KAIMRC Innovations Issue 9

Page 64

A scanning electron micrograph of prostate cancer cells.

Pinning down a genetic cause of increased prostate cancer risk Propensity hinges on the regulatory role of a rare genetic variant 64

June 2021

M

en of African ancestry are more than twice as likely as other populations to develop prostate cancer. Genetic components partly contribute to this disparity, but their role is ill-defined. An international team has now determined how a rare genetic variant prevalent in men of African ancestry increases their risk¹. Several variants at chromosome region 8q24 have been linked with different types of cancer. The region is home to various genes that are more strongly expressed in prostate tumours, including multiple long non-coding genes (lncRNAs) and the protein-coding proto-oncogene MYC, a gene that can contribute to cancer when mutated. The non-coding region of 8q24 also contains rs72725854, a rare genetic variant with a pivotal role in the elevated prostate cancer risks in men of African ancestry. However, the relationship between rs72725854 and its neighbouring genes has been unclear.

Walavalkar, K., Saravanan, B., Singh, A.K, Jayani, R.S., Farooq, U. et al. A rare variant of African ancestry acti-

vates 8q24 lncRNA hub by modulating cancer associated enhancer. Nature Communications 11, 3598 (2020).

S CI E NCE P HOTO L I BR A RY / A L A M Y S TOCK P HOTO

The team devised an approach relating three-dimensional chromatin structure to transcriptional regulation in order to establish the functional relevance of rs72725854. This enabled them to reveal a mechanism behind the heightened prostate cancer risk. “This is the first functional study that mechanistically links a rare variant in non-coding genome with disease susceptibility,” says team leader Dimple Notani, from the Tata Institute for Fundamental Research in India. DNA-protein interaction analysis revealed that the region containing rs72725854 acts as a prostate cancer-specific enhancer. The region was inactive in healthy cells and turned into an extremely active androgen-responsive enhancer in prostate cancer cells. The researchers found that, unlike its non-risk counterparts, the risk allele of rs72725854 amplified the activity of the enhancer by binding to the transcription factor SPDEF, a sequence-specific DNA-binding protein that controls transcription rate. This promoted the response of the enhancer to androgen stimulation. Structural analysis showed that the enhancer physically interacted with lncRNAs and MYC promoters by forming chromatin loops, which increased the expression of the genes. The proximity of allele-bound SPDEF augmented the activity of the enhancer, boosting the expression of nearby lncRNAs and MYC. “This study helps us better understand the causes of complex diseases, such as prostate cancer, which is valuable for designing diagnostic tools and therapeutics,” Notani says. The team is currently planning to apply their approach to understand risk factors to other complex diseases, such as the susceptibilities of the Indian population to metabolic diseases like diabetes. “That would pave the way for more efficient diagnostic tools and, ultimately, treatments for these diseases,” Notani says.


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Articles inside

DIVERSE DISORDERS FROM A SINGLE SOURCE

2min
page 65

PINNING DOWN A GENETIC CAUSE OF PROSTATE CANCER RISK

2min
page 64

SEQUENCING IMMUNE SYSTEM GENES FOR STEM-CELL TRANSPLANTS

2min
pages 60-61

A MOLECULAR LINK BETWEEN DIABETES, OBESITY, AND CELL AGEING

2min
pages 62-63

A KEY ROLE FOR MICROGLIA IN CHILDHOOD GLAUCOMA

2min
pages 58-59

INVESTIGATING THE FACTORS AFFECTING BURN PATIENT SURVIVAL

17min
pages 51-57

AI-SUPPORTED DECISION-MAKING IMPROVES SKIN CANCER DIAGNOSIS

2min
pages 48-49

REDUCING INFLAMMATION REJUVENATES BRAIN CELLS IN MICE

5min
pages 40-41

THE GENETIC ROOTS OF RARE DEVELOPMENTAL DISORDERS

6min
pages 44-45

HOW MELANOMA MANIPULATES ITS WAY TO METASTASIS

2min
pages 46-47

FAMILY SUPPORT HASTENS RECOVERY

2min
page 50

DEPRESSION LINKED TO PREMATURE BRAIN AGEING

5min
pages 42-43

TURNING SCIENTIFIC DISCOVERIES INTO COMMERCIAL SOLUTIONS

4min
pages 38-39

COVID-19 IMPACT DOES NOT END WITH HOSPITAL DISCHARGE

2min
pages 36-37

DNA SEQUENCING ACCELERATES INFECTION DIAGNOSIS

3min
pages 16-19

CHADOX1: MORE THAN A CORONAVIRUS VACCINE

5min
pages 32-34

COVID-19 INFECTION RATE WAS LOW AMONG HEALTHCARE WORKERS EARLY IN THE PANDEMIC

2min
page 27

OPTIMISING INFLUENZA VACCINES TO HARNESS PRE-EXISTING IMMUNITY

2min
pages 10-11

ANTIBIOTIC RESISTANCE IN CIRCULATING BACTERIAL STRAINS

2min
pages 14-15

BETTER ANIMAL MODELS FOR COVID-19 NEEDED

2min
page 35

FIGHTING THE PANDEMIC ON ALL FRONTS

5min
pages 8-9
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