Lung Cancer in Li-Fraumeni Syndrome

Kerrigan, Kathleen; Chan, Jessica; Vagher, Jennie; Kohlmann, Wendy; Naumer, Anne; Anson, Jo; Low, Sara; Schiffman, Joshua D.; Maese, Luke

doi:10.1200/po.20.00468

Cited by 4 publications

(7 citation statements)

References 27 publications

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“…Previous reports revealed that patients with LFS and advanced lung cancer have a higher frequency of associated somatic mutations compared with the general NSCLC population, with EGFR mutation rates of 40% to 45%. 1 , 4 , 5 In one study, 90% of LFS-associated lung tumors (19 of 21) had somatic oncogenic drivers, in which 18 cases were EGFR -mutated with one patient having a ROS1 fusion. 5 In contrast to those with concurrent somatic TP53 and EGFR mutations, patients with germline TP53 and somatic EGFR mutations still benefit from EGFR TKIs, such as osimertinib.…”

Section: Discussionmentioning

confidence: 99%

“…Germline mutations in the TP53 TSG are the defining feature of the cancer predisposition condition known as Li Fraumeni syndrome (LFS). 1 Lung cancer is a component of the LFS tumor spectrum with a risk of 2% to 7%, though the clinical phenotype of these lung cancers is not well described. 2 Though data are limited, most patients with LFS who develop lung cancer are younger and of the female sex, and reports describe a high incidence of somatic EGFR mutations, with an occurrence rate of up to 40% in one report.…”

Section: Introductionmentioning

confidence: 99%

“… 2 Though data are limited, most patients with LFS who develop lung cancer are younger and of the female sex, and reports describe a high incidence of somatic EGFR mutations, with an occurrence rate of up to 40% in one report. 1 …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report

Marks

Liu

2023

JTO Clinical and Research Reports

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report

Marks

Liu

2023

JTO Clinical and Research Reports

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“…TP53 is recognized to cause Li-Fraumeni syndrome, which causes an increased risk of lung and other cancers. 11,12 Other causal germline variants have been reported in a small number of lung cancer families, including in DICER1 13 ; SFTPA1 14 ; the T790M mutation in EGFR [15][16][17] ; HER2 18 ; BAP1 19 ; PARK2 20 and RGSI7. 21 Nevertheless, causal predisposition genes/variants have not been identified for the majority of lung cancer families studied.…”

Section: Introductionmentioning

confidence: 99%

“…Germline causal variants explain some familial lung cancer pedigrees. TP53 is recognized to cause Li‐Fraumeni syndrome, which causes an increased risk of lung and other cancers 11,12 . Other causal germline variants have been reported in a small number of lung cancer families, including in DICER1 13 ; SFTPA1 14 ; the T790M mutation in EGFR 15‐17 ; HER2 18 ; BAP1 19 ; PARK2 20 and RGSI7 21 .…”

Section: Introductionmentioning

confidence: 99%

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall‐cell lung cancer

Cannon‐Albright

Teerlink

Stevens

et al. 2023

Intl Journal of Cancer

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A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall‐cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC‐affected cousin pairs belonging to high‐risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC‐affected cousin pairs from eight high‐risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.

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The diagnosis of hereditary cancer syndromes with atypical manifestation: clinical cases

Makarova,

Nemtsova,

Belenikin

et al. 2023

Malignant Tumours

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Background: Germinal pathogenic variants are the cause of the development of hereditary cancer syndromes (HCS). Various genetic tests are used for HCS detect, from the «frequent» mutations of one or several genes analysis to the full-length gene sequence, next-generation sequencing (NGS) based panel, whole exome (WES) or whole genome sequencing (WGS).There are some HCS cases with atypical clinical manifestations and the family history does not allow one to suspect a specific HCS and limit oneself to the study of only one or a few genes. Conducting research using NGS to assess the selected sample of cancer patient’s genetic characteristics has revealed atypical HCS cases.Aim: To present the WGS diagnosis results for two atypical hereditary tumor syndromes cases.Materials and methods: DNA isolation was performed using Qiagen DNA Isolation kit. WGS for all samples was performed at DNBSEQ-T7 (MGI) and DNBSEQ-G400 (MGI) sequencing platforms using PCR-free protocol with average sample coverage 30x. A standard bioinformatics analysis pipeline was implemented for all the samples data processing.Potential clinically relevant variants were validated using Sanger sequencing. For all patients was received signed a written consent.Results: In the first case report, a pathogenic variant in the TP53 gene was identified: c. 637C > T, p. Arg213Ter, rs397516436, and Li – Fraumeni syndrome was confirmed. In the second case, we detected two pathogenic variants carrier — BRCA2: c. 6644_6647del, p. Tyr2215SerfsTer13, rs80359616 and MSH2: c. 1906G > C, p. Ala636Pro, rs63750875 associated with hereditary breast and ovarian cancer and hereditary colorectal cancer (Lynch syndrome).Conclusion: NGS, including WGS makes it easier to identify all clinically significant germline variants associated with hereditary cancer syndromes in cancer patients, as well as to trace their segregation in relatives.

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Lung Cancer in Li-Fraumeni Syndrome

Abstract: Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 4 publications

References 27 publications

NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report

NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report

A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall‐cell lung cancer

The diagnosis of hereditary cancer syndromes with atypical manifestation: clinical cases

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