For the first time, researchers have illuminated how smoking – a known risk factor for many types of cancer – may lead to a group of blood cancers known as myelodysplastic syndromes (MDS) by way of specific genetic mutations.

The new findings indicate that these potentially harmful mutations accumulate over time, helping to explain why people who smoke more heavily and for a longer period of time can experience worse outcomes with MDS.  

“We have shown that tobacco smoking is associated with specific genetic mutations related to MDS, and when someone smokes for a longer time, they accumulate more mutations and are more likely to progress to MDS,” said Sangeetha Venugopal, MD, the study’s lead author and a physician at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

“Our results show that there is definitely a dose-response relationship and also an association between disease progression and overall survival.” 

MDS develop gradually from several precursor conditions and affect the bone marrow’s ability to produce healthy blood cells. MDS are considered a form of cancer and can also progress to acute myeloid leukaemia, a more aggressive type of blood cancer.

Numerous studies have linked smoking with lung cancer and other solid tumours, but the genetic mechanisms linking smoking with blood cancers such as MDS are not well understood.  

Researchers analysed genetic data, smoking history, and disease progression among nearly 1,900 participants in the National MDS Study, the largest national prospective study of people diagnosed with MDS or one of its precursor conditions.

About half of the participants had a history of smoking and 18% still smoked at the time of their diagnosis.

Among those with any history of smoking, many were heavy tobacco users, reporting smoking about 16 cigarettes per day for nearly 30 years, on average.

Over two-thirds of those with a history of smoking were male, and nearly half were in their seventies.  

Comparing smokers and non-smokers after adjusting for age, sex, and type of disease, the researchers found that smokers had significantly more genetic mutations, with the difference being most pronounced among the heaviest smokers.

Those in the 75th and 90th percentiles for pack-years (a metric that accounts for smoking intensity as well as the total number of years smoked) had 1.8 and 3.5 times the number of mutations, respectively, compared with non-smokers.  

People who had smoked for longer periods of time were also significantly more likely to experience disease progression compared with those who smoked for a shorter period or not at all, with 27% of long-term smokers showing disease progression compared with 18% among nonsmokers and those with a short smoking history.

Some of the genetic mutations implicated in the study, such as ASXL1, had previously been associated with smoking, while several others had not.  

Since the study showed a clear dose-response relationship, meaning that more smoking led to more mutations, researchers said the findings suggest that quitting smoking can potentially help to reduce MDS risk for those with precursor diagnoses, and may lower the risk of MDS progressing to a more aggressive cancer.

Doctors can support patients by broaching the topic multiple times – recognising that quitting can be especially challenging for lifelong smokers – and helping patients access tobacco cessation aids.  

“This study can give doctors more reason to have a discussion with patients who may be still smoking at the time of their diagnosis, to let them know that the progression can be worse and encourage them to consider tobacco cessation,” said Dr. Venugopal.

“I don’t want to encourage patients to blame themselves for their blood cancer, but I also don’t want them to have an unhealthy habit that may affect their disease progression, so we have to strike a balance.” 

Since the research was based on data from a study of people with MDS or precursor conditions, it is unclear whether some of the same mutations identified in the study are also present in people with a history of smoking who do not have these conditions.

Researchers suggested that future studies involving smokers without MDS or related conditions could help to further clarify the genetic mechanisms and risk factors involved.  

This study was funded by the National Heart, Lung, and Blood Institute.  

Source: The American Society of Hematology