Lung Cancer Patients with Germline Mutations Detected by Next-Generation Sequencing and/or Liquid Biopsy

Shukuya, Takehito; Patel, Sandipkumar; Shane-Carson, Kate; He, Kai; Bertino, Erin M.; Shilo, Konstantin; Carbone, David P.

doi:10.1016/j.jtho.2017.09.1962

Cited by 15 publications

(12 citation statements)

References 1 publication

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“…Recent studies have identified genes in which germline mutations are associated with lung cancer, even in non-smokers, including EGFR, BRCA2, TP53 , and others (1, 2). However, little is known about the relationship between lung cancer risk and germline mutations that underlie common hereditary cancer syndromes, such as Lynch syndrome, which is caused by mutations in DNA mismatch repair (MMR) genes including MSH2, MSH6, MLH1 , and PMS2 .…”

Section: Introductionmentioning

confidence: 99%

Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study

et al. 2019

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Background: Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can also detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we also investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients. Methods: A retrospective study of 1,179 lung cancer patients with available paired NGS data was performed to identify germline mutations in the MMR genes MLH1, MSH2, MSH6 , and PMS2 , and evaluate tumor mutation burden (TMB). Microsatellite instability (MSI) testing was done on select cases with MMR gene mutations by either NGS or PCR/capillary electrophoresis approach. Immunohistochemistry (IHC) for MMR proteins was performed in select patients. Results: Pathogenic or likely-pathogenic germline mutations in PMS2, MSH2 , or MSH6 were detected in 0.5% (6/1,179) of lung cancer patients; three of the patients had a family history of colon or gastric cancer. The median age at diagnosis of these cases was 68.5 years old. None of these six patients exhibited MSI or loss of MMR protein expression. Among them, no second hit somatic mutations in MMR genes (including single-nucleotide variants, small insertions or deletions and copy number alterations) were detected, and the median TMB was 4.5 muts/MB. Subsequent genetic testing of family members identified new Lynch syndrome cases in two first-degree relatives. Conclusion: These data imply that lung cancers in Lynch syndrome patients are unrelated to the underlying Lynch syndrome diagnosis and occur spontaneously. Nonetheless, paired tumor-normal NGS can identify germline mutations to help reveal Lynch syndrome in cancer patients. This has important implications for cancer screening and risk reduction in these patients and their families.

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Section: Introductionmentioning

confidence: 99%

Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study

et al. 2019

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“…Our literature search revealed several other studies on plasma cfDNA testing that also used MAF to identify secondary potentially germline findings. However, unlike our case, these studies used germline testing of the same individuals to confirm their findings ( 24 , 25 ). Hu et al reported a patient with metastatic lung adenocarcinoma and positive family history of lung cancer who had both EGFR L858R and EGFR T790M mutations on tissue NGS.…”

Section: Discussion and Review Of Literaturementioning

confidence: 79%

“…Another characteristic of a germline alteration is a relatively consistent MAF over sequential tests. In contrast, somatic alterations tend to fluctuate, as illustrated in the other case report referenced above ( 25 , 27 ). While the alteration identified in our patient’s assay was not one of the BRCA1/2 founder mutations, it is a mutation that is well-documented in the clinical literature as occurring in the germline setting and is known to be pathogenic.…”

Section: Discussion and Review Of Literaturementioning

confidence: 84%

“…An underlying germline mutation was suspected due to the MAF being at a frequency suspicious for germline alterations. Germline status was confirmed after referral to genetic counseling and germline testing ( 25 ). In a third study examining samples from over 10,000 patients, 1.7% ( n = 173) of patients had a putative germline alteration identified on cfDNA, with the majority of these alterations having an MAF ranging between 40 and 55% ( 26 ).…”

Section: Discussion and Review Of Literaturementioning

confidence: 99%

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Secondary Germline Finding in Liquid Biopsy of a Deceased Patient; Case Report and Review of the Literature

et al. 2018

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Liquid biopsies are increasingly used in the care of patients with advanced cancers. These tests are used to find mutations and other genomic alterations, quantify these findings over time, and guide treatment. It is not unexpected that germline mutations contributing to the development of cancer can be identified in cell-free DNA. Consequently, increased use of liquid biopsies has resulted in subsequent rise of secondary identification of germline mutations. Clinicians need to be aware of this potential use of liquid biopsies and the need to evaluate the patient and family members for confirmation. Our case documents a deceased patient’s liquid biopsy result that was confirmed as a germline mutation through a methodical work-up of the patient’s family members. Here, we present the case and provide a brief review of pertinent literature.

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“…However, the existence of acquired resistance mechanisms remains unclear. Although colorectal cancer with Lynch syndrome might respond well to ICIs (5), the effectiveness of ICIs in lung cancer is uncertain due to the distant relationship between lung cancer and Lynch syndrome (6). In this paper, we report a patient diagnosed with advanced lung squamous cell carcinoma with a background of Lynch syndrome and high…”

Section: Introductionmentioning

confidence: 99%

The influence of STK11 mutation on acquired resistance to immunotherapy in advanced non-small cell lung cancer with Lynch syndrome: a case report and literature review

Long¹,

Tang²,

Cai³

et al. 2021

Ann Palliat Med

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Immune checkpoint inhibitors (ICI) monotherapy or combination therapies have become increasingly popular in patients with advanced non-small cell lung cancer (NSCLC). However, there are still many unknowns concerning the predictive bio-markers and resistance mechanisms to immunotherapy.Patients with primary tumor STK11 mutation reportedly to have a lower response rate than the STK11 wildtype and possibly a primary resistance mechanism to ICIs. However, there is presently no data regarding the contribution of STK11 to acquired resistance to ICIs. Herein we report on a patient who was diagnosed with advanced lung squamous cell carcinoma accompanied by Lynch syndrome. The patient developed an STK11 mutation after receiving pembrolizumab as a first-line treatment. Programmed death ligand 1 (PD-L1) was highly expressed (50%) in the biopsy. HRAS Q61L and TP53 R158L were mainly detected.Unexpectedly, the patient carried an MSH6 heterozygous germline mutation, and was classified as proficient mismatch repair (pMMR). The patient subsequently received pembrolizumab (200 mg, ivgtt, q3w) as first line therapy and achieved stable disease (SD) as the best response. After eight treatment cycles, the patient suffered disease progression (PD), and an STK11 frameshift mutation was newly identified in his plasma circulating tumor deoxyribonucleic acid (ctDNA). This case study suggests that STK11 could contribute to pembrolizumab acquired resistance. Furthermore, the patient was also diagnosed with Lynch syndrome, which rarely occurs in lung cancer.

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Lung Cancer Patients with Germline Mutations Detected by Next-Generation Sequencing and/or Liquid Biopsy

Cited by 15 publications

References 1 publication

Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study

Identification of Germline Mismatch Repair Gene Mutations in Lung Cancer Patients With Paired Tumor-Normal Next Generation Sequencing: A Retrospective Study

Secondary Germline Finding in Liquid Biopsy of a Deceased Patient; Case Report and Review of the Literature

The influence of STK11 mutation on acquired resistance to immunotherapy in advanced non-small cell lung cancer with Lynch syndrome: a case report and literature review

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