148 Revealing a common, yet novel cutaneous squamous cell carcinoma driver mutation hidden in the photodamaged skin genome

Australia is the ideal place to study genomic drivers of sun induced cancers. The primary risk factor for non-melanoma skin cancer development is a combination of high lifetime exposure to ultraviolet light and a predominantly fair-skinned population that lacks the photoprotective effect of melanin in darker skin types. While a number of other factors play a role, 95% of skin cancers are related to sun exposure. We recruited 25 volunteers and collected 1x cutaneous squamous cell carcinoma (cSCC), 2x actinic keratosis samples (AK), 1x photo damaged (PD) skin samples and 1x blood sample for whole exome sequencing on 24xSCC, 50xAK and 25xPD. We identified 37 significantly mutated genes in cSCC and AK, including previously known driver genes in cSCC and new genes not previously described in cSCC. We found genes with highly recurrent point mutations, many of which were also enriched in the photo damaged skin samples. Validation using single molecule sequencing with PacBio confirmed two neighbouring point mutations in INTS1 (integrator complex subunit 1) in over 75% if the PD, AK and cSCC samples but was never found in the blood samples. This recurrent point mutation has been overlooked as a driver mutation as its location, in an alternative transcript of INTS1, is not included in many exome capture platforms but is observed in about 4% of melanoma samples studied using whole genome sequencing. The classical function of INTS1, as a component of the integrator complex, a complex involved in 3-prime processing and thereby maturation of small nuclear RNAs (snRNA) U1 and U2, has not be connected to tumour development but has an known important role in UV-induced DNA damage response.