Joseph F. Fraumeni

Second cancers following non-Hodgkin's lymphoma

The risk of second malignancies following non‐Hodgkins lymphoma (NHL) was estimated in 29,153 patients diagnosed with NHL between 1973 and 1987 in one of nine areas participating in the National Cancer Institutes Surveillance, Epidemiology, and End Results Program. Compared with the general population, NHL patients were at a significantly increased risk of developing second cancers (observed/expected [O/E] = 1.18; O = 1231). The O/E ratio increased significantly with time to reach 1.77 in 10‐year survivors. Significant excesses were noted for acute nonlymphocytic leukemia (O/E = 2.88), cancers of the bladder (O/E = 1.30), kidney (O/E = 1.47), and lung (O/E = 1.57), malignant melanoma (O/E = 2.44), and Hodgkins disease (O/E = 4.16). Chemotherapy appeared related to subsequent acute nonlymphocytic leukemia (ANLL) and bladder cancer. Radiation therapy was associated with ANLL and possibly cancers of the lung, bladder, and bone. Malignant melanoma was not clearly related to initial NHL treatment.

Risk of second malignancy after cutaneous T-cell lymphoma

Risk of second primary malignancy was assessed in a population‐based follow‐up survey of all persons who developed cutaneous T‐cell lymphoma (CTCL) in nine geographic areas of the United States covered by the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute during the period 1973 to 1983. Among 544 patients with a first primary tumor reported as CTCL, a second cancer developed in 35 (6%), yielding a significantly elevated relative risk (RR) of 1.7, which reflects excesses for cancers of the lung and colon and non‐Hodgkins lymphoma. Although the excess of lymphoma may be related to the evolution of CTCL to less differentiated T‐cell lymphoma, additional studies are needed to clarify the immunologic, genetic, viral, and environmental factors that may contribute to the development of second cancers.

Risk of lung cancer associated with domestic use of coal in Xuanwei, China: retrospective cohort study

Objective To estimate the risk of lung cancer associated with the use of different types of coal for household cooking and heating. Setting Xuanwei County, Yunnan Province, China. Design Retrospective cohort study (follow-up 1976-96) comparing mortality from lung cancer between lifelong users of “smoky coal” (bituminous) and “smokeless coal” (anthracite). Participants 27u2009310 individuals using smoky coal and 9962 individuals using smokeless coal during their entire life. Main outcome measures Primary outcomes were absolute and relative risk of death from lung cancer among users of different types of coal. Unadjusted survival analysis was used to estimate the absolute risk of lung cancer, while Cox regression models compared mortality hazards for lung cancer between smoky and smokeless coal users. Results Lung cancer mortality was substantially higher among users of smoky coal than users of smokeless coal. The absolute risks of lung cancer death before 70 years of age for men and women using smoky coal were 18% and 20%, respectively, compared with less than 0.5% among smokeless coal users of both sexes. Lung cancer alone accounted for about 40% of all deaths before age 60 among individuals using smoky coal. Compared with smokeless coal, use of smoky coal was associated with an increased risk of lung cancer death (for men, hazard ratio 36 (95% confidence interval 20 to 65); for women, 99 (37 to 266)). Conclusions In Xuanwei, the domestic use of smoky coal is associated with a substantial increase in the absolute lifetime risk of developing lung cancer and is likely to represent one of the strongest effects of environmental pollution reported for cancer risk. Use of less carcinogenic types of coal could translate to a substantial reduction of lung cancer risk.

Risk of second malignancy after cancers of the renal parenchyma, renal pelvis, and ureter

Risk of second primary malignancy was assessed in a population‐based survey of persons who developed cancers of the renal parenchyma, renal pelvis, or ureter in Connecticut during the period 1935–1982. Among 4176 patients with a first primary tumor of the renal parenchyma, a second cancer was reported in 219 (5%), yielding a small but significantly elevated relative risk (RR) of 1.2, which reflects excesses for cancers of the bladder, kidney, and lymphatic‐hematopoietic system. Among 939 patients with a first primary tumor of the renal pelvis or ureter, a second cancer was reported in 155 (17%), associated with a significantly elevated RR of 2.7. This resulted mainly from a 21‐fold increase in risk for bladder cancer, although significant excesses were also found for lung and prostate cancers, and metachronous cancers of the renal pelvis and ureter. These associations seem to reflect the multicentric behavior of tumors arising in the urinary tract, the role of cigarette smoking, and host factors yet to be defined, and some degree of heightened medical surveillance and detection of tumors, especially in the same organ system. Cancer 58:1158‐1161, 1986.

Abstract 2691: Genome-wide association study identifies two susceptibility loci that modify radiation-related risk for breast cancer after childhood cancer: A report from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort

Background: Childhood cancer survivors treated with chest radiotherapy have substantially elevated risk for developing breast cancer. Although numerous breast cancer susceptibility variants have been established, genetic predisposition for breast cancer after childhood cancer remains poorly understood. Methods: We conducted the first genome-wide association study of subsequent breast cancer in female childhood cancer survivors within two large-scale cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study [CCSS; 178 breast cancer cases, 2200 controls (survivors without subsequent neoplasm) of European descent] and the St. Jude Lifetime Cohort (SJLIFE; 29 cases, 574 controls). Genotyping on the Illumina HumanOmni5MExome (CCSS) or Affymetrix 6.0 (SJLIFE) array and imputation based on the 1000 Genomes Project yielded >16 million high quality genotyped or imputed variants available in both studies. Assuming an additive genetic model, we used multivariate Cox regression to quantify the effect of each variant in the overall population and stratified by receipt of ≥10 Gray (Gy) or Results: We identified two loci associated with breast cancer risk among children who received ≥10 Gy radiation to the chest (131 cases, 493 controls): one at 1q41 [rs4342822, risk allele frequency (RAF) = 0.46 in controls, pooled per allele hazard ratio (HR) = 1.94, 95% confidence interval (CI) = 1.50-2.51, P exact = 1.20×10 −8 ] and another at 11q23 (rs74949440, RAF = 0.02 in controls, HR = 3.71, 95%CI = 2.18-6.32, P exact = 2.00×10 −9 ). Neither locus was associated with breast cancer risk among children who received 10% of breast cancers in The Cancer Genome Atlas data. The variant rs74949440 is intronic to TAGLN, whose expression levels have been associated with breast cancer prognosis and altered cell death resistance following irradiation in human carcinoma cell lines. Conclusion: These findings represent the first evidence outside of identified high-risk cancer susceptibility genes that certain individuals are genetically predisposed to developing breast cancer after radiotherapy and suggest that radiation exposure may interact with germline genetics to modify breast cancer risk. Citation Format: Lindsay M. Morton, Joshua N. Sampson, Gregory T. Armstrong, Ting-Huei Chen, Melissa Hudson, Eric Karlins, Casey L. Dagnall, Shenchao Li, Carmen L. Wilson, Kumar Srivastava, Wei Liu, Guolian Kang, Kevin Oeffinger, Tara O. Henderson, Chaya S. Moskowitz, Todd M. Gibson, Diana M. Merino, Jeannette R. Wong, Sue Hammond, Joseph P. Neglia, Lucie M. Turcotte, Jeremy Miller, Laura Bowen, William A. Wheeler, Wendy M. Leisenring, John A. Whitton, Laurie Burdette, Belynda D. Hicks, Mitchell J. Machiela, Aurelie Vogt, Zhaoming Wang, Meredith Yeager, Geoffrey Neale, Matthew Lear, Louise C. Strong, Yutaka Yasui, Marilyn Stovall, Rita E. Weathers, Susan A. Smith, Rebecca Howell, Stella M. Davies, Gretchen A. Radloff, Amy Berrington de Gonzalez, Peter D. Inskip, Preetha Rajaraman, Joseph F. Fraumeni, Smita Bhatia, Stephen J. Chanock, Margaret A. Tucker, Leslie L. Robison. Genome-wide association study identifies two susceptibility loci that modify radiation-related risk for breast cancer after childhood cancer: A report from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2691.