Abstract 3438: Genetic analysis of melanoma from an albino patient
Authors: Bracalente Candelaria , Mundra Piyushkumar , Rinflerch Adriana , Martinez Pablo Garcia , Volonteri Victoria , Trucco Lucas , Galimberti Gaston , Dhomen Nathalie , Rodriguez Valeria Pavet , Marais Richard 
Published: August 2018

Abstract
Melanoma, the deadliest type of skin cancer, derives from the transformation of melanocytes, which protect the skin from ultraviolet radiation (UVR) through the synthesis of melanin. UVR is the major risk factor for melanoma. Intriguingly, in people with oculocutaneous albinism (OCA), who lack or have a reduction in melanin synthesis melanoma is surprisingly rare, whereas other UVR-driven skin cancers are comparatively high. Since UVR exposure and light skin complexion increase melanoma risk, it is unclear why melanoma is rare in OCA. Therefore, we evaluated how the absence of melanin impact the mutation burden in OCA and identify driver mutations by whole exome sequencing (WES) analysis of melanomas from a patient with OCA.
The patient (in their 50s) presented cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in addition to melanoma. The histopathology of one tumor (sample A), located on the left forearm, indicated a desmoplastic nodular melanoma, Clark level III, Breslow of 1 mm and a high mitotic index. The second tumor (sample B) was located on the right knee and presented a superficial spreading melanoma, Clark level II, a Breslow of 0.31 mm and a low mitotic index. For WES, genomic DNA was purified from formalin-fixed paraffin-embedded tissue sections and compared against germline blood. Analysis confirmed a G47D mutation in the TYR gene, which has previously been reported in OCA1B patients. Consistent with sample A coming from an area habitually exposed to UVR, it presented 4874 SNVs and 1556 missense SNVs and a predominant signature 7 mutational process. Similarly, consistent with sample B coming from an area that is habitually protected, it presented only 45 SNVs and 16 missense SNVs and did not present a predominant signature 7 mutational process. Notably, despite the histopathology of the skin adjacent to sample B appeared normal, it presented 39 SNVs and 10 missense SNVs. Intriguingly, all samples harbor NRASQ61K mutations and sample B additionally presented a mutation in NOTCH1, which is more common in SCC. Thus, we show that in OCA, melanomas from a UVR exposed areas present high mutation burden and UV mutational signature, whereas melanomas from UVR protected skin present a low mutation burden. Our data suggest that NRASQ61K is a driver oncogene in melanomas from albinos and that these patients can develop both UVR-driven and UVR-independent melanomas.
Citation Format: Candelaria Bracalente, Piyushkumar Mundra, Adriana Rinflerch, Pablo Garcia Martinez, Victoria Volonteri, Lucas Trucco, Gaston Galimberti, Nathalie Dhomen, Valeria Pavet Rodriguez, Richard Marais. Genetic analysis of melanoma from an albino patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3438.