Capturing Rare Connections with Cancer

Rare genetic mutations could contribute more strongly to telomere length and cancer-related risk than more common variants in the Singaporean-Chinese population.

Thanks in large part to advances in modern medicine, humans are living longer than ever before. However, this extended lifespan has brought with it new health challenges—most prominently a rise in chronic diseases such as cancer. Understanding the mechanisms that drive cancer could yield much needed insight into ways to promote healthy ageing.

Decades of research have led scientists to numerous cellular processes that could contribute to cancer risk. Today, we better understand the genetic and environmental factors that affect the length of telomeres, the structures found at the end of chromosomes that protect the genetic code from degrading. While telomeres naturally shorten with each cell division, lengthened telomeres are a known hallmark of cancer development.

Like many biological processes, genetic variation can contribute to these variations in telomere length. “Heritability, or the proportion of variance in telomere length that is likely to be determined by inherent genetic factors, is estimated to be approximately 40 percent,” said Rajkumar Dorajoo, a Senior Research Scientist at the Agency for Science, Technology, and Research (A*STAR)’s Genome Institute of Singapore. “On that note, the incidence and mortality of cancers that are on the rise in Asia may display ethnicity-specific genomic disparities.”

While many studies have sought to identify genetic variants linked to telomere length, most have focused on mutations found in more than one percent of the population. These “common” variants, however, explain only five percent of telomere length-related heritability, according to prior findings1 by Dorajoo and Heng Chew-Kiat, Associate Professor at the National University of Singapore’s Yong Loo Lin School of Medicine, hinting at the presence of other more significant factors.

Concentrating on a Chinese cohort

Given the apparent importance of genetics to telomere length, Heng and Dorajoo hypothesised and confirmed that different populations harbour varying inherited factors. They then proposed that rarer mutations, found in 0.5-1 percent of the population, could be a strong contributor to telomere length.

The researchers tested this theory in their latest study published in _Communications Biology_2, in which they focused their new study on a single ethnic group: Singapore’s Chinese population. “We have shown that there might be some ethnic disparities in telomere length dysregulation and as such, hypothesised that this may in turn contribute to differing risks of cancers,” Dorajoo explained.

In the first systematic study to examine the link between genetic factors and telomere length in East Asia, the team analysed genetics data and telomere length measurements taken from the blood samples of over 25,000 Chinese individuals across four local studies: the Singapore Chinese Health Study (SCHS), The Singapore Study of Macroangiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), The Diabetic Nephropathy (DN), and SingHEART/Biobank.

By combining these datasets with specific local reference genetic panels, the researchers evaluated nearly two million Asian-specific rare variants linked to telomere length in the Singaporean-Chinese cohort.

Given that the SCHS included Hokkien and Cantonese dialect groups originating from provinces in Southern China, Dorajoo notes that their findings, while Singapore-specific, may still be representative of wider Southern Chinese populations.

Rare yet revealing

Among their Asian-specific variants, the team identified three novel rare mutations in three genes called POT1, TERF1 and STN1 which are known to control telomere length. Compared to a nearby common variant found previously in the POT1 gene, the rarer POT1 mutation was five times more likely to affect telomere length, demonstrating the potential value of these less-familiar modifications.

The remaining two rarer variants were genetically linked to common variants in the TERF1 and STN1 genes, confirming the team’s hypothesis that rarer mutations that affect telomere length do, in fact, exist. “These variants may have higher effects than previously identified common variants and some may also contribute to cancer risk,” the researchers said.

Importantly, the Asian-specific TERF1 variant showed a direct link to colon cancer risk. Not only was this alteration in the TERF1 gene related to deaths caused by cancer in the Singaporean-Chinese cohort, its relationship to colon cancer could also be attributed to its role in regulating telomere length.

Unexpectedly, the researchers found no association between the variants and breast cancer risk, despite other reports showing a link between longer telomere length and likelihood of the disease. The researchers reasoned that this could be due to an insufficient number of female participants in their study, indicating the need for additional, larger-scale follow-ups.

“It should also be noted that all variants we identified, even in combination, do not fully explain the phenotypic variance of telomere length in our study,” Heng said, adding that more research is needed to identify the full set of genetic factors responsible for regulating telomere length. The researchers have since begun studying the link between disease and telomere length, along with other ageing-related markers, in various biological tissues besides blood.

The team also plan to expand their work to other understudied Asian populations, such as Indian and Malay ethnic groups. “We expect these studies to shed additional insights on ethnic disparities to telomere length homeostasis, chronic disease risks and ageing outcomes,” Heng concluded.

References:

1 Dorajoo, R., Chang, X., Gurung, R. L., Li, Z., Wang, L. et al. Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies. Nature Communications 10, 2491 (2019).

2 Chang, X., Gurung, R. L., Wang, L., Jin, A., Li, Z. et al. Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population. Communications Biology 4, 519 (2021).