A Fatal Inheritance: How a Family Misfortune Revealed a Deadly Medical Mystery in Science and Inquiry

Jul 07, 2024 CatReader rated it it was amazing

Shelves: cc, best-of-2024

One of the core parts of my job as a molecular pathologist is characterizing genetic alterations in cancer biopsies. The TP53 gene is the most commonly mutated gene in all human cancers, and anytime I come across a TP53 mutation at heterozygous or greater frequency, I make a point to comment on the report about whether that particular mutation has ever been reported in Li-Fraumeni syndrome, the main topic of this excellent book, so that patients can be referred to genetic counseling and have fol One of the core parts of my job as a molecular pathologist is characterizing genetic alterations in cancer biopsies. The TP53 gene is the most commonly mutated gene in all human cancers, and anytime I come across a TP53 mutation at heterozygous or greater frequency, I make a point to comment on the report about whether that particular mutation has ever been reported in Li-Fraumeni syndrome, the main topic of this excellent book, so that patients can be referred to genetic counseling and have follow-up testing if indicated. Chances are the mutation in their tumor tissue is somatically-derived, but we can't afford to miss the rare germline instances -- Li-Fraumeni syndrome is estimated to impact between 1 in 5,000-20,000 people. Among hereditary cancer predisposition syndromes, Li-Fraumeni is among the most devastating, given its high penetrance (the number of individuals carrying the mutation who will develop at least one cancer in their lifetimes is near 100% in women and around 70% in men) and the diversity of tumor types that can result (making screening and early detection difficult, and prevention basically impossible).

In A Fatal Inheritance, journalist Lawrence Ingrassia tells two overlapping stories. The first is the history of how doctors Frederick Pei Li and Joseph Fraumeni (for whom the syndrome is co-named) established a compelling case for hereditary cancer predisposition starting in the 1960s (which went against the prevailing narrative at the time that cancer was caused by infectious or environmental causes only -- cancer at its core is a genetic disease!), the the dawn of genetics in the 1970s and 1980s that led to the discovery of the TP53 gene, and the research teams who were able to definitively identify familial TP53 mutations in the early 1990s. I wish Ingrassia had continued the story from here, as the last 30+ years have led to many more research advances, the establishment of publicly-accessible databases to catalog and characterize various mutations, the continued importance of genetic counselors who work alongside oncologists and pathologists, and much more -- he did talk nebulously near the end about gene therapies that could insert functional copies of the TP53 gene into cancer, but that's about it.

The second main story is Ingrassia's own tragic family history. Ingrassia's mother, all three of his siblings (pictured on the cover alongside the author), and a nephew passed away from Li-Fraumeni-associated cancers. Li-Fraumeni is inherited in an autosomal dominant fashion, and the author is the only one of his siblings who didn't inherit the faulty copy of TP53 from his mother. The author, his brother, and his nephew were the only ones who had access to genetic testing, as that's another technological innovation that's only become available clinically and not just in research settings in the last ~20 years.

Overall, I thought this book was excellent, and I really appreciated Ingrassia's approach at both examining the medical history of Li-Fraumeni syndrome (I learned a lot) and his vulnerability and candor in sharing his own family story.

Further reading - hereditary cancer syndromes and other diseases:
The Family Gene: A Mission to Turn My Deadly Inheritance into a Hopeful Future - about a still-uncharacterized genetic syndrome
Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and the Science That Rescued Them by Gina Kolata - about Gerstmann-Straussler-Scheinker disease, a hereditary neurodegenerative prion disease
Pandora's DNA: Tracing the Breast Cancer Genes Through History, Science, and One Family Tree - about BRCA1/BRCA2
The Genome Defense: Inside the Epic Legal Battle to Determine Who Owns Your DNA by Jorge Contreras

My statistics:
Book 146 for 2024
Book 1749 cumulatively ...more

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Aug 17, 2024 Kathleen (itpdx) rated it really liked it

Shelves: non-fiction, rws-2024-summer

Ingrassia tells the story of cancer in his family. And parallels it with the discovery and study of the mutated gene that is responsible. He writes about the scientists and doctors that find the mutation, that figure out why the mutation causes so many early and different cancers and the various treatments that have been tried. He writes well and clearly but this is a very sad tale.

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