Next-generation sequencing reveals frequent consistent genomic alterations in small cell undifferentiated lung cancer

Abstract

AimsSmall cell lung cancer (SCLC) carries a poor prognosis, and the systemic therapies currently used as treatments are only modestly effective, as demonstrated by a low 5-year survival at only ∼5%. In this retrospective collected from March 2013 to study, we performed comprehensive genomic profiling of 98 small cell undifferentiated lung cancer (SCLC) samples to identify potential targets of therapy not currently searched for in routine clinical practice.MethodsDNA from 98 SCLC was sequenced to high, uniform coverage (Illumina HiSeq 2500) and analysed for all classes of genomic alterations.ResultsA total of 386 alterations were identified for an average of 3.9 alterations per tumour (range 1–10). Fifty-two (53%) of cases harboured at least 1 actionable alteration with the potential to personalise therapy including base substitutions, amplifications or homozygous deletions in RICTOR (10%), KIT (7%), PIK3CA (6%), EGFR (5%), PTEN (5%), KRAS (5%), MCL1 (4%), FGFR1 (4%), BRCA2, (4%), TSC1 (3%), NF1 (3%), EPHA3 (3%) and CCND1. The most common non-actionable genomic alterations were alterations in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%).ConclusionsGreater than 50% of the SCLC cases harboured at least one actionable alteration. Given the limited treatment options and poor prognosis of patients with SCLC, comprehensive genomic profiling has the potential to identify new treatment paradigms and meet an unmet clinical need for this disease.

Genomic alterations in small cell lung cancer and their clinical relevance

“…The first was our finding that only 58% of our patient cohort carried exome mutations in RB1. Our RB1 results are within the range, however, of several earlier exome studies, which ranged from 39-74% (3)(4)(5)(6)(7). This wide range of results is likely caused by the small cohort sizes studied, as well as the divergent demographic populations of the cohorts.…”

Mutation of cancer driverMLL2results in transcription stress and genome instability

“…For example, the gene encoding MLL2, a histone H3 Lys4 (H3K4) methyltransferase (HMT), is mutated in a large number of different cancers. These include diffuse large B-cell lymphoma (Pasqualucci et al 2011), follicular lymphoma (Okosun et al 2014), medulloblastoma (Parsons et al 2011;Pugh et al 2012), pediatric cancers (Huether et al 2014), breast cancer (Stephens et al 2012), lung carcinomas (The Cancer Genome Atlas Research Network 2012; Ross et al 2014;Yin et al 2014), parathyroid carcinoma (Kasaian et al 2013), esophageal squamous cell carcinoma Song et al 2014), head and neck squamous carcinomas (Seiwert et al 2015), renal carcinoma (Dalgliesh et al 2010), urothelial bladder carcinoma (Balbas-Martinez et al 2013), and prostate cancer (Grasso et al 2012).…”

Molecular and Histological Changes in Post-Treatment Biopsies of Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Study

“…In our case of SCLC transformation, the p.T790M mutation was not detected. In a recent sequencing profiling of SCLC [31], only one case showed the p.T790M mutation, thus confirming the rare occurrence of this resistance mutation in such an histological type known to be resistant to the EGFR targeted therapy.…”