Alisa M. Goldstein

Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), pits of the palms and soles, jaw keratocysts, a variety of other tumors, and developmental abnormalities. NBCCS maps to chromosome 9q22.3. Familial and sporadic BCCs display loss of heterozygosity in this region, consistent with the gene being a tumor suppressor. A human sequence (PTC) with strong homology to the Drosophila segment polarity gene, patched, was isolated from a YAC and cosmid contig of the NBCCS region. Mutation analysis revealed alterations of PTC in NBCCS patients and in related tumors. We propose that a reduction in expression of the patched gene can lead to the developmental abnormalities observed in the syndrome and that complete loss of patched function contributes to transformation of certain cell types.

Mutations in SUFU predispose to medulloblastoma

The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

BACKGROUND A gene on chromosome 9p, p16INK4, has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16INK4 protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16INK4 (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families. METHODS We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected. RESULTS The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16M alleles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P = 0.14), there was a striking difference in the risk of other tumors. In kindreds with p16M alleles, the risk of pancreatic cancer was increased by a factor of 13 in the prospective period (2 cases observed, 0.15 expected; standardized incidence ratio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a factor of 22 in the entire period (7 cases observed, 0.32 expected; standardized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44.8). In contrast, we found no cases of pancreatic cancer in kindred with p16W alleles. CONCLUSIONS The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Chordoma: incidence and survival patterns in the United States, 1973–1995

AbstractBackground: Chordoma, a rare tumor arising from notochordal remnants, has been described to date only by single-institution case series or small population-based surveys. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, 1973–1995, to calculate age-adjusted incidence and survival rates for 400 cases of microscopically confirmed chordoma and to derive information regarding case distribution and risk of second cancer. Results: The age-adjusted chordoma incidence rate (IR) of 0.08 per 100,000 was age-dependent, more common in males (IR 0.10) than females (IR 0.06) and rare among patients aged <40 years and blacks. Within the axial skeleton 32% of cases were cranial, 32.8% spinal and 29.2% sacral. Young age (<26 years; p = 0.0001) and female sex (p = 0.037) were associated with greater likelihood of cranial presentation. There was no overall increased risk for second primary cancers after chordoma. Median survival was 6.29 years; 5- and 10-year relative survival rates were 67.6% and 39.9%, respectively. Comparison with other bone sarcomas revealed racial disparities in incidence for the two developmental tumors, chordoma and Ewings sarcoma. Conclusions: This study provides new data regarding incidence and survival patterns of chordoma in the US. Additional epidemiologic studies are required to elucidate the genetic and environmental determinants underlying this rare, distinctive neoplasm.

A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer.

SummaryIn a population-based case-control study of pancreatic cancer conducted in three areas of the USA, 484 cases and 2099 controls were interviewed to evaluate the aetiologic role of several medical conditions/interventions, including diabetes mellitus, cholecystectomy, ulcer/gastrectomy and allergic states. We also evaluated risk associated with family history of cancer. Our findings support previous studies indicating that diabetes is a risk factor for pancreatic cancer, as well as a possible complication of the tumour. A significant positive trend in risk with increasing years prior to diagnosis of pancreatic cancer was apparent (P-value for test of trend = 0.016), with diabetics diagnosed at least 10 years prior to diagnosis having a significant 50% increased risk. Those treated with insulin had risks similar to those not treated with insulin (odds ratio (OR) = 1.6 and 1.5 respectively), and no trend in risk was associated with increasing duration of insulin treatment. Cholecystectomy also appeared to be a risk factor, as well as a consequence of the malignancy. Subjects with a cholecystectomy at least 20 years prior to the diagnosis of pancreatic cancer experienced a 70% increased risk, which was marginally significant. In contrast, subjects with a history of duodenal or gastric ulcer had little or no elevated risk (OR = 1.2; confidence interval = 0.9–1.6). Those treated by gastrectomy had the same risk as those not receiving surgery, providing little support for the hypothesis that gastrectomy is a risk factor for pancreatic cancer. A significant 40% reduced risk was associated with hay fever, a non-significant 50% decreased risk with allergies to animals, and a non-significant 40% reduced risk with allergies to dust/moulds. These associations, however, may be due to chance since no risk reductions were apparent for asthma or several other types of allergies. In addition, we observed significantly increased risks for subjects reporting a first-degree relative with cancers of the pancreas (OR = 3.2), colon (OR = 1.7) or ovary (OR = 5.3) and non-significantly increased risks for cancers of the endometrium (OR = 1.5) or breast (OR = 1.3). The pattern is consistent with the familial predisposition reported for pancreatic cancer and with the array of tumours associated with hereditary non-polyposis colon cancer.

Genome-wide association study identifies three loci associated with melanoma risk

We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 × 10−7. Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 × 10−27 for rs258322), 11q14-q21 encompassing TYR (P = 2.41 × 10−14 for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 × 10−7 for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.

A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma

We conducted a genome-wide association study of gastric cancer and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 SNPs. We report a combined analysis of 2,240 gastric cancer cases, 2,115 ESCC cases and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex and study, multiple variants at 10q23 had genome-wide significance for gastric cancer and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for gastric cancer (P = 8.40 × 10−9; per-allele odds ratio (OR) = 1.31) and ESCC (P = 3.85 × 10−9; OR = 1.34). The association with gastric cancer differed by anatomic subsite. For tumors in the cardia the association was stronger (P = 4.19 × 10−15; OR = 1.57), and for those in the noncardia stomach it was absent (P = 0.44; OR = 1.05). Our findings at 10q23 could provide insight into the high incidence of both cancers in China.

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of familys mutations) and the Netherlands (c.225_243del19, 90% of familys mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 × 10−9) and BCC (OR = 1.35, P = 1.2 × 10−6). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 × 10−7) and BCC (OR = 1.14, P = 6.1 × 10−4). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.3 × 10−4). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.