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Mysteries, myths, and malignancy in skin cancers; highlighting three new studies in COSMIC v98

23 May 2023

One in every three cancers diagnosed currently is a skin cancer, making this the most commonly diagnosed group of cancers in the UK despite frequent under reporting of cases. Certain skin cancers are considered relatively ‘easy’ to treat and cure, so they’re left out of national cancer statistics, but this isn’t the whole story. ‘Skin cancer’ covers a broad range of unique cancers with varying symptoms, causes and mortality rates, which predominantly fall into two categories:

  • Non-melanoma (between 2-3 million occur globally each year)
    • More commonly occurring of the two categories
    • Covers all skin cancers that arise in the uppermost layers of the skin
    • Two of the most common cancers that fall into this category are basal cell carcinoma and squamous cell carcinoma
    • Known to develop slower than melanomas.
  • Melanoma (around 132,000 occur globally each year)
    • The subject of many public awareness campaigns
    • These cancers develop within melanocytes
    • Often characterised by moles on the skin altering in size, colour and shape
    • Widely known that many melanomas can be directly linked to DNA damage from UV (ultraviolet) radiation.

From segments on talk shows, to far reaching social media initiatives and even apps that scan and analyse concerning skin blemishes, public awareness campaigns surrounding melanoma symptoms have been both prominent and successful in recent years. While this impact is incredible, the causes, symptoms and effects of skin cancers as a whole, span much further than what is common public knowledge and thus, some questions need to be raised.

How aware are the public of rare skin cancers? How do they differ from the most common forms of skin cancer? And of course, what progress is being made in our deeper understanding of these diseases?

With all of these questions in mind, our team of expert curators within COSMIC have been working tirelessly to put together the COSMIC v98 update with a focus of rare skin tumours.

Often, with high occurrence of a disease type in the population, comes over-representation in scientific literature and of course, over-representation in databases. The v98 update aims to tackle these biases directly. We already have a vast amount of data on the most common forms of skin cancer but our expert curators have been hunting for high-quality data on some of the rarer subtypes. With information sourced on adnexal tumours, Merkel cell carcinoma, Kaposi sarcoma and many more, this update covers a plethora of different tumour types, 17 of which are new to our histology classification system.

Taking inspiration from our curation team’s aim to improve representation of these rarer diseases, we wanted to highlight the broad range of information out there that’s rarely in the spotlight. So, here’s a sneak peek into new data coming to COSMIC May 23 2023 and three things you may not know about rare skin tumours and cancers.

Not all skin tumours are linked to UV light exposure

Public communication surrounding skin tumours focuses heavily on self assessment of concerning moles and educating people on the harmful effects of excessive UV light exposure. Encouraging correct use of sun protection creams, recommendations to avoid sunbeds and gel nail polish drying devices, are pieces of advice that have become ingrained in the minds of so many when it comes to reducing the risk of skin cancers. While this may be helpful advice detection and prevention of many types of both melanoma and non-melanomas, this is not the case for all.

One of many examples of this is Kaposi sarcoma (KS). A soft tissue carcinoma, KS arises in endothelial cells and while it does occur on the skin, it can also affect a patient internally (e.g the gastrointestinal tract). KS is known to be caused by the virus: human herpesvirus 8 (HHV-8) (also known as Kaposi's sarcoma-associated herpesvirus (KSHV) which is mostly transmitted sexually. While the virus itself is relatively common, escalation into KS is associated with immunosuppression in the patient and as a result, KS disproportionately affects those living with HIV.

One paper curated as part of the COSMIC v98 update is a first of its kind study into this cancer, which aimed to decipher genetic features that distinguish indolent from aggressive KS (defined as: requiring systemic therapy) through genome wide analysis of whole exome screens of 21 KS patients. G.G. Malouf and team particularly focused on differences in the tumour mutational burden (TMB) (based on total number of non-synonymous somatic, coding, base-substitution, splice-site and indel mutations) between these two forms of KS.

Perhaps unsurprisingly, they found that aggressive KS tumours had significantly higher TMB. 62.5% of aggressive tumours harboured deleterious mutations of significant Cancer Gene Census genes - including CHEK2, FBXW7 and ARID1A. Further to this, their data showed indolent KS tumours contained a maximum of one deleterious somatic mutation in comparison to the aggressive form, where at least three were present in each sample. This implies a link between the number of acquired mutations in driver genes and the aggressiveness of the cancer. Malouf and team also found no association between the type/cause of the KS (e.g HIV, organ transplant) and severity. Longterm, this research aimed to contribute to the improvement of the prediction of outcomes for these tumours.

As mentioned above, KS is just one of a larger number of skin cancers with no link to UV cancer. If you’re curious to explore the subject further, why not read our blog on Dr Carla Daniela Robles-Espinoza’s research into acral lentiginous melanoma, a form of skin cancer disproportionately affecting lower income populations that most frequently develops on the palms of the hands on soles of the feet.

Associated syndromes:

Sebaceous gland carcinoma (SGC) is one of the rarest forms of skin cancer and most commonly presents on the eyelid. While these tumours can arise spontaneously, an interesting facet of this disease is an extremely strong link with other syndromes.

Lynch syndrome (LS), (also known as, hereditary nonpolyposis colorectal cancer (HNPCC)) is an inherited syndrome with increased risk of development of a range of cancers including colorectal, endometrium and stomach. 1 in 279 US citizens are estimated to be living with LS which results from germline mutations in genes involved in DNA mismatch repair (MLH1, MSH2, MSH6, PMS2, and EPCAM) leading to microsatellite instability.

LS is best known for being the leading cause of hereditary colon cancer but one phenotypic variant of this disease also confers a risk of sebaceous gland carcinoma. Muir-Torres (MT) syndrome is an autosomal dominant subtype of Lynch syndrome, characterised by sebacous gland carcinoma co-occuring with other tumours, particularly those in the gastrointestinal tract.

Lynch syndrome cases are widely thought to be under-reported, causing experts to suspect it is more prevalent than statitics suggest and subsequently, so are its associated subtypes such as MT. Better diagnosis of LS can only be achieved through further research into the syndrome itself, such as a 2014 Švec et al study included in the v98 update.

Švec et al conducted molecular genetic analysis of the genomic DNA of a patient suffering with MT and revealed the germline point mutation c. 2194A>T in the last exon of the MLH1 gene. Prior to this research, this mutation had only been reported in one other LS patient, but this patient did not have the MT subtype.

MLH1 gene 3D model

MLH1 (E.coli MutL homolog gene) functions as a component of several MutL complexes which contribute to the recognition and repair of base pair mismatches and small indels which arise during DNA replication.

This nonsense mutation in the gene led to a truncated protein in C-terminal region p. Lys732X, disrupting the function of MutL complexes. More specifically, this prevented interaction with PMS1 and PMS2 (mismatch repair complex components) by impairing the endonuclease active site. As previously mentioned, LS is known to be caused by mutations in DNA mismatch repair genes, making this relatively unique mutation very significant. The significance of the mutation and subsequent loss of MLH1 activity was truly solidified when further testing showed it to be present in samples from every tumour analysed including colon, uterine and gastric in addition to sebaceous.

Complex manifestations of diseases such as LS, MT, gastrointestinal cancer and SGC can easily be under-studied and under-represented in bodies of research focused on more common syndromes and diseases. In such complex relationships such as LS, MT, gastrointestinal cancer and SGC, it is easy for the rarest problem to become swamped under research and information focused on the other syndromes and diseases. While this is understandable, research like that by Švec et al illustrates how detailed study of all facets of a disease can be indispensable to further understanding of the disease and diagnosis.

Merkel cell mysteries:

Between 1999 and 2008, there were only around 1,500 cases of an extremely rare and aggressive form of cancer - Merkel cell carcinoma (MCC) - diagnosed in the UK. It is known that MCC arises in the merkel cells in the epidermis, which have the primary function of responding to light touch stimuli. Due to the rareness of this disease, it has been hard to study.

MCC presents a number of mysteries to the scientific community. Firstly, Merkel cells secrete certain hormones and are thus also known as neuroendocrine cells, but interestingly, the reason behind these hormone secretions is unknown.

The second enigma is understanding the exact cause of MCC. The development, much like KS, is strongly linked to both immunosuppression and a viral infection (in this case, Merkel Cell Polyomavirus (MCPyV)). Around 80% of MCC cases are caused by an MCPyV infection, but unlike KS, one of the other most common causes of this disease is thought to be excessive exposure to UV light. Despite strong evidence linking exposure to disease, the mystery remains as to the exact mechanisms involved.

Thankfully despite the infrequent occurrence of this disease in the general population, a range of research into the complexities of MCC continues. COSMIC V98 includes data from a paper that’s tackling a key conundrum in MCC: Does the cause (e.g viral vs non viral) affect clinical or molecular characteristics of a patient’s specific MCC.

To investigate this, Starrett et al developed their own hybrid capture baitset against the genome of MCPyV to maximise sensitivity of their viral vs non-viral diagnoses. This method allowed for targeted next generation sequencing analysing over 400 genes in the genomes of 71 MCC patients.

Overall, they discovered significant differences between viral and non-viral MCC, but these appeared to be mostly genotypic rather than phenotypic. For example, significant differences in the TMB of the two MCC types. Specifically, they found that non-viral MCC had a much higher TMB than viral MCC and all but one of these non-viral samples contained the UV light mutational signature (SBS38) . The study did find a link between immunosuppression, virus negative MCC and significantly shorter survival time (8 out of 10 immunosuppressed cases were virus negative!).

This research comprised rich characterisations of observed MCC genotypes, phenotypes and mechanisms of tumour development. While studies like Starrett and team’s are not definitive, they do begin to ‘lift the lid’ on these complex and lesser known diseases, in this case highlighting significant risk populations.

More than meets the eye

These rare forms of tumours and skin cancers may directly affect fewer people in comparison to other diseases, but better understanding of the unique mechanisms involved has a much further reach than it first seems. Take SGC for example; an extremely rare disease. Unravelling the inner workings of a disease with a plethora of comorbidities has benefits far beyond one niche population, it impacts a broad spectrum of patients. We’re immensely proud to highlight cancer research that does precisely this, and it’s the anticipation of these positive domino effects among so many more factors that makes our team elated to release COSMIC v98 23 May 2023!

For further updates on the release and all things COSMIC, you can opt in to marketing communications via your account or follow us on twitter and linkedin.


COSMIC, the Catalogue Of Somatic Mutations In Cancer, is the most comprehensive resource for exploring the impact of somatic mutations in human cancer. Here on our news page we aim to give you an insight into what we are doing and why. We will keep you updated with new developments and release information as well as any events we are hosting.









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