Past Issues
Issue 15 | March 2018
Welcome to Strand Genomics
Strand welcomes you to Strand Genomics, our monthly E-zine that includes articles of interest to physicians like you. We have a new version of this e-zine!! Strand Genomics brings the latest news in the world of genetic diagnostics, to your doorstep. We present 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. A new feature is the section that provides updates on clinical trials in India as well as on recently-approved drugs for cancer. Now that Strand and Triesta Sciences have joined hands to create a synergistic, end-to-end diagnostic services company, ask our sales representatives about all the tests we can provide for your specialty! Feel free to write back to us with comments and questions at strandlive@strandls.com.
Breast Cancer in India: Pre-Emptive Testing Can Halt the Disease in its Tracks
– Dr. Shefali Sabharanjak
Strand Life Sciences
Abstract
- Hereditary cancer may prove to be a significant chunk of all kinds of cancers in India.
- Analysis of 1000 breast and ovarian cancer (BOC) cases shows that the prevalence of germline pathogenic mutations in India is as high as 30%.
- Germline mutations in BRCA1, BRCA2, TP53 and PALB2 genes account for a significant share of hereditary mutations.
- A combination of the Strand Germline Cancer test and mutation-specific testing can be effectively leveraged to extend the benefits of genetic testing to probands as well as to their extended families.
- Pre-emptive testing can help to identify carrier individuals, at increased risk for cancer, and enable better medical surveillance for the earliest signs of cancer.
- Development and adoption of India-specific guidelines for genetic testing is the need of the hour.
Introduction
Breast cancer is set to become a major healthcare issue in India. The combined effects of factors such as low awareness about breast cancer, lack of periodic surveillance against signs and symptoms of nascent disease, and social inhibitions leading to inadequate access to healthcare, results in a huge burden of breast cancer on the healthcare system. One silent, yet significant, factor that is likely to play a huge role in the breast cancer burden in India is the prevalence of hereditary mutations that lead to development of breast cancer.
Strand has published a study on the prevalence of hereditary mutations that can increase a person’s lifetime risk for developing cancer, in a small cohort of the 150 breast and ovarian cancer(BOC) cases (Mannan et al. 2016). An expansion of that cohort to a 1000 BOC cases has led to the reaffirmation of the salient finding that the prevalence of hereditary mutations that predispose towards hereditary breast and ovarian cancer (HBOC), is very high in India (Singh et al. 2018). The prevalence of hereditary mutations that increase the risk of HBOC is 30% in the Indian cohort of BOC cases. Additionally, there are 56 novel mutations found in the Indian cohort that are clearly distinct from other known HBOC mutations.
Figure 1: Incidence and distribution of germline mutations in 1000 BOC cases (Ref: Singh et al. 2018)
A significant proportion of mutations lie in the BRCA1 and BRCA2 genes. Mutations in TP53 and PALB2 are the second most frequent class of mutations. In contrast, a study conducted with a predominantly European and North American cohort has shown that the prevalence of hereditary mutations is only 12 % amongst all BOC cases (Buys et al. 2017). Interestingly, the cohort size (35,000 individuals) as well as the size of the gene panel (35 genes) in this study (Buys et al. 2017) are larger than the 1000-case cohort and 19-gene panel germline test, used in the Indian study (Singh et al. 2018). Given that the odds of finding germline mutations are higher in the earlier study, the presence of a surprisingly high number of BRCA1 and BRCA2 mutations in the Indian study, is definitely a red flag.
The high prevalence of germline mutations in India is also reflected in the profile of breast cancer in India. The proportion of triple-negative breast cancer cases, an aggressive and early-onset sub-type of breast cancer is quite high in India (31%) as compared to that seen in North America (12%) (Phuah et al. 2012; Sandhu et al. 2016).
Incidentally, a comparative analysis of the prevalence of hereditary mutations across three different studies shows that distribution of germline mutations is unique to different population groups. This not only makes the extrapolation of results from one to the other difficult, but also underlines the need for differential, population-specific screening strategies.
Inadequate Genetic Testing In India
Awareness about genetic testing is slowly picking up pace with more and more doctors opting for this diagnostic criterion, in addition to other clinico-pathological evaluations, in oncology as well as in rare inherited disorders.
There have been cases where the index case of early-onset breast cancer was not advised genetic testing. Early germline testing, especially in young women, as well as in cases of male breast cancer, can lead to the identification of pathogenic or likely pathogenic variants in the affected individuals. Strand offers a rapid, custom-designed and convenient, mutation-specific test, that can be extended to the immediate and extended family members of probands, in order to understand their status, vis-à-vis the identified hereditary mutation(s).
Pre-emptive Testing Can Increase Surveillance Against Cancer
Converts are often the most ardent zealots, they say. Nothing illustrates this fact more than a recent mega-case that was analyzed at Strand.
Mr. Ramakant Patole*, a progressive agriculturist living near Pune, had been diagnosed with pancreatic cancer at age 56 years and with male breast cancer at the age of 65 years. The incidence of two different primary cancers in the same person is definitely a case for germline testing, as per NCCN guidelines.
The Strand Germline Cancer test was used to identify the presence of a ‘likely pathogenic’ variant of the BRCA2 gene in his genome. Subsequently, he convinced his immediate as well as extended family members to undergo pre-emptive genetic testing for the same gene variant. This massive, co-ordinated testing effort laid out a clear picture of their genetic status, before this family. Three other family members, two of them physicians, tested positive for the same BRCA2 mutation.
Figure 2. Pedigree chart post genetic testing of Mr. Patole’s extended family.
These people were unaffected at the time of testing (Dec 2017-March 2018) and now have a chance to undergo frequent medical surveillance for the earliest signs of cancer.
Dr. Anagha* also has the chance to undergo risk-reduction bilateral salpingo-oophorectomy (RRSO) as well as risk-reduction bilateral mastectomy (RRBM) at a suitable juncture in her life, before cancer is detected.
The pre-emptive testing for germline mutations also provided emotional relief to other family members who tested negative for this BRCA2 mutation.
This family is representative of the kind of prevalence of HBOC in the Indian population.
Summary
- Hereditary cancer may prove to be a significant chunk of all kinds of cancers in India.
- Analysis of 1000 breast and ovarian cancer (BOC) cases shows that the prevalence of germline pathogenic mutations in India is as high as 30%.
- Germline mutations in BRCA1, BRCA2, TP53 and PALB2 genes account for a significant share of hereditary mutations.
- A combination of the Strand Germline Cancer test and mutation-specific testing can be effectively leveraged to extend the benefits of genetic testing to probands as well as to their extended families.
- Pre-emptive testing can help to identify carrier individuals, at increased risk for cancer, and enable better medical surveillance for the earliest signs of cancer.
- Development and adoption of India-specific guidelines for genetic testing is the need of the hour.
*– Fictitious names used to protect patient privacy
References
Buys, Saundra S., John F. Sandbach, Amanda Gammon, Gayle Patel, John Kidd, Krystal L. Brown, Lavania Sharma, Jennifer Saam, Johnathan Lancaster, and Mary B. Daly. 2017. “A Study of over 35,000 Women with Breast Cancer Tested with a 25-Gene Panel of Hereditary Cancer Genes.” Cancer 123 (10): 1721–30. doi:10.1002/cncr.30498.
Mannan, Ashraf U, Jaya Singh, Ravikiran Lakshmikeshava, Nishita Thota, Suhasini Singh, T S Sowmya, Avshesh Mishra, et al. 2016. “Detection of High Frequency of Mutations in a Breast And/or Ovarian Cancer Cohort: Implications of Embracing a Multi-Gene Panel in Molecular Diagnosis in India.” Journal of Human Genetics 61 (6): 515–22. doi:10.1038/jhg.2016.4.
Phuah, Sze-Yee, Lai-Meng Looi, Norhashimah Hassan, Anthony Rhodes, Sarah Dean, Nur Aishah Mohd Taib, Cheng-Har Yip, and Soo-Hwang Teo. 2012. “Triple-Negative Breast Cancer and PTEN (Phosphatase and Tensin Homologue) Loss Are Predictors of BRCA1 Germline Mutations in Women with Early-Onset and Familial Breast Cancer, but Not in Women with Isolated Late-Onset Breast Cancer.” Breast Cancer Research : BCR 14 (6). BioMed Central: R142. doi:10.1186/bcr3347.
Sandhu, Gurprataap S, Sebhat Erqou, Heidi Patterson, and Aju Mathew. 2016. “Prevalence of Triple-Negative Breast Cancer in India: Systematic Review and Meta-Analysis.” Journal of Global Oncology 2 (6). American Society of Clinical Oncology: 412–21. doi:10.1200/JGO.2016.005397.
Singh, Jaya, Nishita Thota, Suhasini Singh, Shila Padhi, Puja Mohan, Shivani Deshwal, Soumit Sur, et al. 2018. “Screening of over 1000 Indian Patients with Breast And/or Ovarian Cancer with a Multi-Gene Panel: Prevalence of BRCA1/2 and Non-BRCA Mutations.” Breast Cancer Research and Treatment, February. doi:10.1007/s10549-018-4726-x.
Open Platform for Rare Diseases OPFORD
The incidence of rare disorders in India is high with 1 in 20 people reported to be affected. Most inherited rare disorders are evident in children younger than 7 years of age. The incidence of late-onset rare disorders like GNE muscular dystrophies is also seen in the Indian population.
Rare disorders are yet to receive their due attention, in terms of widespread availability of diagnostic tests as well as identification of suitable therapeutic options intended to improve the quality of life of afflicted individuals.
Genetic testing can be very gainfully employed to pinpoint the mutations underlying rare disorders. Since a lot rare inherited disorders necessitate constant care and patient management, having a large support system and social network can be very valuable assets for patients and caregivers alike. A recent initiative ‘Open Platform for Rare Disorders’ or OPFORD for short, has been created to support individuals living with rare disorders.
Awareness about rare disorders and community building are the two objectives of OPFORD. OPFORD is a platform where patients and caregivers can come together to gain information about rare disorders as well as to share experiences with other people.
Strand Clinical Exome Test Provides Differential Diagnosis between Friedrich’s Ataxia and Ataxia with Vitamin E Deficiency
– Dr. Shefali Sabharanjak
Strand Life Sciences
Abstract
- The Strand Clinical Exome test helped to identify a ‘likely pathogenic’ variant in the TTPA gene, in the proband suspected to have Friedrich’s ataxia.
- Identification of this mutation indicated a clear diagnosis of Ataxia with Vitamin E Deficiency (AVED) instead of Friedrich’s Ataxia.
- The genetic test also established that the ataxia was curable by supplementation with vitamin E, thereby improving the proband’s quality of life.
- Mutation-specific testing services provided to the proband’s family helped to establish the fact that his sister was also homozygous for the same mutation, although she did not suffer from the same symptoms as her brother.
- Since the sister’s husband was negative for the TTPA mutation, the chances of their unborn fetus inheriting the mutation from the porband’s sister were ascertained.
- The couple proceeded with the pregnancy and had a healthy child, once the risk of transmission of the hereditary mutation was established to be only 50% and the child was unlikely to suffer from ataxia.
- Genetic testing helped to establish therapeutic options for the proband as well as the risk of transmission of the mutation to the unborn child of his sister.
Introduction
The incidence of a rare, inherited disease in a child is always a fraught experience for the infant and parents alike. More often than not, rare congenital disorders require lifelong care. Management and therapy options that can normalize life for the affected individual are few and far between. The anxiety related to inheritance is always heightened if a close relative is known to be afflicted with the disease. This was precisely the problem in this case where the proband’s sister was expecting a child and was anxious about the chances of her child inheriting ataxia, evident in her older brother.
Ataxia disorders like Friedrich’s ataxia, ataxia with oculomotor apraxia types 1 and 2 (AOA1 and AOA2), and others present with features like uncoordinated gait, limited movement of eyes, decreased visual acuity, and loss of physical balance (Pearson, 2016).
Many ataxia disorders are not curable or have limited therapy options. A differential diagnosis between the known disorders is best obtained with a genetic test like the Strand Clinical Exome Test. The distinction between ataxia disorders may sometimes help to arrive at a proper diagnosis and delineate therapeutic options.
Patient Profile
Piyush* and Pratidnya Chakrapani*, aged-26-years and 23- years respectively, are children born to Sameeksha* and Amol Chakrapani*. Piyush presented with slurred speech and problems with movement. He started experiencing speech difficulties when he turned 13-years -old.
His younger sister was unaffected. Pratidnya was married to Sanket in a non-consanguineous union and they were expecting their first baby. Given the incidence of difficulties in gait and speech in her older brother, Pratidnya was worried about her baby’s future as well. The family consulted a geneticist at a prominent hospital in Mumbai. Initially, a diagnosis of Friedrich’s ataxia was suspected, but clinical investigations ruled out this particular form of ataxia. Piyush was then prescribed the Strand Clinical Exome Test in order to understand the genetic changes that could be responsible for his ataxia.
Family History
Piyush’s parents, Sameeksha and Amol, are a consanguineous couple. They are first cousins. Given this history of consanguinity, the Strand Clinical Exome Test was prescribed to Piyush to understand the exact causes of his developmental and neurological issues.
Family Tree Pre-Genetic Testing
Figure 1. Family tree of Piyush and Pratidnya
Results of Genetic Testing
A ‘likely pathogenic’ mutation in exon 1 of the TTPA gene was identified in Piyush’s genome.
- The TTPA gene codes for a protein that binds to vitamin E and facilitates its transport.
- Germline pathogenic variations in the TTPA gene have been shown to be associated with ataxia with vitamin E deficiency (AVED) also known as Friedrich-like ataxia, which manifests in late childhood or early teens as progressive ataxia, clumsiness of the hands, loss of proprioception, areflexia and other features such as dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The phenotype and disease severity vary widely among families and also among siblings. Timely vitamin E supplementation is suggested to completely avert the clinical manifestations of the disease (Schuelke, 1993).
- AVED, caused due to variations in the TTPA gene, is inherited in an autosomal recessive manner, which means two copies of the altered gene in an individual are required for disease manifestation. However, the symptoms of the deficiency and the resulting behavioural and physical challenges can vary from person to person.
- AVED is a treatable disorder. In fact, amongst the hereditary ataxias, this is the only syndrome that can be treated with dietary supplementation of vitamin E (Ko & Park-Ko, 1999; Wysota, Michael, Hiew, Dawson, & Rajabally, 2017).
Mutation-Specific Testing
The principal impetus to go in for a clinical evaluation and genetic testing was the concern about transmitting the same condition to Pratidnya’s unborn child. So, in order to understand the chances of this inheritance, mutation-specific testing was advised to Pratidnya, Sanket, Amol and Sameeksha as well.
The results of the mutation-specific testing are summarized in Table 1.
Table 1. Results of mutation-specific testing of proband’s family members
Conclusions
- Pratidnya was homozygous for the same mutation that Piyush had, although she was unaffected by the symptoms of AVED
- Their parents – Amol and Sameeksha – were found to be heterozygous for the identified mutation, which explains the homozygosity of the mutation in both their children.
- Sanket was not a carrier of this mutation. Therefore, although Pratidnya is homozygous for the TTPA mutation, their child has a 50% chance of being heterozygous for the same mutation.
- Given that the disease is recessive, their child / children are not likely to suffer from AVED
- Strand’s Clinical Exome Test and mutation-specific tests provided a clear actionable diagnosis for the proband and a clear picture of the genetic status of the entire family.
*- Patient names changed to protect privacy
References
Ko, H. Y., & Park-Ko, I. (1999). Electrophysiologic recovery after vitamin E-deficient neuropathy. Archives of Physical Medicine and Rehabilitation, 80(8), 964–7. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/10453775
Pearson, T. S. (2016). More Than Ataxia: Hyperkinetic Movement Disorders in Childhood Autosomal Recessive Ataxia Syndromes. Tremor and Other Hyperkinetic Movements (New York, N.Y.), 6, 368. https://doi.org/10.7916/D8H70FSS
Schuelke, M. (1993). Ataxia with Vitamin E Deficiency. GeneReviews®. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20301419
Wysota, B., Michael, S., Hiew, F. L., Dawson, C., & Rajabally, Y. A. (2017). Severe but reversible neuropathy and encephalopathy due to vitamin E deficiency. Clinical Neurology and Neurosurgery, 160, 19–20. https://doi.org/10.1016/j.clineuro.2017.06.005
Advanced genomic analysis for answers not found before
In the News!
Clinical Trials Update
Phase IV Panitumumab Study in Indian Subjects With Metastatic Colorectal Cancer
Clinical Study Identifier: NCT02301962
Sponsor: GlaxoSmithKline
A trial to understand the clinical efficacy of Panitumumab in metastatic colorectal cancerwherein KRAS and NRAS geens are normal is in progress, in Nagpur.
Patients with the following profile are eligible for this study:
- Subject or subject’s legally acceptable representative has provided informed consent..
- Male or female >=18 years of age.
- Histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum
- Wild-type KRAS (without mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61], and exon 4 [codons 117 and 146]) and wild-type NRAS (without mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61], and exon 4 [codons 117 and 146]) tumor status.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- Measurable or non-measurable disease per RECIST Version 1.1.
- Must have failed after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens for metastatic disease.
Patients with prior therapy with CDK inhibitors as well as patients with high risk of cardiovascular disease including long QT syndrome and Torsade de pointe are not eligible for this study. The trial is being conducted at Manipal and HCG hospitals in Bangalore, India.
More information about the trial: https://clinicaltrials.gov/ct2/show/NCT02301962
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