Issue 08 | August 2017

Welcome to Strand Genomics-A Monthly E-zine from Strand Life Sciences

Strand Life Sciences welcomes you to Strand Genomics, our monthly E-zine that includes articles of interest to physicians. We bring the latest news in the world of genetic diagnostics, to your doorstep. Strand Genomics features carefully crafted articles as well as curated news in the field of cancer therapy and genetic analyses to support the implementation of personalized medical care. We invite you to peruse as well as share these articles. Please also feel free to write back to us with comments and questions at strandlive@strandls.com

Gene Variants Of Predictive Significance in Chemotherapy

Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • Genetic analyses of cancers have focused on identification of pathologic mutations in genes that cause cancer, with the intention of developing targeted drugs.
  • However, the pharmacogenetics of response to generic chemotherapy may still remain a significant area of interest for oncologists. Genes that can modify the response to platinum-based genotoxic drugs can be helpful in predicting patient response, thereby allowing modulation of therapy.
  • Identification of patient genotypes, in such cases, will provide valuable insights into the progress of a patient and yield an inkling of expected outcomes.
  • Deviations from reasonable expectations of patient outcomes can then serve as red flags for timely interventions and modifications of chemotherapy regimens.

Introduction

Genetics and cancer therapy go hand in hand in order to move away from generic chemotherapy and enable targeted therapy. The thrust of research in oncogenetics has been to identify genetic signatures of various cancers and develop therapeutics that can specifically target tumors with distinct and evolving genetic profiles. A case in point is the development of tyrosine kinase inhibitors (TKIs) like afatinib, erlotinib and gefitinib against EGFR mutations, specifically EGFR del 19 and EGFR L858R. Inhibitors against mutations like EGFR T790M which become dominant in response to first-line tyrosine-kinase inhibitors, like Osimertinib and others are also being developed and evaluated in clinical settings. Although the progression of the field towards personalized medicine is rapid and advancing significantly, generic chemotherapy (platinum and taxol-based drugs, folate pathway inhibitors) cannot be simply ignored or discarded overnight. Targeted therapeutics are still being assessed for efficacy in various kinds of solid tumors bearing multiple genetic profiles. Moreover, targeted therapeutic drugs are expensive and possibly out of reach of patients from economically disadvantageous strata, worldwide. Correlations between genetic loci / variants and response to chemotherapy in various cancers would therefore be a valuable prognostic tool for oncologists.

Genetic Variants and Response to Chemotherapy

Predicting the response of a patient to administered therapeutics- generic or targeted- has been another long-standing challenge for oncologists. Evidence from some studies suggests that response to chemotherapy may be linked with the presence of specific variants of some genes.

Genes Involved in DNA Repair Mechanisms

The XPD gene is engaged in the nucleotide excision repair (NER) pathway in mammalian cells. Gene variants in XPD (Lys751Gln; A>C) that can compromise the NER as well as those in another gene XRCC1 (Arg399Gln) which compromise the base excision repair (BER) pathway can increase the risk of development of esophageal adenocarcinoma (1). In a meta-analysis of 24 studies, the same gene variant XPD (Lys751Gln; A>C) has been shown to have predictive and prognostic value in lung cancer patients. Presence of the XPD (Lys751Gln; A>C) polymorphism is associated with a decreased progression-free response in Asian individuals. The effect of this gene variant on the overall response in Caucasian individuals is unremarkable, in contrast (2).

Likewise, in colorectal cancer patients, presence of the XPD (Lys751Gln; A>C) polymorphism is associated with a poor progression in patients of Asian ethnicity, although the variant has no predictive value in Caucasian individuals (3).

Other polymorphisms that have been associated with response to platinum-based chemotherapeutic drugs are: RRM1 (rs12806698), XPC (rs2228000), XPF (rs1799801), hMLH1 (rs1800734), PMS2 (rs1062372), REV3L (rs462779), and FANCC (rs4647554) (4).  In this study, 437 NSCLC patients were studied to identify the role of 97 single nucleotide polymorphisms (SNPs) in 54 genes that function in DNA repair pathways. The SNPs identified in the first cohort were validated against data from a second cohort of 781 NSCLC patients. Taken together, data from both cohorts indicates that presence of the XPC rs2228000 SNP was linked with better tolerance of hemotoxicity, gastrointestinal toxicity, and leukopenia.

In another study with 1002 (694 patients treated with chemotherapy, 308 not treated with chemotherapy) gastric cancer patients of Chinese ethnicity, presence of the ERCC1 (rs2298881A) allele was found to be associated with better survival of patients treated with chemotherapy. Variants of the XRCC gene, namely the XRCC (rs10040363G) allele and the XRCC (rs2075685T) allele were found to be associated with higher risk of death, when treated with chemotherapy (5). The XRCC gene polymorphisms were linked to higher death risk even when present as a single haplotype. Upregulation of XRCC gene expression, when one or both these alleles were present has been postulated as the mechanism that enables survival of gastric cancer cells, despite chemotherapy (5).

Table 1. Genetic Polymorphisms with Predictive Value in Chemotherapy Regimens

No. Gene Polymorphism Observed outcome
1. XPD (Lys751Gln; A>C) Poor prognosis in lung cancer patients of Asian ethnicity
2. XPC rs2228000 SNP Better tolerance of hemotoxicity, GI toxicity and leukopenia in NSCLC patients.
3. ERCC1 (rs2298881A) Better survival of gastric cancer patients of Chinese ethnicity
4. XRCC (rs10040363G) Higher risk of death in gastric cancer patients of Chinese ethnicity, when treated with chemotherapy
5. XRCC (rs2075685T) Higher risk of death in gastric cancer patients of Chinese ethnicity, when treated with chemotherapy
6. TEAD3 (rs2076173 C) Better survival in Chinese liver cancer patients, as against alleles mentioned below
7. TEAD3 (rs11756089T) Better survival in Chinese liver cancer patients, as against alleles mentioned below
8. TEAD3 (rs2304733), TEAD3 (rs10831923), TEAD3 (rs12104362), TEAD3 (rs3745305) Poor survival in Chinese liver cancer patients, when compared against alleles mentioned in rows 6 &7.
9. LATS2 (rs7317471 CT/TT) Decreased risk of death in patients- 1) aged less than 53 years, 2) women, 3) alcohol consumers, 4) smokers, and with Barcelona clinic stage B liver cancer

 

Gene Polymorphisms In Other Signalling Pathways

Polymorphisms in pathways that promote tumorigenesis may also have predictive significance in the progression of cancer patients. The Hippo signalling pathway is engaged in controlling organ size. Although the only gene from this pathway that has been identified in somatic solid tumors is the NF2 gene, there is evidence to show that variants of other genes in this pathway may promote the development of colorectal, gastric, liver, ovarian, breast and pancreatic cancers, as evident from animal models (6). In humans, mutations in the Hippo pathway genes have been identified from ovarian, pancreatic tumors, gliomas, head and neck cancers and colorectal cancer cases (6). Interestingly, these mutations have been found only in somatic cancers, so far. In Chinese liver cancer patients, SNPs of the TEA domain transcription factor gene have been linked to better likelihood of survival. The TEAD3(rs2076173 C) allele and TEAD3 (rs11756089T) allele were linked with longer median survival time as against other SNPs like TEAD3 (rs2304733), TEAD3 (rs10831923), TEAD3 (rs12104362), TEAD3 (rs3745305) (7).

In another study of 331 treatment-naïve, Hepatitis B-positive Chinese liver cancer patients, the LATS2(rs7317471 CT/TT) genotypes were associated with a decreased risk of death in patients – 1) aged less than 53 years, 2) women, 3) alcohol consumers, 4) smokers, and with Barcelona clinic stage B liver cancer. These patients had not received prior chemotherapy or transcatheter hepatic arterial chemoembolization, as well (8).

Summary

  • Genetic analyses of cancers have focused on identification of pathologic mutations in genes that cause cancer, with the intention of developing targeted drugs.
  • However, the pharmacogenetics of response to generic chemotherapy may still remain a significant area of interest for oncologists. Genes that can modify the response to platinum-based genotoxic drugs can be helpful in predicting patient response, thereby allowing modulation of therapy.
  • Identification of patient genotypes, in such cases, will provide valuable insights into the progress of a patient and yield an inkling of expected outcomes.
  • Deviations from reasonable expectations of patient outcomes can then serve as red flags for timely interventions and modifications of chemotherapy regimens.

References

  1. Liu G, Zhou W, Yeap BY, Su L, Wain JC, Poneros JM, et al. XRCC1 and XPD polymorphisms and esophageal adenocarcinoma risk. Carcinogenesis [Internet]. 2007 Jan 18 [cited 2017 Aug 14];28(6):1254–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17264068
  2. Qin Q, Zhang C, Yang X, Zhu H, Yang B, Cai J, et al. Polymorphisms in XPD gene could predict clinical outcome of platinum-based chemotherapy for non-small cell lung cancer patients: a meta-analysis of 24 studies. PLoS One [Internet]. 2013 [cited 2017 Aug 11];8(11):e79864. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24260311
  3. Qian Y-Y, Liu X-Y, Pei D, Xu J-L, Shen H, Chen X-F, et al. The XPD Lys751Gln polymorphism has predictive value in colorectal cancer patients receiving oxaliplatin-based chemotherapy: a systemic review and meta-analysis. Asian Pac J Cancer Prev [Internet]. 2014 [cited 2017 Aug 14];15(22):9699–706. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25520091
  4. Zheng Y, Deng Z, Yin J, Wang S, Lu D, Wen X, et al. The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum-based chemotherapy. Int J Cancer [Internet]. 2017 Aug 9 [cited 2017 Aug 14]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/28791697
  5. Cheng L, Qiu L, Wang M, Zhang R, Sun M, Zhu X, et al. Functional genetic variants of XRCC4 and ERCC1 predict survival of gastric cancer patients treated with chemotherapy by regulating the gene expression. Mol Carcinog [Internet]. 2017 Aug 10 [cited 2017 Aug 14]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/28796378
  6. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer [Internet]. 2013 Mar 7 [cited 2017 Aug 14];13(4):246–57. Available from: http://www.nature.com/doifinder/10.1038/nrc3458
  7. Xia H, Wen J, Zhao W, Gu D, Hu Z, Chen J, et al. The prognostic impacts of TEA domain (TEAD) transcription factor polymorphisms in chinese hepatocellular carcinoma patients. Oncotarget [Internet]. 2017 Jul 17 [cited 2017 Aug 14]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/28754883
  8. Shen L, Wen J, Zhao T, Hu Z, Song C, Gu D, et al. A genetic variant in large tumor suppressor kinase 2 of Hippo signaling pathway contributes to prognosis of hepatocellular carcinoma. Onco Targets Ther [Internet]. 2016 [cited 2017 Aug 14];9:1945–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27110123

 

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Obesity Increases The Risk for Breast Cancer in Asian Women

The incidence of breast cancer in India is rising. In our previous issues, we have looked at the mortality ratio of breast cancer in India which stands at an alarming 50%!

The risk factors for high mortality include a hereditary predisposition, low awareness and reduced access to healthcare interventions. In a recent study conducted by physicians from Tata Memorial Hospital and their collaborators, truncal obesity has been identified as a factor that increases Asian women’s risk for breast cancer. Central obesity, as assessed by the Waist-to-Hip ratio (WHR), can increase the risk of breast cancer in pre- as well as post- menopausal women. Obese and overweight pre-menopausal women are at 4X greater risk of breast cancer than women with a WHR or <0.8. The trend continues in the post-menopausal stage as well.

(Reference:  Nagrani R, Mhatre S, Rajaraman P, Soerjomataram I, Boffetta P, Gupta S, et al. Central obesity increases risk of breast cancer irrespective of menopausal and hormonal receptor status in women of South Asian Ethnicity. Eur J Cancer [Internet]. 2016 Oct [cited 2017 Aug 18];66:153–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27573429).

Genetic Testing Alerts Patient to the Risk of Future Cardiac Arrhythmia

Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • An 11-year-old boy suffered a cardiac arrest during appendectomy, leading to further medical investigations.
  • Presence of the long QT syndrome in the proband was noted.
  • Genetic analysis led to the identification of a ‘likely pathogenic’ variant of the KCNQ1 gene in the proband.
  • The family was counselled to safeguard against such incidents in the future.

Abstract

How many of us can associate a cardiac arrest with an 11 year old boy? Cardiac events are not part of a child’s world and neither should they be. Yet, for 11 year old Karthik*, an unexpected turn of events led to the discovery of his risk for irregular heartbeats (arrhythmias) resulting from an inherited genetic mutation.

Patient Profile

Karthik, aged 11, was scheduled to undergo a surgery to get his appendix removed. During the surgery, the child suffered a cardiac arrest. Although he was revived, the incident was alarming enough for his doctors and parents to investigate the cause of the heart attack.

 

 

Medical Investigations

An ECG (electrocardiogram) revealed that Karthik had an irregular heartbeat, a condition known as ‘long QT’ syndrome in medical parlance. Contractions of the heart are regulated by a series of electrical signals that are delivered as characteristic pulses. Each phase of this pulse is designated by the letters P, Q, R, S, T (See Figure 1).

Figure 1. Normal and Long-QT ECG recordings (Representative Images)

 


The time interval between the Q and T electrical pulses in normal individuals is 0.35-0.43s, which is one-third of the total time of the heartbeat. In individuals suffering from long QT syndrome, this interval lasts for longer than 0.43s. Essentially, this results in an irregular heartbeat. Individuals with long QT syndrome are prone to experiencing arrhythmias triggered by sudden emotional stress like fright or by physical exertion.

Genetic testing was advised to Karthik’s parents to understand the sudden cardiac arrest during his appendectomy.

Genetic Counselling

Karthik’s family history was recorded during a genetic counselling session. Karthik has an elder brother (23 years). Both brothers are born to parents in a non-consanguineous marriage. His parents had aborted two additional pregnancies, owing to the incidence of fetal brain abnormalities.

Karthik’s father (age 50 years) had suffered a heart attack in the preceding years with a resultant angioplasty performed on him. Other family members, like aunts and grandparents, did not have a history of cardiac ailments.

Figure 2: Family History of Proband Presenting with Long QT syndrome

 

pedigree of proband with Long QT Syndrome

Results of Genetic Testing

A ‘likely pathogenic’ mutation of the KCNQ1 gene was identified in Karthik’s genome.

Mutations in KCNQ1 are associated with long QT syndrome type 1 (Giudicessi & Ackerman 2013; Adadi et al. 2017) and are inherited in an autosomal dominant manner. This means that only one defective (mutant) copy of this gene is suffcient for causing the long QT syndrome in this patient. Consequently, heterozygous individuals, which have only one copy of the mutant gene can also suffer from long QT syndrome despite inheriting a second, normal copy of this gene.

Figure3. Identification of a ‘likely pathogenic’ gene variant

proband's results of genetic testing for long QT syndrome

Conclusions

Karthik was found to be heterozygous for a likely pathogenic variant of the KCNQ1 gene, thereby establishing the genetic cause of his long QT syndrome.

Counselling was provided to him and his parents to avoid the incidence of cardiac arrests in the future.

Mutation-specific testing was advised to his parents to understand whether his parents were also heterozygous for this mutation or not. Genetic testing of both parents could have led to an understanding of the risk of cardiac arrest for them as well.

Summary

  • An 11-year-old boy suffered a cardiac arrest during appendectomy, leading to further medical investigations.
  • Presence of long QT syndrome in the proband was noted.
  • Genetic analysis led to the identification of a ‘likely pathogenic’ variant of the KCNQ1 gene in the proband.
  • The family was counselled to safeguard against such incidents in the future.

References

Adadi, N. et al., 2017. Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report. Journal of Medical Case Reports, 11(1), p.88. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28364778 [Accessed May 10, 2017].

Giudicessi, J.R. & Ackerman, M.J., 2013. Genotype- and phenotype-guided management of congenital long QT syndrome. Current problems in cardiology, 38(10), pp.417–55. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24093767 [Accessed May 9, 2017].

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