?Fig

?Fig.22 ). in being associated with myeloma. is a stabiliser of p53. Long term survivorship after high dose DNA damaging chemotherapy with melphalan in this patient is compatible with an increased chemo-sensitivity due to impairment of the DNA repair pathway. gene. This mutation results in a missense substitution of the amino acid asparagine to lysine in the expressed INK4A protein at position 71(N71K) Quinfamide (WIN-40014) and a leucine to methionine substitution in the expressed ARF protein (L86M) (Fig.?2 ). The patients son has since been diagnosed with melanoma at the age of 34?years but he has Quinfamide (WIN-40014) yet to be genetically tested (Fig.?3 ). Otherwise the patients family history is unremarkable and specifically there is no evidence for propensity to pancreatic cancers in family members. Open in a separate window Fig. 2 Chromatogram from Sanger sequencing showing pathogenic heterozygous c.213C? ?A mutation in of patient germline DNA, the homozygous A allele at c.213 representing loss of heterozygosity in the patients lung cancer tissue compared to reference sequence with diagrammatic representation of alternatively spliced products. The gene encodes both p14ARF (green exons) and p16INK4A (red exons), Quinfamide (WIN-40014) generating two transcripts that are translated in alternative reading frames Open in a separate window Fig. 3 Patient pedigree Aside from MM and melanoma the patient has also been diagnosed with two other cancers. Firstly, Quinfamide (WIN-40014) in situ breast cancer at the age of 50 incidentally discovered during routine breast screening and which was treated with a mastectomy. Secondly, stage T2bN1M0 adenocarcinoma of Tsc2 the lung at the age 66 which was diagnosed following whole-body diffusion-weighted MRI investigation, performed as part of her MM follow-up investigation of hip pain. Her lung carcinoma has been treated by lobectomy, adjuvant chemotherapy with carboplatin and vinorelbine in addition to radiotherapy (Fig.?4 ). Mutation testing of the patients lung cancer tissue by PCR amplification and Sanger sequencing as described above revealed a loss of heterozygosity of the C.213C? ?A allele compared to the patients germline DNA (Fig. ?Fig.22 ). Paradoxically her MRI did not show any signs indicative of active MM. Open in a separate window Fig. 4 Timeline of primary malignancies and therapy Discussion and conclusions The pathogenic nature of the specific c.213C? ?A mutation in noted in this patient is suggested by the fact that it has been described previously in several hereditary melanoma families [8C10] as well as a supraglottic squamous cell carcinoma [11]. In silico predictions with the algorithms used by Polyphen-2, SIFT and mutation taster all indicate that this is a pathogenic mutation. Additionally, functional assays of the protein INK4A with this mutation also suggest pathogenicity [12]. The loss of the wild type allele in the patients lung cancer DNA as shown in Fig. ?Fig.22 also suggests that this is a pathogenic mutation causing an increased susceptibility to tumours. To our knowledge this is only the second case of a germline mutation in being reported in association with MM. The previous report described a MM patient who had a strong family history of melanoma consistent with a diagnosis of hereditary Melanoma Syndrome caused by a pathogenic exon 1 mutation. Loss of the wild-type allele was detected in malignant plasma cells consistent with acting as a tumour suppressor in the context of MM in this case report [13]. Typically, germline mutation of is associated with a restricted spectrum of cancers; primarily melanoma and pancreatic carcinoma. However, an increased risk of additional cancers including child years ones, lung, oropharyngeal and breast have been reported albeit at lower rate of recurrence [14]. Evidence for the association of the gene and its association with myeloma susceptibility offers been shown in genome wide association studies which found a susceptibility locus for myeloma at chromosome 9p21.3 variant rs2811710 of [15]. A human population centered study in 1354 people with multiple myeloma also suggests a link between multiple myeloma, melanoma within 1st and second degree relatives [16]. This has been further confirmed in additional studies [17C19]. Such data indicates a wider effect of in tumour aetiology and although rare suggests the relationship with MM is not coincidental. It is perhaps not amazing that impacts within the aetiology of a wide range of tumour types. One of the gene transcripts functions like a stabiliser of p53 through connection with E3 ubiquitin protein ligase MDM2, therefore enhancing p53-dependent transactivation and apoptosis. Mutations in ARF result in destabilisation of p53. Abnormalities of p53 are present in almost all cancers. This can be direct via deletion/mutation or hypermethylation of the p53 promoter, altering its stabilisation through alterations/deletions of ARF or overexpression of MDM2.