Germline variants in DNA repair genes are associated with young-onset head and neck cancer

Cury, Sarah Santiloni; Miranda, Priscila Mayrink de; Marchi, Fábio Albuquerque; Canto, Luísa Matos do; Chulam, Thiago Celestino; Petersen, Annabeth Høgh; Aagaard, Mads M.; Pinto, Clóvis Antônio Lopes; Kowalski, Luiz Paulo; Rogatto, Sílvia Regina

doi:10.1016/j.oraloncology.2021.105545

Cited by 11 publications

(14 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The high prevalence of cancer in young patients is a feature associated with hereditary cancer syndromes. Recent studies described the germline variants of CDKN2A , RECQL4 , and SDHB in the DNA repair genes associated with a high risk of head and neck cancer in young patients [ 21 , 22 , 23 ]. Previously, we described the PHF21B deletion, loss of function, and changes in DNA methylation in HNC patients with a family history of cancer [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…We found rare germline CNVs in 13 of 18 unrelated index patients. No alterations were detected, compared to the gene list of head and neck cancer-associated genes ( Table S1 from reference [ 23 ]). Interestingly, three patients with oral cavity tumors (51.1, 207, and 339) presented gains encompassing WDR genes ( WDR83 , WDR19 , and WDR47 , respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenic germline variants in CDKN2A , RECQL4 , and SDHB were described as associated with a high risk of oral carcinomas in young patients [ 21 , 22 ]. Recently, we described an association between the germline variants in DNA repair genes with an increased risk of HNC development in young patients [ 23 ]. We also found that germline variants in DNA repair genes could improve survival, while the FAT1 germline alterations were associated with worse survival [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we described an association between the germline variants in DNA repair genes with an increased risk of HNC development in young patients [ 23 ]. We also found that germline variants in DNA repair genes could improve survival, while the FAT1 germline alterations were associated with worse survival [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

et al. 2022

Self Cite

View full text Add to dashboard Cite

Inherited cancer predisposition genes are described as risk factors in head and neck cancer (HNC) families. To explore the clinical and epidemiological data and their association with a family history of cancer, we recruited 74 patients and 164 relatives affected by cancer. The germline copy number alterations were evaluated in 18 patients using array comparative genomic hybridization. Two or more first-degree relatives with HNC, tobacco-associated tumor sites (lung, esophagus, and pancreas), or other related tumors (breast, colon, kidney, bladder, cervix, stomach carcinomas, and melanoma) were reported in 74 families. Ten index patients had no exposure to any known risk factors. Family members presented tumors of 19 topographies (30 head and neck, 26 breast, 21 colon). In first-degree relatives, siblings were frequently affected by cancer (n = 58, 13 had HNC). Breast cancer (n = 21), HNC (n = 19), and uterine carcinoma (n = 15) were commonly found in first-degree relatives and HNC in second-degree relatives (n = 11). Nineteen germline genomic imbalances were detected in 13 patients; three presented gains of WRD genes. The number of HNC patients, the degree of kinship, and the tumor types detected in each relative support the role of heredity in these families. Germline alterations may potentially contribute to cancer development.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…High expression of NOTCH1 correlated with better overall and disease-free survival in HNSCC patients [ 30 ]. Young-onset head and neck cancer patients with FAT1 germline variants had a shorter overall survival [ 31 ]; therefore, restoration of the functional NOTCH1 or FAT1 expression in nonsense mutation NOTCH1 or FAT1 in HSNCC is a key issue in anticancer therapy. In this study, we treated two HNSCC cell lines with nonsense mutations of NOTCH1 and FAT1 with PTC124 and measured the change in the cell proliferation of these two tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation

et al. 2022

Biomedicines

View full text Add to dashboard Cite

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate NOTCH downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1–YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a NOTCH signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

show abstract

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late‐onset cancers

Hao,

Zhao,

Fan

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

BackgroundPathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer‐associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late‐onset cancer types has not been comprehensively evaluated to date.MethodsA total of 131 young cancer patients (1–29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late‐onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head–neck cancer. Cancer PGVs were identified and analyzed. based on NGS‐based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity.ResultsTwenty‐three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all‐age patients, was revealed.ConclusionThis study demonstrates the high prevalence of PGVs in young cancer patients with the common late‐onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head–neck cancer.

show abstract

Germline variants in DNA repair genes are associated with young-onset head and neck cancer

Cited by 11 publications

References 50 publications

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

Epidemiological, Clinical, and Genomic Profile in Head and Neck Cancer Patients and Their Families

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation

Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late‐onset cancers

Contact Info

Product

Resources

About