Germline testing

Democratising cancer prevention with germline testing

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Democratising Cancer Prevention with Germline Testing

By Dr. Bani Jolly, Senior Scientist, Genome Informatics, Karkinos Healthcare

Threads of Sorrow, Seeds of Hope 
A hundred years ago, a seamstress, needle pricked with worry, stitched together a tale of familial tragedy to Dr. Aldred Scott Warthin. Cancer, a malevolent tailor, had snipped away generations of her family, leaving her in fear of her inevitable death. She did indeed get endometrial cancer and died of the very disease that she had dreaded. 

Dr. Warthin, a doctor with a nose for genetic mysteries, saw beyond the fabric of coincidence and made efforts to unravel this family’s history thread by thread, creating a macabre tapestry woven with tumours – colon, endometrium, ovary. These were not random stitches, it was a genetic blueprint, a code begging to be deciphered. 

Decades of research followed as more people tried to understand what tied the seamstress’s family to the dreadful threads of cancer, to characterise and record the history of her family – ‘Family G’. Then entered Dr. Henry T. Lynch, an oncologist who meticulously traced the threads of cancer through the family tree. 

In his  landmark 1971 paper ‘Cancer Family G Revisited’, Dr. Lynch details an insidious autosomal dominant trait being passed down from generation to generation, that of a ‘Cancer Family Syndrome’ better known today as Lynch Syndrome. As molecular biology advanced and helped unravel strands of human DNA, the culprit emerged – faulty genes involved in DNA mismatch repair that normally protect us from developing certain cancers. 

Family G, though stitched with sorrow, became a beacon of hope that transformed research into inherited cancers, demanding awareness, detection, and a future where genetic mistakes would not dictate human fate.

Back in the 1970s, when Dr. Mary-Claire King started researching breast cancer, the prevailing knowledge held that it was caused by a virus. While the theory was not entirely off the mark as some cancers are indeed caused by viruses, Dr. King held a different notion and a bit of a lone wolf idea. 

Seeing the alarming prevalence of the disease in certain families she couldn’t help but suspect a genetic force at play. This hunch of hers led her to the discovery of the region on the genome that eventually became known as BRCA1, the first gene linked to a higher risk of breast and ovarian cancer. 

In 2013, the actress Angelina Jolie made headlines when she shared her personal journey of undergoing a preventive double mastectomy after discovering that she carried a mutation in the BRCA1 gene which significantly increased her risk of developing breast and ovarian cancers. She had previously lost her grandmother, mother, and aunt to cancer. 

Jolie’s decision, echoing the whispers of Dr. King’s research, sparked public interest in genetic testing for hereditary cancers. The “Angelina Jolie effect” led to increased awareness, discussions about genetic counseling, and a higher number of individuals seeking genetic testing to assess their risk of developing certain cancers. It also contributed to a broader conversation about the role of genetics in healthcare decisions and the potential for personalised medicine based on an individual’s genetic profile.

BRCA and Beyond: The Genetics of Inherited Cancers

Our DNA, the intricate loom of life, weaves a complex genetic code forming a tapestry of traits. All cancers originate as a result of some aberration in this genetic code in our body. The genomic basis of the development and progression of cancer is a complex interplay between inherited genetic factors (germline variations) and acquired genetic factors (somatic variations). Somatic variations are genetic changes that occur after conception, typically during a person’s lifetime.

Somatic mutations are a normal part of aging and can occur in a person either spontaneously or as a result of environmental factors. If these occur in critical genes like tumour suppressors, they can disrupt the normal functioning of cells, leading to genomic instability and potentially, cancer. However, these changes are specific to certain cells or tissues in the body and will not be passed on to the next generations. 

Germline variations, in contrast, are echoes of our ancestors, woven into the very fabric of our being from conception. These are genetic changes in the DNA of an individual’s gametes. They can be inherited from one or both parents and are present in all cells of the resulting offspring. In some cases, germline mutations become more than mere alterations and if occurring in certain genes, can predispose an individual to developing certain cancers. For example, individuals with specific germline mutations in the BRCA1 and BRCA2 genes have a higher risk of developing breast and ovarian cancer.

While most cancers are sporadic, i.e. driven by somatic mutations, nearly 10% of cancers have germline causes. Because such pathogenic mutations can be passed on from generation to generation, they act as crucial warning bells, illuminating a heightened cancer risk not just for a single person, but for future generations woven from the same loom.

Hereditary cancer syndromes are intricate genetic tales, woven with mutations that cast shadows of predisposition to specific cancers. These mutations don’t guarantee cancer but increase its risk. Some genes are well known to be associated with certain inherited cancers. Mutations in BRCA1 and BRCA2 are known to significantly increase the risk of developing hereditary breast and ovarian cancer while inherited mutations in the PALB2 are also associated with an increased risk of breast cancer.

Mutations in DNA mismatch repair genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM cause Lynch Syndrome, which significantly increases the risk of developing colon, endometrial, and other cancers. Peutz-Jeghers syndrome, caused by defects in the STK11 gene, is an inherited condition that increases the risk of developing certain cancers, including gastrointestinal cancers, breast cancer, and pancreatic cancer.

PTEN mutations causing hamartoma tumour syndrome increase the risk of breast, head, and neck squamous cell carcinoma, lung, and prostate cancers. WT1 gene changes cause Wilms tumour susceptibility syndromes that raise the risk of kidney cancer.

Li-Fraumeni Syndrome caused by mutations in the TP53 gene is another hereditary cancer predisposition syndrome characterised by a wide range of cancers occurring in affected families, particularly in children and young adults, and an increased risk of developing cancer across generations including bone cancer, soft tissue sarcoma, leukemia, breast cancer, brain cancer, and adrenal cortical tumours. RB gene mutations are linked to rare retinoblastoma eye cancers in children. RET gene mutations increase the risk of medullary thyroid carcinoma. 

Pre-emptive testing, a proactive measure, allows individuals with a family history of hereditary cancer syndromes to undergo genetic testing before any symptoms manifest. This early detection not only unveils potential risks but also provides an opportunity for personalised preventive strategies.

Inherited Risk, Individual Solutions: Genomics and Germline Testing for Cancers

Most hereditary cancer syndromes follow an autosomal dominant pattern of inheritance, indicating a 50% chance that a child will be affected if one of their parents carries the genetic mutation. Recognizing this hereditary link early becomes paramount. Pre-emptive testing, a proactive measure, allows individuals with a family history of hereditary cancer syndromes to undergo genetic testing before any symptoms manifest. This early detection not only unveils potential risks but also provides an opportunity for personalised preventive strategies.

Navigating the complexities of genetic predisposition involves not only understanding inheritance patterns but also actively engaging in pre-emptive testing and timely preventive measures, creating a powerful narrative of empowerment against the shadows of hereditary cancer risk. 

Genomics, the study of an individual’s genes and their interactions, play a pivotal role in identifying and understanding hereditary cancer risks. In the past, genetic testing for hereditary cancer syndromes was a costly affair, making it less accessible to many. Even though Angelina Jolie created mass awareness about BRCA testing, at $4,000 per test, it was not a cost-effective option for the general public.

During the time of Dr. Lynch and Dr. King’s research, DNA sequencing was not yet possible, the Polymerase Chain Reaction (PCR) technique was recently developed, and ‘genome sequencing’ was a far-fetched dream. The Human Genome Project’s successful conclusion in 2003 paved the way for researchers to comprehend the fundamental structure of the human genome.

In 2011, Steve Jobs, the CEO of Apple Inc. was among the first 20 people to get his genome sequenced in the hope of finding better treatments to battle his cancer. However, it cost him $100,000 to do this. Advancements in sequencing and analytic techniques have led to the rapid plummet of costs for genome sequencing. Illumina machines can today sequence a genome for approximately $200 (approx Rs 16,000).

Genome sequencing today has reached a turning point, enabling its deployment in clinical settings with rapid turnaround times, and also allowing us to delve deeper into the intricate genetic underpinning of a disease like cancer.

Unlike traditional “one-size-fits-all” approaches, genomic testing equips us to unearth subtle genetic variations that predispose individuals to specific cancers, drive tumour development and progression, and even predict their response to treatment, paving the way for personalised therapeutic strategies.

Pre-emptive Germline Testing for Cancer

With over 1.4 million new cancer cases diagnosed each year, India faces a staggering cancer burden. This staggering figure underscores the critical need for robust strategies to tackle cancer comprehensively. In the realm of cancer management, pre-emptive germline testing emerges as a pivotal tool as early detection and diagnosis remain a linchpin in the fight against cancer. As the nation grapples with the scale of cancer incidence, pre-emptive germline paves the way through the transformative pillars of early detection, carrier screening, cascade testing, and pharmacogenomics.

  • Early Detection

A significant proportion of people in India carry germline mutations that increase the risk of cancer. These ‘high-risk’ individuals traditionally undergo a battery of tests to identify the culprit genetic cause, involving multiple molecular assays including analyzing chromosomal abnormalities, structural changes, and various mutations – a time-consuming approach. Encompassing all genetic testing in a single comprehensive analysis, whole-genome sequencing (WGS) offers a paradigm shift, promising quicker and more precise results compared to the traditional cascade of tests. By identifying patients harboring high-penetrance mutations associated with certain cancers, we can activate proactive screening and prevention measures. This early detection can potentially save lives by catching malignancies in their earliest stages before they wreak havoc.

Beyond direct testing, genomic analysis helps reveal incidental findings with clinical implications. Around 2-3% of individuals in the general population are estimated to carry such actionable insights, as reported in studies worldwide. The American College of Medical Genetics offers guidelines for reporting these findings, focusing on evidence, actionability, and patient benefit. Currently, they encompass 19 inherited cancer syndromes mapped to 28 genes. 

  • Carrier Risk and Cascade Testing

Pre-emptive testing isn’t just about understanding the present; it empowers us to anticipate the future. It reveals if we carry a hidden mutation, silent within ourselves but potentially dangerous for our offspring. Carrying the mutation doesn’t guarantee our own illness, but it can raise the curtain on a higher risk for our children. This is where cascade germline testing also steps in, tracing the genetic domino effect within families. Through cascade germline testing, identifying a specific genetic anomaly in one family member can prompt targeted testing for the same in close relatives. The initial diagnosis triggers targeted assays in blood relatives, pinpointing those who inherited the pathogenic variant. Germline testing in cancer thus unlocks a wealth of possibilities including early detection and prevention, genetic counseling, and informed family planning, thus transforming passive acceptance into proactive control. 

  • Prognosis and Treatment

Traditional cancer treatment often resembled throwing darts in the dark. Pre-emptive genomic testing sheds light on this darkness, fuelling the field of pharmacogenomics – the science of how your genes dictate drug response. By aligning treatment with a patient’s genetic signature, we can maximise efficacy while minimizing the often debilitating side effects. This individualised approach promises not only improved survival rates but also a higher quality of life for cancer patients. For instance, before blasting tumours with fluoropyrimidines, a quick check for germline mutations in the DPYD gene can be a lifesaver. This helps identify patients at risk for severe drug toxicity, allowing doctors to adjust doses or choose alternative therapies. It’s a shining example of how pharmacogenomics empowers personalised cancer care, maximizing treatment effectiveness while minimizing harsh side effects. 

Can We Democratise Cancer Prevention with Germline Testing?

As the cost of sequencing plummets and our understanding of cancer genetics leaps forward, a critical debate surrounds who should undergo germline testing and how widely it should be offered. Some argue for focusing on high-risk groups or cases where results can directly inform treatment, while others see potential for universal testing due to cost drops and increasing knowledge. Genetic counseling is crucial for navigating these issues and maximizing the benefits of testing, particularly as risk calculations become more personalised. Ultimately, the future of germline testing in cancer holds immense promise, and finding the right balance between broad access and responsible application will require a coordinated effort from medical professionals, researchers, and society as a whole. Imagine a future where every individual, armed with their unique genetic blueprint, can proactively navigate their cancer risk through tailored screening, lifestyle choices, and potentially life-saving preventive measures. 

Germline testing and whole-genome sequencing have thus emerged as a transformative tool for, facilitating a shift from a “reactive” strategy, where genetic tests are conducted as needed, to a pre-emptive approach by testing and reporting all actionable variants in a single comprehensive test, offering a lifetime of valuable test results. In the face of India’s formidable cancer challenge, the adoption of pre-emptive germline testing, early diagnosis strategies, cascade testing, and the integration of pharmacogenomics collectively contribute to a more nuanced and personalised approach to cancer care, offering hope for improved outcomes and reduced cancer burdens in the future.

Beyond Coincidences – Taking Control of Your Cancer Risk

In families with an inherited faulty gene, a unique pattern of specific cancers often weaves through generations, painting a story that’s deeply intertwined with your family’s history. Understanding the strength of this genetic tale involves a closer look at who in your family has faced the challenge of cancer, the types they’ve encountered, and their age at diagnosis. The more relatives who share similar or related cancer experiences, especially if they were diagnosed at a younger age, the more significant the impact of your family history. It’s like decoding a genetic puzzle where each family member’s journey adds a crucial piece. 

If cancers emerged at a young age, if multiple close relatives on one side of your family faced cancer, or if they battled the same or different cancers linked to the same gene fault, these are signals that your family history might hold genetic insights. However, a strong family history doesn’t mean you’re doomed. But it’s a red flag urging you to be proactive. 

Talk to your doctor, map your family’s medical history, and consider genetic testing. It’s not about painting a dark future, but about taking control. Knowledge is power, and when it comes to cancer, early detection can change everything.

Bani JollyDr Bani Jolly is a scientist and bioinformatician with extensive experience in genomics, particularly in human and pathogen studies. With a background in Computer Science and a Ph.D. in Genome Informatics from CSIR-Institute of Genomics and Integrative Biology, she has previously led the analytics efforts for several large-scale NGS projects, including the sequencing of India’s first 1000 whole-genomes. She played a vital role in advancing genomic surveillance of SARS-CoV-2 in India, contributing to understanding transmission dynamics and viral lineage emergence while working closely with the World Health Organization (WHO) to enhance the genomic surveillance capabilities in the Southeast Asia region.
As a Senior Scientist in Genome Informatics at Karkinos, she focuses on developing and applying cutting-edge informatics and technology solutions for NGS data analysis, particularly in cancer research. Her focus extends to leveraging genomics for early detection and diagnosis, as well as therapy planning in the field of cancer research.

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