Issue 10 | October 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. This e-zine 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. Please also feel free to write back to us with comments and questions at strandlive@strandls.com

Breast Cancer in India: Are We Looking At A Grim Future?

Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • Heritable pathogenic mutations in BRCA1, BRCA2 and associated genes are highly prevalent in the Indian population.
  • The incidence of these mutations is 3-times higher (30%) than that in Western populations (~10%).
  • Higher genetic predisposition coupled with lack of awareness about regular surveillance measures are possible factors that contribute towards the high mortality of breast cancer.
  • Rigid adherence to guidelines for genetic testing may result in omission of women who can potentially benefit from genetic testing.
  • Pre-emptive genetic testing of all women, possibly in their 20s, could lead to more effective surveillance and possibly detection of cancer at early stages. Early stage detection can also facilitate choice of multiple therapeutic options and better odds of survival.
  • Genetic testing could probably be advised to first- and second-degree relatives of breast and ovarian cancer patients, even if they do not present with symptoms.

Introduction

India has had considerable success in controlling the spread and health sequelae of some infectious diseases like polio and leprosy. Although the burden of communicable diseases has not been entirely eliminated, the increasing weight of non-communicable diseases, like cancer, is an added stress on the system (Nongkynrih et al. 2004; Yadav & Arokiasamy 2014). Breast cancer, in particular, is poised to be a unique health problem for Indian women. Data from GLOBOCAN (2012) shows that India’s mortality-to-incidence ratio for breast cancer stood at 50% (Figure 1).

Breast Cancer Mortality Ratios

Figure 1: Mortality to Incidence Ratio of Breast Cancer – USA, China, and India

A recent analysis of data from several Indian cancer registries has also confirmed this trend. Out of 25.8 new breast cancer cases per 100,000 women, 12.7 cancer patients lose their lives to the disease (Malvia et al. 2017). Essentially, the trend of 50% mortality-to-incidence ratio has remained intact and is likely to persist in the foreseeable future.

Factors Contributing Towards Breast Cancer Mortality

Lack of Awareness About Breast Cancer

Lack of awareness about breast cancer is a very strong factor that contributes towards the mortality resulting from this malady. A meta-analysis of surveys including 7066 women, across various socio-economic strata, showed that the awareness of hereditary breast cancer ranged between 13-58% (Gupta et al. 2015). Knowledge about other factors influencing the incidence of breast cancer, like reproductive history (1-88%) and obesity (11-51%), was also limited. Nurses and healthcare workers had higher levels of awareness; however, dissemination of knowledge about breast cancer, in the general population, seems to be quite low (Gupta et al. 2015).

Most of the breast cancer cases in India are diagnosed at stages II, III and IV, instead of getting diagnosed in stage I, purely because of lack of information and therefore absence of regular breast self-examinations or clinical breast examinations (Khokhar 2012; Khokhar 2013).

Urbanization, rising incomes for women and delayed childbirth are also factors that contribute towards the incidence of breast cancer in Indian women.

Higher Genetic Predisposition To Breast Cancer

Estimates show that ~5% of all cancers are hereditary. Inheritance of mutations in BRCA1, BRCA2, PALB2, STK 11 and other genes (total tally 19) can increase a person’s risk for suffering from cancer. Results from a recent study show that the prevalence of BRCA1 and BRCA2 mutations is high in the Indian population (Figure 2) (Mannan et al. 2016).
prevalence of BRCA1 and BRCA2 mutations in Indian population is high

Figure 2. Prevalence of Hereditary Pathogenic Mutations in Indian Breast Cancer Patients

BRCA1 and BRCA2 mutations are found in ~73% of patients that bear hereditary pathogenic mutations. A significant 27% of patients with a hereditary predisposition to breast cancer also harbor mutations in other genes known to cause breast cancer.

Stratification of the data into discrete age groups shows that the prevalence of pathogenic mutations in very high – 44%-  in women of age 40 y or younger (Figure 3).

In the 40-50 y age group, this number stands at 53% and in women older than 50 y, the prevalence of pathogenic mutations is 27%.
prevalence of pathogenic mutations by age at diagnosis

Figure 3. Prevalence of Pathogenic Mutations – Agewise Stratification

In contrast, the prevalence of mutations that elevate the risk of hereditary breast cancer, in a study of 35,000 women (predominantly North European) was 10% (Buys et al. 2017).

Interestingly, a 25-gene test was used in the 35,000 cohort study (Buys et al. 2017), whereas the Strand study was conducted using a 13-gene test for screening (Mannan et al. 2016). So, although the probability of catching mutations was higher in the larger study, the numbers show a low prevalence of hereditary breast cancer. In contrast, the high prevalence of heritable mutations in the Indian population is a definite cause for concern.

Guidelines – Rigid Adherence or Discretionary Use

Screening for the presence of heritable mutations is, in effect, a post facto activity – predominantly used in patients who have been diagnosed with breast or ovarian cancer. NCCN guidelines indicate that women above the age of 50 years should be screened for the presence of germline (hereditary) mutations in genes that create a predisposition towards cancer. Other guidelines stipulated for recommending genetic testing increase the complexity in making use of genetic tests for identifying germline mutation carriers. In India, however, early-onset breast cancer is evident in patients as young as 30 years old. So, how should guidelines be used for genetic testing? With rigid compliance or should physicians prescribe genetic tests at their discretion, overriding age criteria? Given the high prevalence of hereditary mutations, in the Indian population, there is a high chance of missing out on identification of ‘carriers’, if testing guidelines are implemented rigorously and younger women are excluded.

In fact, even in the West, cases of genetic predisposition to hereditary breast cancer are getting missed out, if guidelines for genetic testing are adhered to rigidly (Grindedal et al. 2017). In a cohort of 1371 women newly diagnosed with breast cancer, 3.1 % of women were found to have germline (heritable) pathogenic mutations that heighten risk for breast cancer. Significantly, these investigators also identified one mutation-positive ‘carrier’ person in the family (asymptomatic) per every mutation-positive breast cancer ‘patient’. If age <40 years or incidence of TNBC were considered as indicative factors for genetic testing, only 34% carriers were identified. Adherence to international guidelines for testing resulted in the identification of ~68% (range 45-90%) of carrier individuals. Genetic testing of all women (independent of their eligibility by international guidelines) younger than 60 years resulted in identification of 90% of the carrier individuals (Grindedal et al. 2017). The data suggests that although guidelines are useful in identifying germline mutation carriers, they may not always be comprehensive. Pre-emptive determination of the genetic profile (vis-à-vis germline mutations for hereditary cancer) of all women, is the strategy that is most likely to succeed in identifying ‘carrier’ individuals. Carrier individuals can benefit from frequent medical surveillance for the earliest symptoms of breast and ovarian cancer.

Taken together, the data suggests that Indian women and their kin can benefit from pre-emptive (before the symptoms of breast cancer are evident) genetic testing to determine their personal risk for breast cancer. A predictive genetic test can empower women by establishing the need for adopting frequent surveillance measures. In turn, these steps are likely to result in detection of breast cancer in the early stages. As an initial step, perhaps, genetic testing should be advised to asymptomatic relatives of every breast and ovarian cancer patient.

Summary

  • Heritable pathogenic mutations in BRCA1, BRCA2, and associated genes are highly prevalent in the Indian population.
  • The incidence of these mutations is 3-times higher (30%) than that in Western populations (~10%).
  • Higher genetic predisposition coupled with lack of awareness of regular surveillance measures are possible factors that contribute towards the high mortality of breast cancer.
  • Rigid adherence to guidelines for genetic testing may result in omission of women who can potentially benefit from genetic testing.
  • Pre-emptive genetic testing of women, possibly in their 20s, could lead to more effective surveillance and possibly early detection of cancer.
  • Genetic testing could probably be advised to first- and second-degree relatives of breast and ovarian cancer patients, even if they do not present with symptoms.

References

Buys, S.S. et al., 2017. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer, 123(10), pp.1721–1730. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28085182 [Accessed October 13, 2017].

Grindedal, E.M. et al., 2017. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC cancer, 17(1), p.438. Available at: http://www.ncbi.nlm.nih.gov/pubmed/28637432 [Accessed July 10, 2017].

Gupta, A., Shridhar, K. & Dhillon, P.K., 2015. A review of breast cancer awareness among women in India: Cancer literate or awareness deficit? European Journal of Cancer.

Khokhar, A., 2012. Breast cancer in india: Where do we stand and where do we go? Asian Pacific Journal of Cancer Prevention, 13(10), pp.4861–4866.

Khokhar, A., 2013. View point: How to make women familiar with their breasts? Asian Pacific journal of cancer prevention : APJCP, 14(9), pp.5539–42. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24175855 [Accessed October 11, 2017].

Malvia, S. et al., 2017. Epidemiology of breast cancer in Indian women. Asia-Pacific Journal of Clinical Oncology, 13(4), pp.289–295. Available at: http://doi.wiley.com/10.1111/ajco.12661 [Accessed August 16, 2017].

Mannan, A.U. 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), pp.515–22. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26911350.

Nongkynrih, B., Patro, B.K. & Pandav, C.S., 2004. Current status of communicable and non-communicable diseases in India. The Journal of the Association of Physicians of India, 52, pp.118–23. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15656045 [Accessed October 10, 2017].

Yadav, S. & Arokiasamy, P., 2014. Understanding epidemiological transition in India. Global health action, 7, p.23248. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24848651 [Accessed October 10, 2017].

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Breast Cancer Subtypes In India and North America

A quick comparison of the distribution of breast cancer subtypes prevalent in India and North America shows that triple-negative breast cancer has a higher prevalence in the Indian population as against that seen in North America. Incidence of TNBC is an indication for genetic testing since the prevalence of BRCA1 and BRCA2 mutations is high in TNBC patients. The distribution of breast cancer subtypes underscores the need for preventive genetic testing in Indian women.

(References: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053128/; https://www.ncbi.nlm.nih.gov/pubmed/24777111; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493252/)

Hereditary Breast and Ovarian Cancer: Not Just a BRCA1 & 2 Playground

Dr. Shefali Sabharanjak
Strand Life Sciences

Abstract

  • Ameeta, a 59- year old woman had been diagnosed with cervical cancer at the age of 45 y and subsequently with breast cancer at the age of 59 y.
  • The incidence of multiple cancers in the same individual is a criterion for genetic testing to identify germline mutations in genes that can cause cancer(s).
  • Genetic testing showed that Ameeta has a single copy of a pathogenic variant of the MLH1 gene that is associated with Lynch Syndrome predisposition.
  • The identified variant has been previously reported in a patient affected with breast cancer from a Danish Lynch syndrome cohort and the variant has been classified as ‘pathogenic’ (Jensen et al. 2010). In another study on a Danish Lynch syndrome cohort, the identified variant has been reported as a frequently occurring pathogenic variant (Nilbert et al. 2009).
  • Manifestation of Lynch Syndrome as breast and ovarian cancer has been noted in studies with Asian patients as well (Wong et al. 2016).
  • Multi-gene tests, including genes other than BRCA1, BRCA2 and TP53, are the need of the hour for identifying ‘carriers’ of germline mutations that increase the risk of cancer.

Introduction

Genetic testing for identification of single gene mutations is a cost-effective solution from a patient’s point of view. Indeed, most cases of hereditary breast and ovarian cancer can be attributed to mutations in BRCA1 and BRCA2 genes. Yet, the utility of multi-gene tests in estimating the risk for hereditary cancer cannot be overlooked. In an Indian cohort of breast cancer patients, ~27% patients had mutations in genes other than BRCA1.

Patient Profile

Ameeta Srivastava had come to terms with the fact that she had been diagnosed with cervical cancer at the age of 45 years. Cancer treatment was tough but she had survived it and gained some control over her health and life. Fate, or perhaps her own genes, however, had more surprises in store for her. Ameeta consulted a leading oncologist at a prominent hospital in Delhi, at the age of 59 years for pain in her breasts. She was diagnosed with breast cancer, in her second brush with cancer. The incidence of multiple cancers in the same person is definitely a red flag for the presence of inherited genetic mutations. Cervical cancer is predominantly caused by infection with the human papillomavirus (HPV). However, genetic mutations in human proteins that interact with viral proteins can increase susceptibility towards multiple cancers, cervical cancer being one of them (Kutikhin & Yuzhalin 2012). Also, a case of a cervical tumor resulting from the presence of Lynch Syndrome in a young woman has been reported . Additionally, patients suffering from Peutz-Jeghers syndrome, resulting from mutations in STK11 gene, have been shown to be at a high risk for pancreatic and cervical cancer (Resta et al. 2013). Incidentally, breast cancer can also be a manifestation of Puetz-Jeghers syndrome (Song et al. 2006; Tchekmedyian et al. 2013). Considering these possibilities, Ameeta’s oncologist advised her to undergo genetic testing.

Pedigree Analysis: Pre-Test Genetic Counselling

Considering her status as a cervical cancer survivor and the current incidence of breast cancer, her oncologist advised her to undergo genetic counselling. This was done to understand her family history and choose an appropriate genetic test- Germline or Somatic- in order to decide upon therapy options for her. Ameeta’s brother had been diagnosed with pancreatic cancer at the age of 55 years. Her paternal uncle had also suffered from cancer although the family was not able to specify the type of cancer.

Figure 1. Pedigree Chart Showing Incidence of Cancer In Ameeta’s Family.

 

Pedigree Analysis: Pre-Test Genetic Counselling

The Strand Germline Cancer Test was advised to Ameeta, based on the incidence of multiple cancers in herself as well as pancreatic cancer in her first-degree relative. This test for estimation of risk of hereditary breast and ovarian cancer is designed to identify mutations in 19 genes that are potentially, pathogenic. This comprehensive coverage includes high risk genes for hereditary cancer syndromes like Lynch, Li-Fraumeni, Cowden and Peutz-Jeghers syndrome in addition to BRCA1, BRCA2 and TP53.

genetic test result for Ameeta

Figure 2. Identification of a Pathogenic Mutation in the MLH1 gene in Ameeta’s DNA

 

Ameeta was found to be heterozygous for a pathogenic variant in the MLH1 gene. She has a deletion mutation in exon 16 of this gene.

Key Interpretations

  • Ameeta has a single copy of a pathogenic variant of the MLH1 gene that is associated with Lynch Syndrome predisposition. Germline pathogenic variations in the MLH1 and MSH2 genes account for about 90% of Lynch syndrome cases.
  • The MLH1 gene is required for corrections of mismatched base pairs during DNA synthesis.
  • Mutations associated with Lynch syndrome can be inherited in an autosomal dominant manner. Therefore, having a single copy of the pathogenic variant increases the risk of getting cancer.
  • The identified variant has been previously reported in a patient affected with breast cancer from a Danish Lynch syndrome cohort and the variant has been classified as ‘pathogenic’ (Jensen et al. 2010). In another study on a Danish Lynch syndrome cohort, the identified variant has been reported as a frequently occurring pathogenic variant (Nilbert et al. 2009).
  • Manifestation of Lynch Syndrome as breast and ovarian cancer has been noted in studies with Asian patients as well (Wong et al. 2016).

Treatment Options

Ameeta was provided chemotherapy for her breast cancer. Recently, the US FDA has granted accelerated approval for the use of pembrolizumab for the treatment of solid tumors resulting from mutations of genes involved in the DNA mismatch repair (dMMR) pathway (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm). Lynch syndrome is a manifestation of mutations in genes in the same pathway. Therefore, Ameeta’s physician can prescribe this drug to her, at his discretion.

Summary

  • Ameeta’s personal history of breast cancer could be due to the mutation in the MLH1 gene which is involved in the DNA mismatch repair process.
  • Ameeta’s family has now been alerted to the presence of this inheritable pathogenic mutation in their genomes. Her sister, sister’s children as well as Ameeta’s children should be tested for this particular mutation to understand their own risks for developing cancer.
  • Multi-gene tests, such as the Strand Germline Cancer Test, that include genes other than BRCA1, BRCA2 and TP53 are useful in identifying syndromes like Lynch syndrome that may also manifest breast and ovarian cancer, in addition to colorectal cancers.
  • Mutations in MLH1 can increase a person’s risk for developing colon cancer as well as endometrial cancer (Jasperson et al. 2010). Ameeta was counselled regarding surveillance and risk reduction measures against these tumors, as per NCCN guidelines.

References

Jasperson, K.W. et al., 2010. Hereditary and familial colon cancer. Gastroenterology, 138(6), pp.2044–58. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20420945 [Accessed June 20, 2017].

Jensen, U.B. et al., 2010. Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Research and Treatment, 120(3), pp.777–782. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19575290 [Accessed May 8, 2017].

Kutikhin, A.G. & Yuzhalin, A.E., 2012. Inherited variation in pattern recognition receptors and cancer: dangerous liaisons? Cancer management and research, 4, pp.31–8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22427729 [Accessed June 20, 2017].

Nilbert, M. et al., 2009. Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Familial Cancer, 8(1), pp.75–83. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18566915 [Accessed May 8, 2017].

Resta, N. et al., 2013. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: Results of an Italian multicenter study. Digestive and Liver Disease, 45(7), pp.606–611. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23415580 [Accessed June 20, 2017].

Song, S.-H. et al., 2006. Peutz-Jeghers Syndrome with multiple genital tract tumors and breast cancer: a case report with a review of literatures. Journal of Korean medical science, 21(4), pp.752–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16891826 [Accessed June 20, 2017].

Tchekmedyian, A. et al., 2013. Findings from the Peutz-Jeghers syndrome registry of uruguay. PloS one, 8(11), p.e79639. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24260271 [Accessed June 20, 2017].

Wong, E.S.Y. et al., 2016. Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore. npj Genomic Medicine, 1, p.15003. Available at: http://www.nature.com/articles/npjgenmed20153 [Accessed December 6, 2016].

Yousef, I. et al., 2014. Cervical neuroendocrine tumor in a young female with Lynch Syndrome. Neuro endocrinology letters, 35(2), pp.89–94. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24878972 [Accessed June 20, 2017].

https://www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf

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