Germline mutation and aberrant transcripts of <i>WWOX</i> in a syndrome with multiple primary tumors

Xu, Ao; Wang, Wei; Nie, Jinfu; Lui, Vivian Wai Yan; Hong, Bo; Lin, Wenchu

doi:10.1002/path.5288

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…Another study reported that germline variants (p.W606X, IVS1762-1G > A, p.T507fs, and p.T642fs) in EXT2 were found in 4 out of 1026 patients with non-small cell lung cancer [ 32 ]. Interestingly, a female patient with early-onset multiple primary tumors was reported to have a germline homozygous WWOX variant (NC_000016.9:g.79245877_79245881dup) [ 33 ]. Multiple germline variants in GATA2 predispose individuals to familial myelodysplastic/acute leukemia syndrome [ 34 , 35 ], while germline GPC3 variants are observed in Simpson-Golabi-Behmel syndrome, an overgrowth syndrome that increases the risk of developing Wilms tumor, hepatoblastoma, and neuroblastoma [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Lee,

Hum,

Zihara

et al. 2023

Hum Genomics

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Background Cancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung. Methods Exome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case–control association analyses were performed. Results Altogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations. Conclusions We have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.

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Section: Discussionmentioning

confidence: 99%

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Lee,

Hum,

Zihara

et al. 2023

Hum Genomics

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“…Recently, a 26‐year‐old patient with early occurrence of multiple primary tumors was identified with a germline homozygous insertion variant c.1425_1426insGTAAA in the 3′ UTR of WWOX (NM_016373.3). Even though multiple abnormal WWOX transcripts were detected in the patient's normal intestinal tissue, this subject did not present any neurological phenotypes (Xu et al, 2019). Further follow‐up of long‐term survivors with WOREE syndrome may provide further clinical clues whether there is an increased cancer risk.…”

Section: Discussionmentioning

confidence: 96%

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Chong

Cao

Fung

et al. 2022

American J of Med Genetics Pt A

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WWOX biallelic loss‐of‐function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX‐related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

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“…Loss or reduced expression of WWOX has been associated with breast cancer development and progression [ 23 , 25 , 52 – 58 ]. As a tumor suppressor gene and a scaffold protein, WWOX plays a crucial role in regulating multiple cellular processes, including cell growth, apoptosis, DNA repair, and maintenance of genomic stability [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection

Bidany-Mizrahi,

Shweiki,

Maroun

et al. 2024

Cell Death Discov.

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Breast cancer is the leading cause of cancer-related deaths in women worldwide, with the basal-like or triple-negative breast cancer (TNBC) subtype being particularly aggressive and challenging to treat. Understanding the molecular mechanisms driving the development and progression of TNBC is essential. We previously showed that WW domain-containing oxidoreductase (WWOX) is commonly inactivated in TNBC and is implicated in the DNA damage response (DDR) through ATM and ATR activation. In this study, we investigated the interplay between WWOX and BRCA1, both frequently inactivated in TNBC, on mammary tumor development and on DNA double-strand break (DSB) repair choice. We generated and characterized a transgenic mouse model (K14-Cre;Brca1fl/fl;Wwoxfl/fl) and observed that mice lacking both WWOX and BRCA1 developed basal-like mammary tumors and exhibited a decrease in 53BP1 foci and an increase in RAD51 foci, suggesting impaired DSB repair. We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis.

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Germline mutation and aberrant transcripts of WWOX in a syndrome with multiple primary tumors

Cited by 4 publications

References 12 publications

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection

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