bims-lifras 2022-07-24 papers

Int J Clin Oncol. 2022 Jul 23.

Prevalence of pathogenic germline variants in the circulating tumor DNA testing.

Yoshihiro Yamamoto, Keita Fukuyama, Masashi Kanai, Tomohiro Kondo, Masahiro Yoshioka, Tadayuki Kou, Pham Nguyen Quy, Reiko Kimura-Tsuchiya, Takahiro Yamada, Shigemi Matsumoto, Shinji Kosugi, Manabu Muto.

BACKGROUND: Somatic and germline variants are not distinguishable by circulating tumor DNA (ctDNA) testing without analyzing non-tumor samples. Although confirmatory germline testing is clinically relevant, the criteria for selecting presumed germline variants have not been established in ctDNA testing. In the present study, we aimed to evaluate the prevalence of pathogenic germline variants in clinical ctDNA testing through their variant allele fractions (VAFs).
METHODS: A total of consecutive 106 patients with advanced solid tumors who underwent ctDNA testing (Guardant360®) between January 2018 and March 2020 were eligible for this study. To verify the origin of pathogenic variants reported in ctDNA testing, germline sequencing was performed using peripheral blood DNA samples archived in the Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan) under clinical research settings.
RESULTS: Among 223 pathogenic variants reported in ctDNA testing, the median VAF was 0.9% (0.02-81.8%), and 88 variants with ≥ 1% VAFs were analyzed in germline sequencing. Among 25 variants with ≥ 30% VAFs, seven were found in peripheral blood DNA (BRCA2: n = 6, JAK2: n = 1). In contrast, among the 63 variants with VAFs ranging from 1 to < 30%, only one variant was found in peripheral blood DNA (TP53: n = 1). Eventually, this variant with 15.6% VAF was defined to be an acquired variant, because its allelic distribution did not completely link to those of neighboring germline polymorphisms.
CONCLUSION: Our current study demonstrated that VAFs values are helpful for selecting presumed germline variants in clinical ctDNA testing.

Keywords: Circulating tumor DNA testing; Confirmatory germline sequencing; Presumed germline pathogenic variants; Variant allele fractions

DOI: https://doi.org/10.1007/s10147-022-02220-x

Pancreatology. 2022 Jun 22. pii: S1424-3903(22)00454-9. [Epub ahead of print]

Tissue methylated DNA markers for sporadic pancreatic cancer are strongly associated with familial and genetically predisposed pancreatic cancer.

Shounak Majumder, William R Taylor, Patrick H Foote, Brianna J Gysbers, Xiaoming Cao, Douglas W Mahoney, Kelli N Burger, Karen A Doering, Rondell P Graham, Fergus J Couch, Gloria M Petersen, John B Kisiel.

High-risk individuals (HRIs) with familial and genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) are eligible for screening. There is no accurate biomarker for detecting early-stage PDAC. We previously demonstrated that a panel of methylated DNA markers (MDMs) accurately detect sporadic PDAC. In this study we compared the distribution of MDMs in DNA extracted from tissue of PDAC cases who carry germline mutations and non-carriers with family history, with control tissue and demonstrate high discrimination like that seen in sporadic PDAC. These results provide scientific rationale for examining plasma MDMs in HRIs with the goal of developing a minimally-invasive early detection test.

Keywords: Biomarker; DNA methylation; Pancreatic cancer

DOI: https://doi.org/10.1016/j.pan.2022.06.259

Cancer Discov. 2022 Jul 22. OF1

Novel Germline Loci Are Associated with Clonal Hematopoiesis Risk.

Novel germline loci were associated with the risk of clonal hematopoiesis (CH) within the UK Biobank.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-132

J Hum Genet. 2022 Jul 21.

Ovarian cancer risk of Chinese women with BRCA1/2 germline pathogenic variants.

Lu Yao, Jie Sun, Li Hu, Jiuan Chen, Juan Zhang, Ye Xu, Yuntao Xie.

Estimating the lifetime risk of ovarian cancer in Chinese women with BRCA1/2 germline pathogenic variants (PVs) is of great importance for the clinical management of BRCA1/2 carriers. This cohort study recruited 9903 unselected Chinese breast cancer patients whose BRCA1/2 status was determined. Of these, 3984 probands completed family history questionnaires, which investigated the health status of their relatives, including 11,997 female first-degree relatives. The ovarian cancer risk of BRCA1/2 germline pathogenic carriers was estimated using the ovarian cancer history of proband first-degree female relatives via the Kin-cohort method. Of the 3984 probands, 126 (3.2%) carried BRCA1 PVs, and 183 (4.6%) carried BRCA2 PVs. The estimated cumulative risks of ovarian cancer by age 70 were 15.3% (95% CI 8.4-18.6%) for BRCA1 carriers, 5.5% (95% CI 2.0-10.2%) for BRCA2 carriers, and 0.4% (95% CI 0.3-0.7%) for noncarriers. The cumulative risks of ovarian cancer were very low before the age of 40 for both BRCA1 and BRCA2 carriers and were an increase up to age 45. The cumulative ovarian cancer risk of BRCA1 carriers was approximately three times higher than that of BRCA2 carriers, and BRCA1 and BRCA2 carriers had 38- and 14-fold higher risks than non-BRCA carriers, respectively. The findings indicate that Chinese women with BRCA1/2 PVs have high risks of ovarian cancer in their lifetime, especially BRCA1 carriers. These results are useful for devising optimal strategies to reduce ovarian cancer risk in BRCA1/2 carriers.

DOI: https://doi.org/10.1038/s10038-022-01065-6

EJHaem. 2021 Aug;2(3): 508-513

Next-generation sequencing reveals the presence of DDX41 mutations in acute lymphoblastic leukemia and aplastic anemia.

Yang Zhang, Fang Wang, Xue Chen, Hong Liu, Xiaoliang Wang, Jiaqi Chen, Panxiang Cao, Xiaoli Ma, Hongxing Liu.

Limited studies have been described DEAD-box helicase 41 (DDX41) mutations in hematological diseases other than myeloid neoplasms. In this study, DDX41 mutations were identified in 0.8% of myeloid neoplasms, 0.9% of acute lymphoblastic leukemia (ALL), and 1.0% of aplastic anemia (AA). A total of 15 causal DDX41 variants in 14 patients were detected; seven of which have not been reported previously. In myeloid neoplasms, the median age of patients with germline missense was lower than that of germline nonsense mutations. In ALL, the characteristics of DDX41 mutation were distinct. This study first reported DDX41 mutations in ALL and AA, expanding its mutation and phenotypic spectrum.

Keywords: DDX41 mutations; acute lymphoblastic leukemia; aplastic anemia; genetic predisposition

DOI: https://doi.org/10.1002/jha2.256