Abstract
The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1, XPD, XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1, TP53 and MDM2 genes in 61 patients who received radio-chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC (P=0.015). The resultant variant was also involved in the onset of sporadic ESCC (P=0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 print issues and online access
$259.00 per year
only $43.17 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Ftpj.2015.41/MediaObjects/41397_2016_Article_BFtpj201541_Fig1_HTML.jpg)
Similar content being viewed by others
References
Fekete F, Mosnier H, Belghiti J, Uribe M, Sauvanet A . Esophageal cancer after mediastinal irradiation. Dysphagia 1994; 9: 289–291.
Micke O, Schafer U, Glashorster M, Prott FJ, Willich N . Radiation-induced esophageal carcinoma 30 years after mediastinal irradiation: case report and review of the literature. Jpn J Clin Oncol 1999; 29: 164–170.
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366: 2087–2106.
Zablotska LB, Chak A, Das A, Neugut AI . Increased risk of squamous cell esophageal cancer after adjuvant radiation therapy for primary breast cancer. Am J Epidemiol 2005; 161: 330–337.
Morton LM, Gilbert ES, Hall P, Andersson M, Joensuu H, Vaalavirta L . Risk of treatment-related esophageal cancer among breast cancer survivors. Ann Oncol 2012; 23: 3081–3091.
Smith AG, Worrillow LJ, Allan JM . A common genetic variant in XPD associates with risk of 5q- and 7q-deleted acute myeloid leukemia. Blood 2007; 109: 1233–1236.
Ellis NA, Huo D, Yildiz O, Worrillow LJ, Banerjee M, Le Beau MM et al. MDM2 SNP309 and TP53 Arg72Pro interact to alter therapy-related acute myeloid leukemia susceptibility. Blood 2008; 112: 741–749.
Parl FF . Glutathione S-transferase genotypes and cancer risk. Cancer Lett 2005; 221: 123–129.
Hong Y, Miao X, Zhang X, Ding F, Luo A, Guo Y et al. The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res 2005; 65: 9582–9587.
Proestling K, Hebar A, Pruckner N, Marton E, Vinatzer U, Schreiber M . The Pro allele of the p53 codon 72 polymorphism is associated with decreased intratumoral expression of BAX and p21, and increased breast cancer risk. PLoS One 2012; 7: e47325.
Paszkowska-Szczur K, Scott RJ, Serrano-Fernandez P, Mirecka A, Gapska P, Gorski B et al. Xeroderma pigmentosum genes and melanoma risk. Int J Cancer 2013; 133: 1094–1100.
Vineis P, Manuguerra M, Kavvoura FK, Guarrera S, Allione A, Rosa F et al. A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility. J Natl Cancer Inst 2009; 101: 24–36.
Rumiato E, Cavallin F, Boldrin E, Cagol M, Alfieri R, Basso D et al. ERCC1 C8092A (rs3212986) polymorphism as a predictive marker in esophageal cancer patients treated with cisplatin/5-FU-based neoadjuvant therapy. Pharmacogenet Genomics 2013; 23: 597–604.
Borchiellini D, Etienne-Grimaldi MC, Thariat J, Milano G . The impact of pharmacogenetics on radiation therapy outcome in cancer patients. A focus on DNA damage response genes. Cancer Treat Rev 2012; 38: 737–759.
Goode EL, Ulrich CM, Potter JD . Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 2002; 11: 1513–1530.
Wang Z, Chen JQ, Liu JL, Qin XG, Huang Y . Polymorphisms in ERCC1, GSTs, TS and MTHFR predict clinical outcomes of gastric cancer patients treated with platinum/5-Fu-based chemotherapy: a systematic review. BMC Gastroenterol 2012; 12: e137.
Toyama T, Zhang Z, Nishio M, Hamaguchi M, Kondo N, Iwase H et al. Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients. Breast Cancer Res 2007; 9: R34.
Wegman P, Stal O, Askmalm MS, Nordenskjold B, Rutqvist LE, Wingren S . p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients. Pharmacogenet Genomics 2006; 16: 347–351.
Zafereo ME, Sturgis EM, Liu Z, Wang LE, Wei Q, Li G . Nucleotide excision repair core gene polymorphisms and risk of second primary malignancy in patients with index squamous cell carcinoma of the head and neck. Carcinogenesis 2009; 30: 997–1002.
Gal TJ, Huang WY, Chen C, Hayes RB, Schwartz SM . DNA repair gene polymorphisms and risk of second primary neoplasms and mortality in oral cancer patients. Laryngoscope 2005; 115: 2221–2231.
Metzger R, Warnecke-Eberz U, Alakus H, Kutting F, Brabender J, Vallbohmer D et al. Neoadjuvant radiochemotherapy in adenocarcinoma of the esophagus: ERCC1 gene polymorphisms for prediction of response and prognosis. J Gastrointest Surg 2012; 16: 26–34.
Chen P, Wiencke J, Aldape K, Kesler-Diaz A, Miike R, Kelsey K et al. Association of an ERCC1 polymorphism with adult-onset glioma. Cancer Epidemiol Biomarkers Prev 2000; 9: 843–847.
Yu JJ, Lee KB, Mu C, Li Q, Abernathy TV, Bostick-Bruton F et al. Comparison of two human ovarian carcinoma cell lines (A2780/CP70 and MCAS) that are equally resistant to platinum, but differ at codon 118 of the ERCC1 gene. Int J Oncol 2000; 16: 555–560.
Giovannetti E, Pacetti P, Reni M, Leon LG, Mambrini A, Vasile E et al. Association between DNA-repair polymorphisms and survival in pancreatic cancer patients treated with combination chemotherapy. Pharmacogenomics 2011; 12: 1641–1652.
Parliament MB, Murray D . Single nucleotide polymorphisms of DNA repair genes as predictors of radioresponse. Semin Radiat Oncol 2010; 20: 232–240.
Popanda O, Marquardt JU, Chang-Claude J, Schmezer P . Genetic variation in normal tissue toxicity induced by ionizing radiation. Mutat Res 2009; 667: 58–69.
Wilson DM 3rd, Thompson LH . Life without DNA repair. Proc Natl Acad Sci USA 1997; 94: 12754–12757.
Seedhouse C, Bainton R, Lewis M, Harding A, Russell N, Das-Gupta E . The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia. Blood 2002; 100: 3761–3766.
Hayes JD, Pulford DJ . The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 1995; 30: 445–600.
Allan JM, Wild CP, Rollinson S, Willett EV, Moorman AV, Dovey GJ et al. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci USA 2001; 98: 11592–11597.
Khrunin AV, Moisseev A, Gorbunova V, Limborska S . Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients. Pharmacogenomics J 2010; 10: 54–61.
Michael D, Oren M . The p53-Mdm2 module and the ubiquitin system. Semin Cancer Biol 2003; 13: 49–58.
Dumont P, Leu JI, Della Pietra AC 3rd, George DL, Murphy M . The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 2003; 33: 357–365.
Sullivan A, Syed N, Gasco M, Bergamaschi D, Trigiante G, Attard M et al. Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo. Oncogene 2004; 23: 3328–3337.
Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004; 119: 591–602.
Arva NC, Gopen TR, Talbott KE, Campbell LE, Chicas A, White DE et al. A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J Biol Chem 2005; 280: 26776–26787.
Allan JM, Rabkin CS . Genetic susceptibility to iatrogenic malignancy. Pharmacogenomics 2005; 6: 615–628.
Menashe I, Rosenberg PS, Chen BE . PGA: power calculator for case-control genetic association analyses. BMC Genet 2008; 9: 36.
Chai J, Jamal MM . Esophageal malignancy: a growing concern. World J Gastroenterol 2012; 18: 6521–6526.
Ruol A, Castoro C, Portale G, Cavallin F, Sileni VC, Cagol M et al. Trends in management and prognosis for esophageal cancer surgery: twenty-five years of experience at a single institution. Arch Surg 2009; 144: 247–254.
Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK . Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol 2013; 10: 289–301.
Wood ME, Vogel V, Ng A, Foxhall L, Goodwin P, Travis LB . Second malignant neoplasms: assessment and strategies for risk reduction. J Clin Oncol 2012; 30: 3734–3745.
Allan JM, Travis LB . Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer 2005; 5: 943–955.
Best T, Li D, Skol AD, Kirchhoff T, Jackson SA, Yasui Y et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin’s lymphoma. Nat Med 2011; 17: 941–943.
Boldrin E, Rumiato E, Fassan M, Cappellesso R, Rugge M, Chiarion-Sileni V et al. Genetic features of metachronous esophageal cancer developed in Hodgkin’s lymphoma or breast cancer long-term survivors: an exploratory study. PLoS One 2015; 10: e0117070.
Benhamou S, Sarasin A . ERCC2 /XPD gene polymorphisms and lung cancer: a HuGE review. Am J Epidemiol 2005; 161: 1–14.
Hu YY, Yuan H, Jiang GB, Chen N, Wen L, Leng WD et al. Associations between XPD Asp312Asn polymorphism and risk of head and neck cancer: a meta-analysis based on 7,122 subjects. PLoS One 2012; 7: e35220.
Liu G, Zhou W, Yeap BY, Su L, Wain JC, Poneros JM et al. XRCC1 and XPD polymorphisms and esophageal adenocarcinoma risk. Carcinogenesis 2007; 28: 1254–1258.
Pan J, Lin J, Izzo JG, Liu Y, Xing J, Huang M et al. Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis 2009; 30: 785–792.
Tse D, Zhai R, Zhou W, Heist RS, Asomaning K, Su L et al. Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk. Cancer Causes Control 2008; 19: 1077–1083.
Ye W, Kumar R, Bacova G, Lagergren J, Hemminki K, Nyren O . The XPD 751Gln allele is associated with an increased risk for esophageal adenocarcinoma: a population-based case-control study in Sweden. Carcinogenesis 2006; 27: 1835–1841.
Duan XL, Gong H, Zeng XT, Ni XB, Yan Y, Chen W et al. Association between XPD Asp312Asn polymorphism and esophageal cancer susceptibility: a meta-analysis. Asian Pac J Cancer Prev 2012; 13: 3299–3303.
Yang R, Zhang C, Malik A, Shen ZD, Hu J, Wu YH . Xeroderma pigmentosum group D polymorphisms and esophageal cancer susceptibility: a meta-analysis based on case-control studies. World J Gastroenterol 2014; 20: 16765–16773.
Wolfe KJ, Wickliffe JK, Hill CE, Paolini M, Ammenheuser MM, Abdel-Rahman SZ . Single nucleotide polymorphisms of the DNA repair gene XPD/ERCC2 alter mRNA expression. Pharmacogenet Genomics 2007; 17: 897–905.
Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK et al. XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 2000; 21: 551–555.
Rzeszowska-Wolny J, Polanska J, Pietrowska M, Palyvoda O, Jaworska J, Butkiewicz D et al. Influence of polymorphisms in DNA repair genes XPD, XRCC1 and MGMT on DNA damage induced by gamma radiation and its repair in lymphocytes in vitro. Radiat Res 2005; 164: 132–140.
Acknowledgements
This work was supported by the following grants: Associazione Italiana per la Ricerca sul Cancro (AIRC, Ref. 10430), Ministero della Istruzione, della Università e della Ricerca (MIUR, Prot. 2010MCLPLB-003), Veneto Institute of Oncology IOV-IRCCS 5xmille.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
This paper is dedicated to the friendship and memory of Savina Aversa.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
Supplementary information
PowerPoint slides
Rights and permissions
About this article
Cite this article
Boldrin, E., Rumiato, E., Fassan, M. et al. Genetic risk of subsequent esophageal cancer in lymphoma and breast cancer long-term survival patients: a pilot study. Pharmacogenomics J 16, 266–271 (2016). https://doi.org/10.1038/tpj.2015.41
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tpj.2015.41