Book Review: A Fatal Inheritance – How a family misfortune revealed a deadly medical mystery

A Fatal Inheritance: How a Family Misfortune Revealed a Deadly Medical Mystery
By Lawrence Ingrassia
Published by Henry Holt and Company
ISBN-10: 1250837227, ISBN-13: 978-1250837226
Buy this book from Amazon UK

Lawrence Ingrassia, former deputy managing editor at the New York Times, lies at the centre of the Ingrassia-Iacono family tree, surrounded by his ancestors, children, siblings, and nephews. Ingrassia's book A Fatal Inheritance: How a Family Misfortune Revealed a Deadly Medical Mystery begins with his family tree. However, when it comes to this particular tree, immediately you realise there is something different about it.

Many of the names printed in bold and are followed by a number in brackets. This includes Lawrence's mother, Regina Iacono Ingrassia (42), as well as his three siblings: Paul Ingrassia (69), Gina Ingrassia (32), and Angela Ingrassia (24). The label in the bottom left reveals:

'Parentheses in chart denote age of death for family members with cancer; bold type denotes known or presumed p53 mutation'.

It's a striking opening for a book where trees like this play front and centre as both familial curses and elegant scientific opportunities.

The Ingrassia family is affected by Li-Fraumeni syndrome, a condition caused by an inherited mutation in the p53 gene. This gene, known as 'the guardian of the genome', is responsible for inducing cell death, known as 'apoptosis', when a cell becomes aberrant. If p53 is mutated, aberrant cells are allowed to thrive, driving cancer development.

Consequently, carriers of p53 mutations are not just prone to cancer, but are almost guaranteed it, often at a very early age. Moreover, since it is a dominant condition, if one parent is a carrier, their children have a 50 percent chance of also being a carrier. By narrating his family history alongside that of p53, Ingrassia weaves a fascinating story that combines the evolving fields of oncology and genetics with the aggrievement and pain of his own family, as well as the ever-changing ways in which we perceive and treat cancer.

Li-Fraumeni syndrome is named after Drs Frederick Pei Li and Joseph Fraumeni Jr, physicians at the National Cancer Institute in Bethesda, Maryland, who, in 1967, came across Ned and Darrel Kilius, a father and son being treated for cancer in the same hospital. At this time, cancer was still considered a consequence of viruses and environment as opposed to genetics. In an extraordinary effort of investigative epidemiology, Drs Li and Fraumeni were able to map out the huge Kilius family tree, which is displayed after Ingrassia's own tree and, accounting for modern updates, contains over 80 people across seven generations. Although it would take decades to reveal the source of the scourge of cancers plaguing the Kilius family, the heredity is starkly clear.

It is also a credit to Ingrassia who, despite not being a science journalist himself, confidently displays the beauty and clarity of Drs Li and Fraumeni's research into the Kilius family, who became known as 'Family A'. Every family member who died early from cancer was a direct descendent of a certain Minnie Mefford Stansberry (32). Nobody who married into the family suffered from cancer in the same way. In addition, of the direct descendants who didn't suffer from cancer, and so were presumed to not be carriers, none of their children were carriers either. How could this be anything other than an inherited condition?

However, where Ingrassia's true talents lie is in recounting the human stories that developed as the scientific discoveries accumulated. Since the overall story is told broadly chronologically, we hear how Ingrassia's mother passed away from breast cancer in 1968, the year after Drs Li and Fraumeni first encountered the Kilius family, and three years before Dr Alfred Knudson Jr would publish his seminal 'two-hit' hypothesis, which would provide a framework for how hereditary cancers may act. I've rarely seen the story of a discovery told so intrinsically with the problem it was attempting to solve, and it made every victory sweeter, and every defeat even more bitter.

These are especially reserved for Ingrassia's family itself. One person who is present throughout the book is his nephew, Charlie, who miraculously survived a rhabdomyosarcoma when he was two years old that left him needing reconstructive face surgery at 12. He then went on to become a star American football player. However, as I basked in his glory, I turned to the front of the book and simply read: 'Charlie Ingrassia (39)'.

While it became abundantly clear that there was a genetic cause of the cancers haunting the Ingrassia family, it wasn't until 2014 that Ingrassia's brother, Paul, found that he was a p53 mutation carrier, and 2015 when Ingrassia himself found that he wasn't. It would beg the question of what might have happened if it was Drs Li and Fraumeni who had met Ingrassia's mother, or if they were one of the initial research families. However, the uncomfortable truth was that, beyond rigorous screening, there wasn't too much that could have been done for then.

This aspect is mentioned multiple times, especially by younger members of the Kilius family, and was fascinating in how this single family encompassed so many contemporary discussions about cancer treatment. At what point do the benefits of treating cancer start to wear off? Is it wise to have children if you know that they may carry a p53 mutation? How does screening affect not just you, but your immediate family? There are enough discussions among the Kilius family to provoke every opinion. Nevertheless, Ingrassia's sensitivity with these topics, as well as stating the case for more research to be conducted, is a good place to start.

Where I think Ingrassia may have struggled, among the stunning storytelling, is with the more rigorous biochemistry behind p53 and its discovery. Partially, this may have been because the detective work that made Drs Li and Fraumeni's work seem exciting does not translate in a laboratory setting – anybody would struggle with two pages on how a Southern blot works.

I think that some additional focus on the biological relevance of p53 beyond its inherited status may have demonstrated how this research into Drs Li-Fraumeni syndrome, experienced by only around 1000 families worldwide, has had such impact on cancer research. After all, p53 is mutated in around half of human cancers, and is often considered an important early driving event. Yet, 'apoptosis' is not mentioned until page 219, while other research is described more in quotes and analogies than simply being stated.

That said, these are minor points in an expansive, masterful piece of science communication, which doubles beautifully as memoir and biography of modern oncology. In the book's final chapter, Ingrassia writes:

'If I do feel guilty, it's for not probing more about what was going on', adding 'I rationalise it by saying that we had an explanation for our family cancers, that we were certain they had something to do with our dad having worked with chemicals that may have been carcinogenic. But maybe that was just an excuse not to dig further.'

For Ingrassia to create something inspiring, uplifting, and informative from this story is truly wonderful.

Buy A Fatal Inheritance: How a Family Misfortune Revealed a Deadly Medical Mystery from Amazon UK.