Showing papers by "David W. Hogg published in 2004"

Somatic mutations of KIT in familial testicular germ cell tumours.

Abstract: Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

Genetic susceptibility in familial melanoma from northeastern Italy

Abstract: Cutaneous malignant melanoma (CMM) is a potentially fatal form of skin cancer, whose incidence and mortality are increasing in the Western world.1,2 Approximately 3–12% of cutaneous malignant melanoma develops in families with multiple cases of melanoma.3–5 Worldwide studies of large families prone to melanoma have demonstrated linkage to a locus on chromosome 9p21 (MIM 600160) in the majority of kindreds, and probable linkage to 1p22 6 and 1p36 7,8 in others. About one third of 9p21 linked families carry mutations in the CDKN2A tumour suppressor gene,9,10 which encodes the p16 cell cycle inhibitor. Rare kindreds may also possess mutations of the coding sequences of CDK4 (MIM 12829),11,12 or p14ARF (translated from exons 1β and 2 of CDKN2A ).13–15 More studies are needed to understand the genetic basis of melanoma. In Italy, the melanoma prone families studied to date are mostly from the north16 and northwestern areas,15,17,18 the centre,19 and the Sardinia region.20 These families are generally characterised by small numbers of melanoma cases, and a relatively high frequency of CDKN2A mutations. We studied families prone to melanoma from northeastern Italy, to characterise genetic susceptibility to melanoma in this population. ### Study population The study group was comprised of 55 families: 44 (80%) from southern Emilia Romagna and northern Marche (close to the border between the two regions); 10 families, all with two cases per family, from other areas of Italy (four from the south, three from the centre, two from the north, and one from Sardinia), and one family from Russia. All the families were recruited at the Dermatology Unit of the Bufalini Hospital in Cesena, Italy. Bufalini Hospital’s and the National Cancer Institute’s Ethical Committees approved the study, and written informed consent was obtained …

Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study.

Abstract: BACKGROUND Data addressing the interfamilial heterogeneity of melanoma are limited. In the current study, the authors assessed melanoma risk according to family history of melanoma and other melanoma-associated malignancies and evaluated the familial heterogeneity of melanomas, pancreatic malignancies, and gastrointestinal malignancies. METHODS The authors obtained patient histories of malignancy in first-degree relatives as part of a clinic-based case–control study. The case group included 737 newly diagnosed patients with invasive melanoma, and the control group included 1021 outpatients from clinics at the same medical centers. To assess heterogeneity of risk among families affected by melanoma, a nonparametric method was used to detect extrabinomial variation. In addition, selected patients with melanoma (n = 133) were tested for germline mutations in CDKN2A. RESULTS The adjusted odds ratio associated with a family history of melanoma was 1.7 (95% confidence interval, 1.1–2.7). Family histories of pancreatic, gastrointestinal, brain, breast, or lymphoproliferative disease did not increase the risk of melanoma significantly. Among case families, significant evidence of familial heterogeneity was found for melanomas, but not for pancreatic or gastrointestinal malignancies. Two mutations in CDKN2A previously associated with melanoma risk were identified among the 133 patients tested in the case group; mutation detection did not differ between families with low and high heterogeneity scores. CONCLUSIONS Familial heterogeneity testing in the study population did not improve the selection of high-risk families for genetic study. Even in a large case–control study, few families that had multiple members with melanoma were identified, and family members with pancreatic malignancies were rare. Cancer 2004. Published 2004 by the American Cancer Society.