks associated with PC. The study also elucidates common characteristics of patients with these mutations, which is used to recommend potential changes to current screening protocols for greater screening efficacy. We analyzed 8 syndromes and their respective variants: Hereditary Breast and Ovarian Cancer (BRCA1/2), Familial Atypical Multiple Mole Melanoma Syndrome (CDKN2A), Peutz-Jeghers Syndrome (STK11), Lynch Syndrome (PMS2, MLH1, MSH2, MSH6, EPCAM), Ataxia Telangiectasia (ATM), Li-Fraumeni Syndrome (TP53), Fanconi Anemia (PALB2), and Hereditary Pancreatitis (PRSS1, SPINK1, CFTR). Of 587 studies evaluated, 79 studies fit into our inclusion criteria. Information from each study was analyzed to draw conclusions on these variants as well as their association with pancreatic cancer. Information from this review is intended to improve precision medicine and improve criteria for screening.

DOI: https://doi.org/10.1016/j.pan.2022.05.005

Cancer Res. 2022 Jul 08. pii: can.22.0172. [Epub ahead of print]

Benign single-nucleotide polymorphisms in the coding region of TP53: finding the needles in a haystack of pathogenic variants.

Thierry Soussi.

With the recent explosion in high-throughput genotyping technology, the amount and quality of single-nucleotide polymorphism (SNP) data have increased exponentially and led to the discovery of multiple uncommon SNPs in the human population. To provide unified and centralized resources for the scientific community, several repositories have been developed, for example, ExAc or gnomAD. These repositories aggregate numerous population studies and serve widely as references to filter natural variants in genetic analyses. However, they are largely biased toward European populations. TP53 is the most frequently mutated gene in human cancer. Furthermore, pathogenic germline TP53 variants are associated with several cancer susceptibility disorders such as Li-Fraumeni syndrome. For these reasons, it is essential that benign TP53 SNPs are rigorously evaluated to avoid any misidentification that could impair patient management. The recent discovery of numerous benign SNPs within the coding region of the TP53 gene can be attributed to the survey of both these global repositories and population-specific databases, the latter enabling the recognition of additional population-specific TP53 SNPs in the Japanese, African and Indian populations. This review is aimed at summarizing the body of evidence behind the identification of 21 TP53 variants and the information defining them as bona fide SNPs.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-0172

Curr Hematol Malig Rep. 2022 Jul 04.

Germline and Somatic Defects in DDX41 and its Impact on Myeloid Neoplasms.

Talha Badar, Timothy Chlon.

PURPOSE OF REVIEW: While DDX41 mutation (m) is one of the most prevalent predisposition genes in adult myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), most patients do not always present with a family history of MDS/AML. In this review, we will be highlighting epidemiological data on DDX41m, roles of DDX41 in oncogenesis, mechanisms of clonal evolution with somatic DDX41m, and clinical phenotypes and management of MDS/AML in patients harboring DDX41m.
RECENT FINDINGS: DDX41 encodes a DEAD-box helicase protein that is considered essential for cell growth and viability. High incidence of myeloid malignancies and other cancers in patients bearing DDX41m suggests that defects in DDX41 lead to loss of a tumor suppressor function, likely related to activities in RNA splicing and processing pathways. Seventy percent of cancer cases with DDX41m are associated with MDS/AML alone. More than 65% of familial cases harbor heterozygous germline frameshift mutations, of which p.D140Gfs*2 is the most common. A somatic DDX41m of the second allele is acquired in 70% of cases, leading to hematological malignancy. Myeloid neoplasms with DDX41m are typically characterized by long latency, high-risk disease at presentation with normal cytogenetics and without any additional molecular markers. Recent reports suggests that a subgroup of these patients have an indolent clinical course and have a better long-term survival compared to favorable or intermediate risk AML. Distinct clinical/pathologic features and favorable outcomes in MDS/AML highlight the need for standardized classification and gene specific guidelines that could assist in management decisions in patients with DDX41m.

Keywords: AML; DDX41; Familial MDS/leukemia; MDS

DOI: https://doi.org/10.1007/s11899-022-00667-3

Pediatr Int. 2022 Jan;64(1): e15135

Hepatoblastoma with bone/bone marrow metastasis in Li-Fraumeni syndrome patient.

Masataka Hasegawa, Minako Sugiyama, Yukayo Terashita, Yuko Cho, Atsushi Manabe.

Keywords: Li-Fraumeni syndrome; bone/bone marrow metastasis; comprehensive genome profiling; hepatoblastoma

DOI: https://doi.org/10.1111/ped.15135

Blood Cancer J. 2022 Jul 08. 12(7): 106

Mithun Vinod Shah, Abhishek A Mangaonkar, Kebede H Begna, Hassan B Alkhateeb, Patricia Greipp, Ahmad Nanaa, Michelle A Elliott, William J Hogan, Mark R Litzow, Kristen McCullough, Ayalew Tefferi, Naseema Gangat, Mrinal M Patnaik, Aref Al-Kali, Rong He, Dong Chen.

Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with <5% bone marrow blasts (124.5 vs. 16.3 months, P < 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A, TET2, or ASXL1 (DTA-genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.

DOI: https://doi.org/10.1038/s41408-022-00703-8