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153. Cancer Survivorship—Genetic Susceptibility and Second Primary Cancers: Research Strategies and Recommendations

Author

Travis, Lois B., Rabkin, Charles S., Brown, Linda Morris, Allan, James M., Alter, Blanche P., Ambrosone, Christine B., Begg, Colin B., Caporaso, Neil, Chanock, Stephen, DeMichele, Angela, Figg, William Douglas, Gospodarowicz, Mary K., Hall, Eric J., Hisada, Michie, Inskip, Peter, Kleinerman, Ruth, Little, John B., Malkin, David, Ng, Andrea K., Offit, Kenneth, Pui, Ching-Hon, Robison, Leslie L., Rothman, Nathaniel, Shields, Peter G., Strong, Louise, Taniguchi, Toshiyasu, Tucker, Margaret A., and Greene, Mark H.

Published
2006

179. Mining mutation contexts across the cancer genome to map tumor site of origin.

Author

Chakraborty, Saptarshi, Martin, Axel, Guan, Zoe, Begg, Colin B., and Shen, Ronglai

Subjects
GENETIC mutation, GENE mapping, DNA sequencing, SOMATIC mutation, NUCLEOTIDE sequence, GENE clusters
Abstract

The vast preponderance of somatic mutations in a typical cancer are either extremely rare or have never been previously recorded in available databases that track somatic mutations. These constitute a hidden genome that contrasts the relatively small number of mutations that occur frequently, the properties of which have been studied in depth. Here we demonstrate that this hidden genome contains much more accurate information than common mutations for the purpose of identifying the site of origin of primary cancers in settings where this is unknown. We accomplish this using a projection-based statistical method that achieves a highly effective signal condensation, by leveraging DNA sequence and epigenetic contexts using a set of meta-features that embody the mutation contexts of rare variants throughout the genome. The vast majority of somatic mutations observed in tumors are rare. Here, the authors show that these large numbers of rare mutations are more predictive of the tissue of origin of a tumor than the information from a few common driver mutations. [ABSTRACT FROM AUTHOR]

Published
2021
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183. Relationship of Chromosome Arm 10q Variants to Occurrence of Multiple Primary Melanoma in the Population-Based Genes, Environment, and Melanoma (GEM) Study

Author

Miles, Jonathan A., primary, Orlow, Irene, additional, Kanetsky, Peter A., additional, Luo, Li, additional, Cust, Anne E., additional, Armstrong, Bruce K., additional, Kricker, Anne, additional, Anton-Culver, Hoda, additional, Gruber, Stephen B., additional, Gallagher, Richard P., additional, Zanetti, Roberto, additional, Rosso, Stefano, additional, Sacchetto, Lidia, additional, Dwyer, Terence, additional, Gibbs, David C., additional, Busam, Klaus J., additional, Mavinkurve, Vikram, additional, Ollila, David W., additional, Begg, Colin B., additional, Berwick, Marianne, additional, Thomas, Nancy E., additional, Begg, Colin, additional, Roy, Pampa, additional, Leong, Siok, additional, Corrales-Guerrero, Sergio, additional, Sadeghi, Keimya, additional, Reiner, Anne, additional, Boyce, Tawny W., additional, Venn, Alison, additional, Tucker, Paul, additional, Lai, Agnes, additional, Marrett, Loraine D., additional, From, Lynn, additional, Huang, Shu-Chen, additional, Conway, Kathleen, additional, Groben, Pamela A., additional, Edmiston, Sharon N., additional, Hao, Honglin, additional, Parrish, Eloise, additional, Frank, Jill S., additional, Rebbeck, Timothy R., additional, Lee Taylor, Julia, additional, and Madronich, Sasha, additional

Published
2019
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185. MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort

Author

Pellegrini, Cristina, primary, Botta, Francesca, additional, Massi, Daniela, additional, Martorelli, Claudia, additional, Facchetti, Fabio, additional, Gandini, Sara, additional, Maisonneuve, Patrick, additional, Avril, Marie-Françoise, additional, Demenais, Florence, additional, Bressac-de Paillerets, Brigitte, additional, Hoiom, Veronica, additional, Cust, Anne E, additional, Anton-Culver, Hoda, additional, Gruber, Stephen B, additional, Gallagher, Richard P, additional, Marrett, Loraine, additional, Zanetti, Roberto, additional, Dwyer, Terence, additional, Thomas, Nancy E, additional, Begg, Colin B, additional, Berwick, Marianne, additional, Puig, Susana, additional, Potrony, Miriam, additional, Nagore, Eduardo, additional, Ghiorzo, Paola, additional, Menin, Chiara, additional, Manganoni, Ausilia Maria, additional, Rodolfo, Monica, additional, Brugnara, Sonia, additional, Passoni, Emanuela, additional, Sekulovic, Lidija Kandolf, additional, Baldini, Federica, additional, Guida, Gabriella, additional, Stratigos, Alexandros, additional, Ozdemir, Fezal, additional, Ayala, Fabrizio, additional, Fernandez-de-Misa, Ricardo, additional, Quaglino, Pietro, additional, Ribas, Gloria, additional, Romanini, Antonella, additional, Migliano, Emilia, additional, Stanganelli, Ignazio, additional, Kanetsky, Peter A, additional, Pizzichetta, Maria Antonietta, additional, García-Borrón, Jose Carlos, additional, Nan, Hongmei, additional, Landi, Maria Teresa, additional, Little, Julian, additional, Newton-Bishop, Julia, additional, Sera, Francesco, additional, Fargnoli, Maria Concetta, additional, Raimondi, Sara, additional, Alaibac, Mauro, additional, Ferrari, Andrea, additional, Valeri, Barbara, additional, Sicher, Mariacristina, additional, Mangiola, Daniela, additional, Nazzaro, Gianluca, additional, Tosti, Giulio, additional, Mazzarol, Giovanni, additional, Giudice, Giuseppe, additional, Ribero, Simone, additional, Astrua, Chiara, additional, Mazzoni, Laura, additional, Orlow, Irene, additional, Mujumdar, Urvi, additional, Hummer, Amanda, additional, Busam, Klaus, additional, Roy, Pampa, additional, Canchola, Rebecca, additional, Clas, Brian, additional, Cotignola, Javiar, additional, Monroe, Yvette, additional, Armstrong, Bruce, additional, Kricker, Anne, additional, Litchfield, Melisa, additional, Tucker, Paul, additional, Stephens, Nicola, additional, Switzer, Teresa, additional, Theis, Beth, additional, From, Lynn, additional, Chowdhury, Noori, additional, Vanasse, Louise, additional, Purdue, Mark, additional, Northrup, David, additional, Rosso, Stefano, additional, Sacerdote, Carlotta, additional, Leighton, Nancy, additional, Gildea, Maureen, additional, Bonner, Joe, additional, Jeter, Joanne, additional, Klotz, Judith, additional, Wilcox, Homer, additional, Weiss, Helen, additional, Millikan, Robert, additional, Mattingly, Dianne, additional, Player, Jon, additional, Tse, Chiu-Kit, additional, Rebbeck, Timothy, additional, Walker, Amy, additional, Panossian, Saarene, additional, Setlow, Richard, additional, Mohrenweiser, Harvey, additional, Autier, Philippe, additional, Han, Jiali, additional, Caini, Saverio, additional, Hofman, Albert, additional, Kayser, Manfred, additional, Liu, Fan, additional, Nijsten, Tamar, additional, Uitterlinden, Andre G., additional, Kumar, Rajiv, additional, Bishop, Tim, additional, Elliott, Faye, additional, Lazovich, DeAnn, additional, Polsky, David, additional, Hansson, Johan, additional, Pastorino, Lorenza, additional, Gruis, Nelleke A., additional, Bouwes Bavinck, Jan Nico, additional, Aguilera, Paula, additional, Badenas, Celia, additional, Carrera, Cristina, additional, Gimenez-Xavier, Pol, additional, Malvehy, Josep, additional, Puig-Butille, Joan Anton, additional, Tell-Marti, Gemma, additional, Blizzard, Leigh, additional, Cochrane, Jennifer, additional, Branicki, Wojciech, additional, Debniak, Tadeusz, additional, Morling, Niels, additional, Johansen, Peter, additional, Mayne, Susan, additional, Bale, Allen, additional, Cartmel, Brenda, additional, Ferrucci, Leah, additional, Pfeiffer, Ruth, additional, Palmieri, Giuseppe, additional, Kypreou, Katerina, additional, Bowcock, Anne, additional, Cornelius, Lynn, additional, Council, M. Laurin, additional, Motokawa, Tomonori, additional, Anno, Sumiko, additional, Helsing, Per, additional, Andresen, Per Arne, additional, Guida, Stefania, additional, and Wong, Terence H., additional

Published
2019
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187. One statistical test is sufficient for assessing new predictive markers

Author

Begg Colin B, Cronin Angel M, and Vickers Andrew J

Subjects
Medicine (General), R5-920
Abstract

Abstract Background We have observed that the area under the receiver operating characteristic curve (AUC) is increasingly being used to evaluate whether a novel predictor should be incorporated in a multivariable model to predict risk of disease. Frequently, investigators will approach the issue in two distinct stages: first, by testing whether the new predictor variable is significant in a multivariable regression model; second, by testing differences between the AUC of models with and without the predictor using the same data from which the predictive models were derived. These two steps often lead to discordant conclusions. Discussion We conducted a simulation study in which two predictors, X and X*, were generated as standard normal variables with varying levels of predictive strength, represented by means that differed depending on the binary outcome Y. The data sets were analyzed using logistic regression, and likelihood ratio and Wald tests for the incremental contribution of X* were performed. The patient-specific predictors for each of the models were then used as data for a test comparing the two AUCs. Under the null, the size of the likelihood ratio and Wald tests were close to nominal, but the area test was extremely conservative, with test sizes less than 0.006 for all configurations studied. Where X* was associated with outcome, the area test had much lower power than the likelihood ratio and Wald tests. Summary Evaluation of the statistical significance of a new predictor when there are existing clinical predictors is most appropriately accomplished in the context of a regression model. Although comparison of AUCs is a conceptually equivalent approach to the likelihood ratio and Wald test, it has vastly inferior statistical properties. Use of both approaches will frequently lead to inconsistent conclusions. Nonetheless, comparison of receiver operating characteristic curves remains a useful descriptive tool for initial evaluation of whether a new predictor might be of clinical relevance.

Published
2011
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188. Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

Author

Thomas, Nancy E., primary, Edmiston, Sharon N., additional, Orlow, Irene, additional, Kanetsky, Peter A., additional, Luo, Li, additional, Gibbs, David C., additional, Parrish, Eloise A., additional, Hao, Honglin, additional, Busam, Klaus J., additional, Armstrong, Bruce K., additional, Kricker, Anne, additional, Cust, Anne E., additional, Anton-Culver, Hoda, additional, Gruber, Stephen B., additional, Gallagher, Richard P., additional, Zanetti, Roberto, additional, Rosso, Stefano, additional, Sacchetto, Lidia, additional, Dwyer, Terence, additional, Ollila, David W., additional, Begg, Colin B., additional, Berwick, Marianne, additional, Conway, Kathleen, additional, Begg, Colin, additional, Roy, Pampa, additional, Reiner, Anne, additional, Leong, Siok, additional, Guerrero, Sergio Corrales, additional, Sadeghi, Keimya, additional, Boyce, Tawny W., additional, Venn, Alison, additional, Tucker, Paul, additional, Marrett, Loraine D., additional, From, Lynn, additional, Huang, Shu-Chen, additional, Thomas, Nancy E., additional, Groben, Pamela A., additional, Parrish, Eloise, additional, Frank, Jill S., additional, Rebbeck, Timothy R., additional, Lee Taylor, Julia, additional, and Madronich, Sasha, additional

Published
2018
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189. Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data.

Author

Ostrovnaya, Irina, Mauguen, Audrey, Seshan, Venkatraman E., and Begg, Colin B.

Subjects
SOMATIC mutation, LIKELIHOOD ratio tests, CLONE cells, TUMORS
Abstract

A common task for the cancer pathologist is to determine, in a patient suffering from cancer, whether a new tumor in a distinct anatomic site from the primary is an independent occurrence of cancer or a metastasis. As mutational profiling of tumors becomes more widespread in routine clinical practice, this diagnostic task can be greatly enhanced by comparing mutational profiles of the tumors to determine if they are sufficiently similar to conclude that the tumors are clonally related, that is, one is a metastasis of the other. We present here a likelihood ratio test for clonal relatedness in this setting and provide evidence of its validity. The test is unusual in that there are two possible alternative hypotheses, representing the two anatomic sites from which the single clonal cell could have initially emerged. Although evidence for clonal relatedness is largely provided by the presence of exact mutational matches in the two tumors, we show that it is possible to observe data where the test is statistically significant even when no matches are observed. This can occur when the mutational profile of one of the tumors is closely aligned with the anatomic site of the other tumor, suggesting indirectly that the tumor originated in that other site. We exhibit examples of this phenomenon and recommend a strategy for interpreting the results of these tests in practice. [ABSTRACT FROM AUTHOR]

Published
2021
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191. Association of Known Melanoma Risk Factors with Primary Melanoma of the Scalp and Neck.

Author

Wood, Renee P., Heyworth, Jane S., McCarthy, Nina S., Mauguen, Audrey, Berwick, Marianne, Thomas, Nancy E., Millward, Michael J., Anton-Culver, Hoda, Cust, Anne E., Dwyer, Terence, Gallagher, Richard P., Gruber, Stephen B., Kanetsky, Peter A., Orlow, Irene, Rosso, Stefano, Moses, Eric K., Begg, Colin B., and Ward, Sarah V.

Abstract

Background: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns. Methods: Participants were cases from the Western Australian Melanoma Health Study (n = 1,200) and the Genes, Environment, and Melanoma Study (n = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region. Results: Compared with other sites, increased odds of SN and facial melanoma were observed in older individuals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92-1.80, Ptrend = 0.016; Face: OR = 4.57, 95% CI = 3.34-6.35, Ptrend < 0.001] and those carrying IRF4-rs12203592*T (SN: OR = 1.35, 95% CI = 1.12-1.63, Ptrend = 0.002; Face: OR = 1.29, 95% CI = 1.10-1.50, Ptrend = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37-0.64, P < 0.001; Face: OR = 0.66, 95% CI = 0.53-0.82, P < 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49-0.89, P = 0.006; Face: OR = 0.65, 95% CI = 0.52-0.83, P < 0.001). Conclusions: Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of IRF4-rs12203592 with both SN and facial melanoma. [ABSTRACT FROM AUTHOR]

Published
2020
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192. Cancer, genes, and the environment

Author

Spector, Nelson, Shapiro, Burton L., Peto, Richard, Begg, Colin B., Lichtenstein, Paul, Kaprio, Jaakko, and Hemminki, Kari

Subjects
Cancer -- Causes of
Published
2000

193. Racial differences in the treatment of early-stage lung cancer

Author

Campbell, Diane E., Greenberg, E. Robert, Polednak, Anthony P., DeShazer, Charles, Bach, Peter B., Cramer, Laura D., Begg, Colin B., and Warren, Joan L.

Subjects
Lung cancer -- Demographic aspects, Health and race -- Analysis, Social status -- Health aspects
Published
2000

195. An Efficient Basket Trial Design

Author

Cunanan, Kristen M., Iasonos, Alexia, Shen, Ronglai, Begg, Colin B., and Gönen, Mithat

Subjects
Clinical Trials as Topic, animal structures, Clinical Trials, Phase II as Topic, nervous system, Neoplasms, Mutation, Humans, Antineoplastic Agents, Computer Simulation, Molecular Targeted Therapy, Biostatistics, Article, Software
Abstract

The landscape for early phase cancer clinical trials is changing dramatically because of the advent of targeted therapy. Increasingly, new drugs are designed to work against a target such as the presence of a specific tumor mutation. Because typically only a small proportion of cancer patients will possess the mutational target, but the mutation is present in many different cancers, a new class of basket trials is emerging, whereby the drug is tested simultaneously in different baskets, that is, subgroups of different tumor types. Investigators desire not only to test whether the drug works but also to determine which types of tumors are sensitive to the drug. A natural strategy is to conduct parallel trials, with the drug 's effectiveness being tested separately, using for example, the popular Simon two-stage design independently in each basket. The work presented is motivated by the premise that the efficiency of this strategy can be improved by assessing the homogeneity of the baskets ' response rates at an interim analysis and aggregating the baskets in the second stage if the results suggest the drug might be effective in all or most baskets. Via simulations, we assess the relative efficiencies of the two strategies. Because the operating characteristics depend on how many tumor types are sensitive to the drug, there is no uniformly efficient strategy. However, our investigation demonstrates that substantial efficiencies are possible if the drug works in most or all baskets, at the cost of modest losses of power if the drug works in only a single basket. Copyright © 2017 John WileySons, Ltd.

Published
2017

196. MITFE318K's effect on melanoma risk independent of, but modified by, other risk factors

Author

Berwick, Marianne, MacArthur, Jamie, Orlow, Irene, Kanetsky, Peter, Begg, Colin B, Luo, Li, Reiner, Anne, Sharma, Ajay, Armstrong, Bruce K, Kricker, Anne, Cust, Anne E, Marrett, Loraine D, Gruber, Stephen B, Anton-Culver, Hoda, Zanetti, Roberto, Rosso, Stefano, Gallagher, Richard P, Dwyer, Terence, Venn, Alison, Busam, Klaus, From, Lynn, White, Kirsten, Thomas, Nancy E, and GEM Study Group

Subjects
Oncology, Skin Neoplasms, Medical and Health Sciences, Neoplasms, Multiple Primary, Gene Frequency, Multiple Primary, Risk Factors, single nucleotide polymorphism, Neoplasms, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, Family history, Melanoma, Cancer, Genetics, Nevus, Pigmented, integumentary system, Biological Sciences, Microphthalmia-associated transcription factor, Neoplasm Proteins, Phenotype, Risk, medicine.medical_specialty, Mutation, Missense, Single-nucleotide polymorphism, Dermatology, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Pigmented, Clinical Research, Internal medicine, Consensus Sequence, melanoma, medicine, Humans, Point Mutation, Nevus, Allele, Hair Color, Allele frequency, Protein Processing, Alleles, Case-controlstudy, Microphthalmia-Associated Transcription Factor, MITF, Dermatology & Venereal Diseases, Human Genome, Post-Translational, Sumoylation, GEM Study Group, Odds ratio, medicine.disease, Amino Acid Substitution, Mutation, Missense, Protein Processing, Post-Translational
Abstract

A rare germline variant in the microphthalmia-associated transcription factor (MITF) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma [odds ratio (OR) 1.7, 95% confidence interval (CI) = 1.1, 2.7, P = 0.03]; adjusted for age, sex, center, age × sex interaction, pigmentation characteristics, family history of melanoma, and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (P for interaction, 0.03) and in those with no moles than some or many moles (P for interaction

Published
2014

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