Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy

Kamalesh Dattaram Mumbrekar, Satish Rao Bola Sadashiva, Shama Prasada Kabekkodu, Donald Jerard Fernandes, Bejadi Manjunath Vadhiraja, Tomo Suga, Yoshimi Shoji, Fumiaki Nakayama, Takashi Imai, Kapaettu Satyamoorthy

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage–repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. Methods and Materials The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. Results Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3′-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene–gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). Conclusions The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene–gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.

Original languageEnglish
Pages (from-to)118-127
Number of pages10
JournalInternational Journal of Radiation Oncology Biology Physics
Volume97
Issue number1
DOIs
Publication statusPublished - 01-01-2017

Fingerprint

breast
radiation therapy
genes
Radiotherapy
cancer
Breast Neoplasms
magnetic permeability
Skin
polymorphism
toxicity
Radiation Oncology
Genes
grade
Multifactor Dimensionality Reduction
Alleles
cdc Genes
polymerase chain reaction
biomarkers
nucleotides
antioxidants

All Science Journal Classification (ASJC) codes

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

@article{b17c886453e64d6ebea369b71b5b5080,
title = "Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy",
abstract = "Purpose Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10{\%} of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage–repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. Methods and Materials The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. Results Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3′-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene–gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). Conclusions The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene–gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.",
author = "Mumbrekar, {Kamalesh Dattaram} and {Bola Sadashiva}, {Satish Rao} and Kabekkodu, {Shama Prasada} and Fernandes, {Donald Jerard} and Vadhiraja, {Bejadi Manjunath} and Tomo Suga and Yoshimi Shoji and Fumiaki Nakayama and Takashi Imai and Kapaettu Satyamoorthy",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.ijrobp.2016.09.017",
language = "English",
volume = "97",
pages = "118--127",
journal = "International Journal of Radiation Oncology Biology Physics",
issn = "0360-3016",
publisher = "Elsevier Inc.",
number = "1",

}

Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy. / Mumbrekar, Kamalesh Dattaram; Bola Sadashiva, Satish Rao; Kabekkodu, Shama Prasada; Fernandes, Donald Jerard; Vadhiraja, Bejadi Manjunath; Suga, Tomo; Shoji, Yoshimi; Nakayama, Fumiaki; Imai, Takashi; Satyamoorthy, Kapaettu.

In: International Journal of Radiation Oncology Biology Physics, Vol. 97, No. 1, 01.01.2017, p. 118-127.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy

AU - Mumbrekar, Kamalesh Dattaram

AU - Bola Sadashiva, Satish Rao

AU - Kabekkodu, Shama Prasada

AU - Fernandes, Donald Jerard

AU - Vadhiraja, Bejadi Manjunath

AU - Suga, Tomo

AU - Shoji, Yoshimi

AU - Nakayama, Fumiaki

AU - Imai, Takashi

AU - Satyamoorthy, Kapaettu

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Purpose Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage–repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. Methods and Materials The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. Results Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3′-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene–gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). Conclusions The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene–gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.

AB - Purpose Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage–repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. Methods and Materials The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFβR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade <2) and overresponders (Radiation Therapy Oncology Group grade ≥2) for analysis. Results Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 3′-UTR of CD44 was significantly (P=.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (P=.0107) gene–gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (P=.0302). Conclusions The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene–gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.

UR - http://www.scopus.com/inward/record.url?scp=85003782020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85003782020&partnerID=8YFLogxK

U2 - 10.1016/j.ijrobp.2016.09.017

DO - 10.1016/j.ijrobp.2016.09.017

M3 - Article

VL - 97

SP - 118

EP - 127

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

IS - 1

ER -