| 1. |
- Johansson, Peter A., et al.
(författare)
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Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma
- 2019
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Ingår i: Melanoma Research. - 0960-8931 .- 1473-5636. ; 29:5, s. 483-490
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations of BRCA1 and BRCA2 predispose individuals to a high risk of breast and ovarian cancer, and elevated risk of other cancers, including those of the pancreas and prostate. BRCA2 mutation carriers may have increased risk of uveal melanoma (UM) and cutaneous melanoma (CM), but associations with these cancers in BRCA1 mutation carriers have been mixed. Here, we further assessed whether UM and CM are associated with BRCA1 or BRCA2 by assessing the presence, segregation and reported/predicted pathogenicity of rare germline mutations (variant allele frequency < 0.01) in families with multiple members affected by these cancers. Whole-genome or exome sequencing was performed on 160 CM and/or UM families from Australia, the Netherlands, Denmark and Sweden. Between one and five cases were sequenced from each family, totalling 307 individuals. Sanger sequencing was performed to validate BRCA1 and BRCA2 germline variants and to assess carrier status in other available family members. A nonsense and a frameshift mutation were identified in BRCA1, both resulting in premature truncation of the protein (the first at p.Q516 and the second at codon 91, after the introduction of seven amino acids due to a frameshift deletion). These variants co-segregated with CM in individuals who consented for testing and were present in individuals with pancreatic, prostate and breast cancer in the respective families. In addition, 33 rare missense mutations (variant allele frequency ranging from 0.00782 to 0.000001 in the aggregated ExAC data) were identified in 34 families. Examining the previously reported evidence of functional consequence of these variants revealed all had been classified as either benign or of unknown consequence. Seeking further evidence of an association between BRCA1 variants and melanoma, we examined two whole-genome/exome sequenced collections of sporadic CM patients (total N = 763). We identified one individual with a deleterious BRCA1 variant, however, this allele was lost (with the wild-type allele remaining) in the corresponding CM, indicating that defective BRCA1 was not a driver of tumorigenesis in this instance. Although this is the first time that deleterious BRCA1 mutations have been described in high-density CM families, we conclude that there is an insufficient burden of evidence to state that the increased familial CM or UM susceptibility is because of these variants. In addition, in conjunction with other studies, we conclude that the previously described association between BRCA2 mutations and UM susceptibility represents a rare source of increased risk.
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| 2. |
- Harbst, Katja, et al.
(författare)
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Multiple metastases from cutaneous malignant melanoma patients may display heterogeneous genomic and epigenomic patterns.
- 2010
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Ingår i: Melanoma Research. - 0960-8931. ; 20:5, s. 381-391
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Tidskriftsartikel (refereegranskat)abstract
- Disseminated melanoma is an aggressive disease with fatal outcome. Better understanding of the underlying biology is needed to find effective treatment. We applied microarray-based comparative genomic hybridization, gene expression and CpG island methylation analysis of primary tumors and multiple metastases from five melanoma patients with the aim of analyzing the molecular patterns of melanoma progression. Epigenetic profiling showed that the multiple metastases after a single primary melanoma share similar methylation patterns for many genes, although differences in methylation between the lesions were evident for several genes, example, PTEN, TFAP2C, and RARB. In addition, DNA copy number and global gene expression profiles of tumors from individual patients were highly similar, confirming common origin of metastases. Some of the identified genomic aberrations, for example, gain of chromosome 6p and loss of chromosomes 6q and 10, persisted during progression, indicating early changes highly important for melanoma development. Homozygous deletions at 3p26.1 and 6q23.2-q23.3 appeared in two consecutive metastases originating from the same primary tumor, respectively, in a mutually exclusive manner that provides evidence for two genetically different subclones. However, in another case, the similarity of the copy number aberrations in subsequent metastatic lesions suggests sequential metastatic development through the clonal evolution. These data are further corroborated by a switch in CDH1 and CDH2 expression between metastases from the same patient. In conclusion, our results provide evidence for different models of metastatic progression in melanoma.
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| 3. |
- Måsbäck, A, et al.
(författare)
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Clinical and histopathological characteristics in relation to aetiological risk factors in cutaneous melanoma : a population-based study
- 1999
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Ingår i: Melanoma Research. - 0960-8931. ; 9:2, s. 97-189
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Tidskriftsartikel (refereegranskat)abstract
- In this population-based, case-control study from Sweden using data collected from 1988 to 1990, an increased risk of melanoma was associated with the number of sunburns, propensity to freckle, the number of raised naevi and a family history of melanoma. Furthermore, a decreased risk was associated with occupational sun exposure. The purpose of this study was to investigate whether different histopathological features of the melanoma and clinical factors were related to the different aetiological risk factor patterns. All the confirmed primary cutaneous melanomas (n = 366) were included in the study. Both univariate analyses with tests for interaction and multivariate analyses were performed. Patients with melanoma on the trunk and patients with thin melanomas had an excess of close relatives with a history of melanoma (odds ratios [ORs] = 2.7 and 2.3, respectively). A relationship was also seen between melanomas in younger persons and a family history of melanoma (OR = 2.6). The presence of raised naevi on the arm had a tendency to be closer related to melanoma of the nodular type (OR = 4.3) than melanoma of the superficial spreading type (OR = 1.6). Patients with outdoor occupations during summer had a decreased risk of developing melanoma on the extremities. Melanoma diagnosed in patients born before 1939 had an association with sunburns (OR = 1.9) and freckling (OR = 2.0), while melanomas in patients born in 1939 or later were related to a family history of melanoma (OR = 2.2). These results suggest that different histopathological and clinical features of melanoma are associated with different risk factor patterns, which may imply diverging tumour genesis.
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| 4. |
- Måsbäck, Anna, et al.
(författare)
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Clinical and histopathological features of malignant melanoma in germline CDKN2A mutation families
- 2002
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Ingår i: Melanoma Research. - 0960-8931. ; 12:6, s. 549-557
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Tidskriftsartikel (refereegranskat)abstract
- Primary cutaneous malignant melanomas (CMMs) from 26 individuals belonging to nine families with an identified CDKN2A mutation were clinically and histopathologically compared with 78 matched CMM controls and with a population-based series of CMMs (n=667). All tumours were histopathologically re-examined. CDKN2A-associated cases were significantly less invasive compared with the matched controls, with an adjusted odds ratio (adjOR) of 2.9 and a 95% confidence interval (CI) of 1.0-8.1 (P=0.04). According to the odds ratio (OR) values, CDKN2A-associated cases seemed to have tumours more often located on the head and neck (adjOR 2.9, 95% CI 0.6-13.7), with less inflammation (adjOR 0.7, 95% CI 0.3-1.8) and regression (adjOR 0.6, 95% CI 0.2-1.8) but more frequent histological ulceration (adjOR 1.9, 95% CI 0.6-5.8). In comparison with the population-based material, CDKN2A-associated cases were significantly younger at diagnosis (crude OR 3.5, 95% CI 1.6-7.5, divided at 50 years) and had less regressive reaction in their tumours (crude OR 0.355 95% CI 0.2-0.8). No significant differences were seen for tumour thickness between the different groups. On multivariate analysis, the overall survival was significantly worse for thicker tumours and older age (P=0.04 for both). To our knowledge this is the first description of the histopathological features of CMMs from families with mutations in the CDKN2A gene.
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| 5. |
- Måsbäck, Anna, et al.
(författare)
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Prognostic factors in invasive cutaneous malignant melanoma: a population-based study and review
- 2001
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Ingår i: Melanoma Research. - 0960-8931. ; 11:5, s. 435-445
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Tidskriftsartikel (refereegranskat)abstract
- A population-based study from Sweden identified 711 patients with cutaneous malignant melanoma diagnosed in 1965, 1975, 1985 and 1989. Prognostic factors were evaluated and a review of the literature was performed. On univariate analysis, thick tumours (> 0.8 mm) (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.6-2.1), increasing Clark level (OR 1.8, 95% CI 1.6-2.0), ulceration (OR 1.8, 95% CI 1.6-2.0), nodular melanoma (OR 1.5, 95% CI 1.3-1.6) and increasing age (continuous variable, P < 0.0001) were associated with a shorter survival. Location on extremities (OR 0.8, 95% CI 0.7-0.9), inflammation (OR 0.8, 95% CI 0.7-0.9) and female gender (OR 0.8, 95% CI 0.8-0.9) were associated with improved survival. On multivariate analysis, thick tumours (> 0.8 mm) (OR 1.5, 95% CI 1.2-1.7) and ulceration (OR 1.4, 95% CI 1.2-1.6) were independently related to a poor prognosis, while location on extremities (OR 0.8, 95% CI 0.7-0.9), inflammation (OR 0.8, 95% CI 0.7-0.9) and female gender (OR 0.8, 95% CI 0.8-1.0) were associated with improved survival. No difference in mean tumour thickness was seen over time, but there was a significant increase in the percentage of thin melanomas (< 0.8 mm) in 1985 (P = 0.01) and 1989 (P = 0.002) compared with 1965. The incidence of melanomas with inflammation increased significantly (P = 0.04), as did age at diagnosis (P = 0.005).
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| 6. |
- Nielsen, Kari, et al.
(författare)
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Swedish CDKN2A mutation carriers do not present the atypical mole syndrome phenotype.
- 2010
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Ingår i: Melanoma Research. - 0960-8931. ; Jul 1, s. 266-272
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.
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| 7. |
- Westerdahl, J, et al.
(författare)
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Is the use of sunscreens a risk factor for malignant melanoma?
- 1995
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Ingår i: Melanoma Research. - 0960-8931. ; 5:1, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- The relation between use of sunscreens, different host factors and malignant melanoma was investigated in a population-based, matched case-control study of malignant melanoma in the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, between 1 July 1988 and 30 June 1990. In total, 400 melanoma patients and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire regarding different epidemiologic variables, including questions on use of sunscreens and different constitutional factors. The use of sunscreens was not found to protect against developing malignant melanoma. Instead, an unexpected relation between the use of sunscreens and the risk of developing malignant melanoma was seen (odds ratio (OR) 1.8 for almost always vs never using sunscreens). A tentative dose-response relation was found. Virtually the same ORs were seen in both sexes. Furthermore, persons younger than 50 years had a higher OR than persons older than 50 years. When different melanoma presentation sites were considered, lesions of the trunk were associated with sunscreen use in females (adjusted OR = 3.7 for almost always vs never using sunscreens), while lesions of the extremity or head and neck were associated with sunscreen use in males (adjusted OR = 3.2 for almost always vs never using sunscreens). Raised naevi on the left arm and freckling were shown to be the major constitutional risk factors (OR = 3.9 for more than three naevi vs none and OR = 1.4, respectively). The results were essentially unaltered in a histopathologically re-examined material. Further investigations are needed in order to form a basis for melanoma prevention.
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