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CACNG2 polymorphisms associate with chronic pain after mastectomy

Bortsov, Andrey V.a; Devor, Marshallb; Kaunisto, Mari A.c; Kalso, Eijad; Brufsky, Adame; Kehlet, Henrikf; Aasvang, Eskef; Bittner, Reinhardg; Diatchenko, Ludah; Belfer, Innai,*

doi: 10.1097/j.pain.0000000000001432
Research Paper

Chronic postmastectomy pain (PMP) imposes a major burden on the quality of life of the ever-increasing number of long-term survivors of breast cancer. An earlier report by Nissenbaum et al. claimed that particular polymorphisms in the gene CACNG2 are associated with the risk of developing chronic PMP after breast surgery (Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson AK, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res 2010;20:1180–90). This information is important because in principle, it can inform the surgical, radiological, and chemotherapeutic decision-making process in ways that could mitigate the increased risk of chronic pain. In this study, we revisited this claim by independently evaluating the proposed marker haplotype using 2 different patient cohorts recruited in different research settings. Meta-analysis of these new postmastectomy cohorts and the original cohort confirmed significant association of the CACNG2 haplotype with PMP. In addition, we tested whether the same markers would predict chronic postsurgical pain in men who underwent surgery for inguinal hernia repair, and whether there is significant genetic association with cutaneous thermal sensitivity in postmastectomy and postherniotomy patients. We found that the biomarker is selective because it did not predict pain after laparoscopic hernia repair and was not associated with pain sensitivity to experimentally applied noxious thermal stimuli. We conclude that the A-C-C haplotype at the 3 single-nucleotide polymorphisms (rs4820242, rs2284015, and rs2284017) in the CACNG2 gene is associated with increased risk of developing PMP. This information may advance current knowledge on pathophysiology of PMP and serve as a step forward in the prediction of clinical outcomes and personalized pain management.

Genotyping for 3 CACNG2 gene polymorphisms provides important information about the risk of mastectomy pain persistence and serves as a step forward in personalized pain management.

aDepartment of Anesthesiology, Center for Translational Pain Medicine, Duke University, Durham, NC, United States

bDepartment for Cell and Developmental Biology, Institute of Life Sciences and Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem, Israel

cInstitute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

dDepartment of Perioperative, Intensive Care and Pain Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

eDepartment of Medicine, University of Pittsburgh, Pittsburgh, PA, United States

fSection for Surgical Pathophysiology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark

gDepartment of General and Visceral Surgery, Centre for Minimal Invasive Surgery, Marienhospital Stuttgart, Stuttgart, Germany

hAlan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada

iNational Center for Complementary and Integrative Health, NIH, Bethesda, MD, United States

Corresponding author. Address: Division of Extramural Research National Center for Complementary and Integrative Health (NCCIH) NIH, DHHS, Democracy II, Suite 401, 6707 Democracy Blvd, Bethesda, MD 20892-5484, United States. Tel.: 301-435-1573. E-mail address: (I. Belfer).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

We dedicate this paper in remembrance of Prof. Ariel Darvasi (1962-2018), a brilliant geneticist from the Hebrew University of Jerusalem, Israel, and senior author of the initial findings on CACNG2 effects on pain.

Received June 17, 2018

Received in revised form September 29, 2018

Accepted October 09, 2018

© 2019 International Association for the Study of Pain
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