A team of doctors and researchers say they have found a new, rare type of small cell lung cancer that worryingly, primarily affects younger people who have never smoked.
Their findings – published in Cancer Discovery and which include a detailed analysis of the clinical and genetic features of the disease – also highlight vulnerabilities that could help doctors make better treatment decisions for people diagnosed with it.
“It’s not every day you identify a new subtype of cancer,” said Natasha Rekhtman, MD, PhD, a pathologist at Memorial Sloan-Kettering Cancer Centre (MSK) who specialises in lung cancer and is the first author of the paper that presents the team’s analysis.
“This new disease type has distinct clinical and pathological features, and a distinct molecular mechanism,” she added.
The study brought together the expertise of 42 physicians and researchers across MSK – from the doctors who treat lung cancer and the pathologists who evaluate cells and tissues to make a diagnosis, to specialists in tumour genetics and computational analysis.
“Understanding this new cancer required a broad spectrum of expertise from the laboratory to the clinic,” said Charles Rudin, MD, PhD, a lung cancer specialist and the study’s senior author.
Defining new lung cancer subtype
Small cell lung cancer (SCLC) is relatively rare to begin with, accounting for 10% to 15% of all lung cancers, according to the American Cancer Society. And the newly discovered subtype accounts for just a fraction of those. Out of 600 patients with SCLC whose cancers were analysed for the study, only 20 people (or 3%) were found to have the rare subtype.
SCLC is normally characterised by the deactivation of two genes that protect against the development of cancer – RB1 and TP53 – but patients with the new subtype have intact copies of those genes. Instead, most carried a signature “shattering” of one or more of the chromosomes in their cancer cells, an event known as chromothripsis.
The new subtype appears to arise through a transformation of lower-grade neuroendocrine tumours (pulmonary carcinoids) into more aggressive carcinomas. The research team has dubbed the new type “atypical small cell lung carcinoma”.
“Patients who develop small cell lung cancer tend to be older and have a significant history of smoking,” said Dr Charles Rudin, deputy director of MSK’s Cancer Centre.
“The first patient we identified with atypical SCLC, and whose case led us to look for more, was just 19-years-old and not a smoker.”
This held true for the others with the subtype as well. The mean age at diagnosis was 53 – which is considered young; the average age for a lung cancer diagnosis is 70. Sixty-five percent of these patients were never smokers, while 35% reported a history of light smoking (less than 10 pack-years).
Treatment
The analysis also found that the unique genomic changes that give rise to atypical SCLC mean that standard, first-line, platinum-based chemotherapies don’t work as well. And their findings point toward some treatment strategies that may work better.
“We often talk about cancer as an ongoing build up of mutations,” Rekhtman said.
“But this cancer has a very different origin story. With chromothripsis, there’s one major catastrophic event that creates a Frankenstein out of the chromosome, rearranging things in a way that creates multiple gene aberrations, including amplification of certain cancer genes.”
That's why patients with atypical SCLC may benefit, for example, from investigational drugs that target the unusual DNA structures that result from chromothripsis, known as extra-chromosomal circular DNA, the researchers note
Study details
Chromothripsis-mediated small cell lung carcinoma.
Natasha Rekhtman, Sam Tischfield, Charles Rudin et al.
Published in Cancer Discovery on 26 August 2024
Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis – massive, localised chromosome shattering – recurrently involving chromosomes 11 or 12, and resulting in extrachromosomal (ecDNA) amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumours exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterised mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumours or their progenitors. Conversely, SCLC in never-smokers harbouring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.
Cancer Discovery article – Chromothripsis-mediated small cell lung carcinoma (Open access)
See more from MedicalBrief archives:
Updated US guidelines urge more lung cancer screening
Do regular cancer screenings extend life?
Stopping smoking before 45 can wipe out 87% of lung cancer risk