bims-lifras 2022-03-06 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022–03–06
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

A Novel TP53 Tandem Duplication in a Child with Li-Fraumeni Syndrome.
Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study.
Reviewing the occurrence of large genomic rearrangements in patients with inherited cancer predisposing syndromes: importance of a comprehensive molecular diagnosis.
Prevalence of Tumor Genomic Alterations in Homologous Recombination Repair Genes Among Taiwanese Breast Cancers.
A novel bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia: case report.
Incidence and Prevalence of Intraductal Papillary Mucinous Neoplasms in Individuals With BRCA1 and BRCA2 Pathogenic Variant.

Cold Spring Harb Mol Case Stud. 2022 Mar 01. pii: mcs.a006181. [Epub ahead of print]

A Novel TP53 Tandem Duplication in a Child with Li-Fraumeni Syndrome.

Feng Xu, Erfan Aref-Eshghi, Jinhua Wu, Jeffrey Schubert, Gerald Wertheim, Tricia Bhatti, Jennifer Pogoriler, Maha Patel, Kajia Cao, Ariel Long, Zhiqian Fan, Elizabeth Denenberg, Elizabeth Fanning, Donna Wilmoth, Minjie Luo, Laura Conlin, Aleksandra Sarah Dain, Sarah Baldino, Kristin Zelley, Naomi J Balamuth, Suzanne Macfarland, Marilyn M Li, Yiming Zhong.

  Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy number changes in TP53 are rare and account for less than 1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-Seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nucleotides of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nucleotides is expected to result in a frameshift with a stop codon 18 codons downstream of the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy number variants as well as SNVs/indels using NGS panels.

Keywords:  Acute myeloid leukemia; Osteosarcoma

DOI:  https://doi.org/10.1101/mcs.a006181
Cancer Sci. 2022 Mar 02.

Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study.

Kodai Abe, Minoru Kitago, Kenjiro Kosaki, Mamiko Yamada, Eisuke Iwasaki, Shintaro Kawasaki, Keijiro Mizukami, Yukihide Momozawa, Chikashi Terao, Hiroshi Yagi, Yuta Abe, Yasushi Hasegawa, Shutaro Hori, Masayuki Tanaka, Yutaka Nakano, Yuko Kitagawa.

  Environmental and genetic factors play a critical role in the pathogenesis of pancreatic cancer, which is likely to follows a multi-step process that includes intraductal papillary mucinous neoplasm. The pathogenesis of familial pancreatic cancer has been reported; however, epidemiological characteristics and causative genes remain unclear. This study aimed to determine the relationship between the family history of pancreatic cancer and tumor malignancy and identify novel susceptible germline variants of pancreatic cancer. We performed an epidemiologic study at our institute on a cohort of 668 patients with intraductal papillary mucinous neoplasm and 242 with pancreatic cancer but without associated intraductal papillary mucinous neoplasm stratified by family history of pancreatic cancer. Whole-exome sequencing was conducted for 10 patients from seven families with familial pancreatic cancer and intraductal papillary mucinous neoplasm. We found that patients who have intraductal papillary mucinous neoplasm with positive family history of pancreatic cancer within first-degree relatives, were more likely to develop malignancy in a shorter period than those without family history. Duplicate frameshift variants in TET2 c.3180dupG (p.Pro1061fs) and ASXL1 c.1934dupG (p.Gly646fs) in one family and POLN c.1194dupT (p.Glu399fs) in another were identified as pathogenic truncating germline variants which were previously recognised susceptibility genes. Moreover, PDIA2 c.1403C>T (p.Pro468Leu) and DPYSL4 c.926C>A (p.Pro309Gln) were shared in four and two patients, respectively. In particular PDIA2 was identified as a novel candidate for one of deleterious variants of familial pancreatic cancer.

Keywords:  cancer susceptibility genes; cross-sectional study; familial pancreatic cancer; germline variant; intraductal papillary mucinous neoplasm

DOI:  https://doi.org/10.1111/cas.15316
Expert Rev Mol Diagn. 2022 Mar 02.

Reviewing the occurrence of large genomic rearrangements in patients with inherited cancer predisposing syndromes: importance of a comprehensive molecular diagnosis.

Débora Leite Rocha, Patrícia Ashton-Prolla, Clévia Rosset.

   INTRODUCTION: Hereditary cancer predisposition syndromes are caused by germline pathogenic or likely pathogenic variants in cancer predisposition genes (CPG). The majority of pathogenic variants in CPGs are point mutations, but large gene rearrangements (LGRs) are present in several CPGs. LGRs can be much more difficult to characterize and perhaps they may have been neglected in molecular diagnoses.
AREAS COVERED: We aimed to evaluate the frequencies of germline LGRs in studies conducted in different populations worldwide through a qualitative systematic review based on an online literature research in PubMed. Two reviewers independently extracted data from published studies between 2009 and 2020. In total, 126 studies from 37 countries and 5 continents were included in the analysis. The number of studies in different continents ranged from 3 to 48 and for several countries there was an absolute lack of information. Asia and Europe represented most of the studies, and LGR frequencies varied from 3.04 to 15.06% in different continents. MLPA was one of the methods of choice in most studies (93%).
EXPERT OPINION: The LGR frequencies found in this review reinforce the need for comprehensive molecular testing regardless of the population of origin and should be considered by genetic counseling providers.

Keywords:  cancer predisposition genes; cancer predisposition syndromes; large gene rearrangements; molecular diagnosis; molecular techniques

DOI:  https://doi.org/10.1080/14737159.2022.2049247
Ann Surg Oncol. 2022 Feb 28.

Prevalence of Tumor Genomic Alterations in Homologous Recombination Repair Genes Among Taiwanese Breast Cancers.

Chi-Cheng Huang, Yi-Fang Tsai, Chun-Yu Liu, Pei-Ju Lien, Yen-Shu Lin, Ta-Chung Chao, Chin-Jung Feng, Yen-Jen Chen, Jiun-I Lai, Nam Nhut Phan, Chih-Yi Hsu, Jen-Hwey Chiu, Ling-Ming Tseng.

PURPOSE: Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations.
METHODS: We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues.
RESULTS: Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes.
CONCLUSIONS: The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

DOI: https://doi.org/10.1245/s10434-022-11347-0
BMC Med Genomics. 2022 Mar 04. 15(1): 46

A novel bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia: case report.

Woo Yong Shin, Seug Yun Yoon, Rojin Park, Jung-Ah Kim, Ho Hyun Song, Hae In Bang, Jong-Ho Won, Jieun Kim.

   BACKGROUND: The germline mutations of DDX41, also known as DEAD box RNA helicase 41, have been found in about 1.5% of myeloid neoplasms (MNs). Development of MDS/AML is relatively common in germline DDX41 mutations. However, a variety of hematological malignancies (HMs) have been reported.
CASE PRESENTATION: We report a novel case of bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia (B-ALL), with unusual location of DDX41 mutations. The gene expression profile (GEP) of Ph + B-ALL with bi-alleleic DDX41 mutations showed heterogeneously transitional GEP and altered gene expression levels of genes involved in the process essential for red blood cells and myeloid cell differentiation were noted.
CONCLUSIONS: We report that DDX41 mutations are unusual but can be an underlying event in Ph + B-ALL and screening DDX41 mutations can be also informative for patients awaiting for haploidentical stem cell transplantation and choosing the therapy.

Keywords:  B-cell lymphoblastic leukemia; Case report; DDX41 germline mutation; Gene expression

DOI:  https://doi.org/10.1186/s12920-022-01191-2
J Clin Gastroenterol. 2022 Feb 28.

Incidence and Prevalence of Intraductal Papillary Mucinous Neoplasms in Individuals With BRCA1 and BRCA2 Pathogenic Variant.

Ishani Shah, Andy Silva-Santisteban, Katharine A Germansky, Vaibhav Wadhwa, Nadine Tung, Dora C Huang, Cinthana Kandasamy, Jack Mlabasati, Mohammad Bilal, Mandeep S Sawhney.

BACKGROUND: The natural history of branch-duct intraductal papillary neoplasm (BD-IPMN) in BRCA1/2 patients is unknown. Our goal was to estimate the incidence and prevalence of BD-IPMN and other pancreatic lesions in BRCA1/2 patients and compare it to that for average-risk individuals.
METHODS: We identified a cohort of BRCA1/2 patients followed at our institution between 1995 and 2020. Medical records and imaging results were reviewed to determine prevalence of pancreatic lesions. We then identified those who had undergone follow-up imaging and determined the incidence of new pancreatic lesions. We categorized pancreatic lesions as low, intermediate, or high-risk based on their malignant potential.
RESULTS: During the study period, 359 eligible BRCA1/2 patients were identified. Average patient age was 56.8 years, 88.3% were women, and 51.5% had BRCA1. The prevalence of low-risk pancreatic lesions was 14.4%, intermediate-risk 13.9%, and high-risk 3.3%. The prevalence of BD-IPMN was 13.6% with mean cyst size 7.7 mm (range: 2 to 34 mm). The prevalence of pancreatic cancer was 3.1%. Subsequent imaging was performed in 169 patents with mean follow-up interval of 5.3 years (range: 0 to 19.7 y). The incidence of BD-IPMN was 20.1%, with median cyst size 5.5 mm (range: 2 to 30 mm). The incidence of pancreatic cancer was 2.9%. BRCA2 patients were almost 4-times more likely to develop pancreatic cancer than BRCA1 patients, however, there was no difference in incidence or prevalence of BD-IPMN.
CONCLUSIONS: Incidence and prevalence of BD-IPMNs in BRCA1/2 patients was similar to that reported for average-risk individuals. BRCA2 patients were more likely than BRCA1 patients to develop pancreatic cancer but had similar rates of BD-IPMN.

DOI: https://doi.org/10.1097/MCG.0000000000001683