• References

    Degasperi A et al. (2022). Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, science.abl9283

    Hu W et al. (2022). Changing trends in the disease burden of non-melanoma skin cancer globally from 1990 to 2019 and its predicted level in 25 years. BMC Cancer 22, 836

    Martincorena I et al. (2015). Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886

    Muse M et al. (2022). Genome-scale DNA methylation analysis identifies repeat element alterations that modulate the genomic stability of melanocytic nevi. J Invest Dermatol 142, 1893-1902

    Shain A et al. (2015). The genetic evolution of melanoma from precursor lesions. N Engl J Med 373, 1926-1936

    Stark M et al. (2018). Whole-exome sequencing of acquired nevi identifies mechanisms for development and maintenance of benign neoplasms. J Invest Dermatol 138, 1636-1644

    Tang J et al. (2020). The genomic landscapes of individual melanocytes from human skin. Nature 586, 600-605

    Vandiver A et al. (2015). Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol 16, 80

     

It Takes a Village: How a Dysfunctional Cellular Community Could Raise a Melanoma

08 February, 2023
It Takes a Village: How a Dysfunctional Cellular Community Could Raise a Melanoma

2022 Bio-Rad Science Writing Competition Winner

Katie’s article about her PhD research topic was both engaging and informative. The judges were particularly impressed by her “it takes a village” analogy to explain how it is the combination of multiple factors that tips the balance toward melanoma formation. 

Katie Lee is a PhD student at the Frazer Institute, University of Queensland, Australia. She has been working on melanoma early detection and prevention research for 10 years, ranging from skin pigmentation genetics to long-running clinical studies of mole and melanoma surveillance. Her PhD project examines the contribution of general genomic landscape dysfunction to melanoma initiation.

We are delighted to publish her entry below:

The skin is a weird and wonderful organ. It’s a tough barrier to protect the rest of our body from the outside world, but that leaves it vulnerable to accumulating damage itself. Visually normal skin is positively awash with mutations – so many more than in another organ, you would suspect cancer (Martincorena et al. 2015). In fact, one third of all human cancers are skin cancers, mostly basal cell carcinomas, squamous cell carcinomas and melanomas (Hu et al. 2022).

Melanomas are particularly deadly skin cancers, although they also have a high cure rate when they’re caught early enough. They usually look similar to benign moles and have many of the same genetic mutations as moles, such as mutations in the BRAF and NRAS genes. Melanoma-linked mutations in these genes encourage a melanocyte cell to divide more often than it needs to (say, to replace itself or repair wounded skin), causing the cells to proliferate into a group of clones. This is an essential first step to forming both moles and melanomas (Shain et al. 2015).

Some melanomas even arise in pre-existing moles, but most pop up on otherwise normal-looking skin with no precursor lesion. You might think that this happens where there are cancer-linked mutations, but it turns out these mutations are also scattered widely across the skin. So why aren’t there melanomas everywhere too?

Figure: There are a million mutations in this image where will the melanoma appear?

Your cells are constantly talking to one another, sending signals asking each other to make more or less of some protein, divide or remain single, migrate, or stay still. They can even detect another cell going rogue and tell it to self-destruct. These signals form a molecular micro-environment that tells each cell what it should do — even what it should be. Usually, this results in a highly regulated, well-functioning group of cells that has everything it needs to be a healthy patch of skin — a self-governing village, if you will. It seems like this regulation is what keeps cells with melanoma mutations in check, so they don’t proliferate out of control.

But there are lots of things that can tip this well-regulated community off balance. In fact, there are several measures of genomic or molecular dysfunction that gradually increase from normal skin, through sun-damaged skin and moles, to melanomas.

The most basic one is mutation burden: the number of mutations per megabase of DNA. Most mutations in the skin are caused by UV light, which leaves a characteristic signature changing C bases to T bases, especially where there are two Cs together (CC > TT). A day at the beach can cause up to 100,000 mutations in each sun-exposed cell. Your skin cells have DNA repair machinery to deal with damage as it happens, but it doesn’t pick up all mutations, and faults in this DNA repair machinery can introduce its own characteristic mutations. Over the years, the missed damage accumulates. As you might expect, skin that is routinely sun-exposed, like the face, has a higher mutation burden than skin that is routinely protected, like the buttock. But as you probably didn’t expect, mutation burden varies wildly across a single small patch of skin in an individual, even though the sites in a single patch presumably have similar UV exposure (Tang et al. 2020). Moles carry more UV signature mutations than the normal skin just beside them, and melanomas have the most mutations of all (Stark et al. 2018, Degasperi et al. 2022).

Another genomic feature of increasing dysfunction is copy number aberrations. These are when large chunks of genes are deleted or amplified so that there are several copies instead of one. There are also structural rearrangements, where large chunks of one or more genes are flipped around, moved to another part of the genome, or broken up into fragments and put back in the wrong order. These aberrations and variants are very common in oncogenes and tumor suppressor genes in melanomas. In moles, they are also very common, but there seems to be a balance between tumor-promoting and tumor-suppressing changes, and more aberrations in sun-exposed moles than sun-protected moles (Stark et al. 2018). We once thought these aberrations were completely absent from normal skin, but more sensitive techniques have shown that they are present in low numbers (Tang et al. 2020).

There are also large changes in DNA methylation, which acts like a long-term off switch for genes that the cell won’t need except under unusual circumstances. Here is where we see big differences between sun-damaged and sun-protected skin, accumulating with age. In people under 35 years old, there are 12 large blocks of DNA that are differently methylated in sun-protected skin compared to sun-exposed skin, but in people over 60 years old, that has jumped to 239 blocks. Many of these demethylated blocks of DNA promote the proliferation of the cells (Vandiver et al. 2015). Moles also have major differences in methylation from normal skin, especially dysplastic moles, an intermediate state between a normal, benign mole and an early melanoma. These have often lost methylation on transposable elements, stretches of DNA that, when not switched off by methylation, can move around the genome by itself and disrupt other genes (Muse et al. 2021). And of course, there are even more methylation changes in melanoma. The amount of demethylation increases as a melanoma progresses, but many tumor suppressor genes have extra methylation, switching them off.

What combination of these factors allows a mutated melanocyte to tip over into a melanoma? For now, we have more questions than answers. Over the next few years, we’ll be able to use new techniques like spatial morphological analysis to show whether there are concentrated collections of these varied types of dysfunction that form “microlesions”, lawless villages of unusually poorly regulated cells that struggle to keep potential melanomas in check. With this information, we hope to target surveillance programs to particularly risky sections of an individual's body. Perhaps it will even reveal drug targets for preventing early melanoma altogether.

In the meantime, take good care of your skin by protecting it from excessive UV exposure on any day when the UV index is above three. Your skin works hard for you — give it a fighting chance!

 

Bio-Rad's Science Writing Competition Results

We were delighted to receive entries from PhD/Grad Students from all around the world. The judges were impressed by the high standard of submitted articles across a vast range of topics. Katie is the winner of a commemorative trophy, a copy of ’The Scientist’s Guide to Writing: How to Write More Easily and Effectively throughout Your Scientific Career’, and Science Writing mentorship.

 

References

Degasperi A et al. (2022). Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, science.abl9283

Hu W et al. (2022). Changing trends in the disease burden of non-melanoma skin cancer globally from 1990 to 2019 and its predicted level in 25 years. BMC Cancer 22, 836

Martincorena I et al. (2015). Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880-886

Muse M et al. (2022). Genome-scale DNA methylation analysis identifies repeat element alterations that modulate the genomic stability of melanocytic nevi. J Invest Dermatol 142, 1893-1902

Shain A et al. (2015). The genetic evolution of melanoma from precursor lesions. N Engl J Med 373, 1926-1936

Stark M et al. (2018). Whole-exome sequencing of acquired nevi identifies mechanisms for development and maintenance of benign neoplasms. J Invest Dermatol 138, 1636-1644

Tang J et al. (2020). The genomic landscapes of individual melanocytes from human skin. Nature 586, 600-605

Vandiver A et al. (2015). Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol 16, 80

 

 

Pen Timer Coaster