Editorial

Genetic anticipation and mentorship

It has been exactly 40 years since Richard M. Fox, MB, PhD, FRACP; Tatiana Jelihovsky, MBBS, DCP, FRCPA, FRCPath; and I published our paper on genetic anticipation in germ cell malignancy.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

It wasn’t my first published paper (that was a letter to The New England Journal of Medicine in the days when I understood its editorial policy), but it was important to me in that it shaped my thoughts about mentorship while advancing some potentially interesting hypotheses about the genesis of germ cell malignancy.

Importance of mentorship

Professor Dick Fox — a brilliant biochemical pharmacologist/oncologist in Australia — was one of my first oncology bosses. We saw a case of father-son pairing where the father had been treated curatively for a seminoma and the son had developed an aggressive embryonal carcinoma. As the oncology fellow on the team, I offered to write it up, and after many hours of agony, self-editing and literature dredging, I triumphantly presented a really boring case series that made the major biological statement that “sometimes fathers and sons get germ cell tumors — perhaps there is some sort of gene involved.”

Dick challenged me on the underlying concepts that I was trying to postulate, debated their relevance to tumor biology and then offered to edit the paper; he kept it for a weekend and returned an opus entitled, “Father-son testicular malignancy: Does genetic anticipation occur?” We proposed the concept of linear evolution of germ cell malignancy, through familial generations, with the parental setting being a harbinger of the aggressiveness of the disease process in the next generation — namely, genetic anticipation.

The important tenet of mentorship was Dick’s ability to look at my tyro efforts, see the essence of an interesting idea, and evolve it to an entity that taught me an important concept.

In addition, the idea was one that could be published in a substantial cancer journal of the day and provoke others to consider its implications for clinical practice and an understanding of a basic mechanism in tumor biology.

From that process, I gained a broader insight into thinking scientifically out of the box (always predicated on a fundamental hypothesis), and Dick’s editing sharpened my ability to write (when I saw where the red lines had been inserted). How much easier would it have been for the mentor simply to state that this was not a particularly important study and unlikely to be published?

With the changing relationship between mentors and mentees in medical education, predicated on the exigencies of the Taylor Laws and other work- and lifestyle-based constraints, we must be careful not to lose the Socratic principle within our professional education process, which requires time commitment and purpose from both parties. Those who focus only on work-life balance and monitoring the time clock risk losing that precious element of medical learning.

‘Close interplay of science and medicine’

But, I digress. This topic came to mind because of a fascinating study by Coorens and colleagues published last month in Science that identified potential mechanisms that could explain genetic anticipation.

In the intervening decades since our paper, a great deal has been learned about the genetic basis of testicular cancer, often through genome-wide association studies, including the demonstration of the more common linkages with the short arm of chromosome 12, expression of c-KIT (a homolog of the steel gene that is associated with teratoma formation in 129 strain mice) and occasional association with p53 mutations and aberrations of NRAS/KRAS, among others. However, most testicular cancers appear to occur in the absence of these changes, so alternative mechanisms to explain testicular oncogenesis and its association with cryptorchidism, family history and infertility still have been required.

Coorens and colleagues studied a different model — pediatric Wilms tumor — focusing on premalignant clonal expansion of renal tissue and gene expression in Wilms tumor tissue, normal kidney and parental specimens. To identify potential precursors, these investigators used somatic mutations to infer the phylogenetic relationship between cancers and corresponding normal tissues (kidney and blood). This was predicated on variant allele frequencies and distribution of mutations in the tissues studied.

The reason this is potentially relevant to the biology of germ cell tumors is that Wilms tumor is a prototypical embryonal malignancy of children, arises from abnormal fetal nephrogenesis (which it resembles morphologically and transcriptionally), and occurs sporadically or occasionally bilaterally, and sometimes in association with urogenital developmental disorders. In other words, there are substantial biological similarities between Wilms tumor and germ cell tumors.

Coorens and colleagues analyzed 229 whole-genome sequences of 54 individuals, including 23 children with Wilms tumor and 16 parents of affected children, and various other renal tumors or control tissues. In 14 of the 23 cases, the researchers identified premalignant clonal expansion in normal renal tissue that antedated the formation of Wilms tumor. In a confirmatory set of samples — including an additional 15 unilateral Wilms tumors with available normal tissues — clonal nephrogenesis was again discerned as a harbinger of malignancy. Researchers identified clonal nephrogenesis in all of four cases of bilateral Wilms tumor.

The investigators searched for driver events, as the clonal nephrogenesis mutations were predominantly noncoding or did not generate likely oncogenic events. They found hypermethylation of the H19 locus in seven of 12 normal kidney tissues with clonal nephrogenesis, but in none of the normal kidney tissues (or in blood samples) in which clonal nephrogenesis was absent. Further, these associations did not occur in renal cell carcinoma.

This work may well have relevance to the genesis of germ cell tumors and other malignancies that arise in pediatric and young adult populations, perhaps linking the genesis of familial and nonfamilial variants. Moreover, aberrations of DNA methylation during embryonic development are associated with defective spermatogenesis and infertility, which also are linked to the genesis of testicular cancer.

As noted by Coorens and colleagues, these malignancies may represent insurrections on the background of a premalignant tissue bed, driven by an epigenetic mechanism. Eventually the ability to interfere with aspects of clonal nephrogenesis (or germ cell genesis, if this is a relevant analogy) may allow the prevention of a range of pediatric malignancies.

These extraordinary studies and concepts require close interplay of science and medicine. It will be so sad if our focus on pragmatism and time-clock watching in medical education leads to a process in which young physicians think only inside the box and stop trying to link biology with clinical outcomes in their various domains of medical endeavor.

References:

Coorens THH, et al. Science. 2019;doi:10.1126/science.aax1323.

Raghavan D, et al. Cancer. 1980;45:1005-1009.

Raghavan D, et al. N Engl J Med. 1980;302:811.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.

Disclosure: Raghavan reports no relevant financial disclosures.

It has been exactly 40 years since Richard M. Fox, MB, PhD, FRACP; Tatiana Jelihovsky, MBBS, DCP, FRCPA, FRCPath; and I published our paper on genetic anticipation in germ cell malignancy.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

It wasn’t my first published paper (that was a letter to The New England Journal of Medicine in the days when I understood its editorial policy), but it was important to me in that it shaped my thoughts about mentorship while advancing some potentially interesting hypotheses about the genesis of germ cell malignancy.

Importance of mentorship

Professor Dick Fox — a brilliant biochemical pharmacologist/oncologist in Australia — was one of my first oncology bosses. We saw a case of father-son pairing where the father had been treated curatively for a seminoma and the son had developed an aggressive embryonal carcinoma. As the oncology fellow on the team, I offered to write it up, and after many hours of agony, self-editing and literature dredging, I triumphantly presented a really boring case series that made the major biological statement that “sometimes fathers and sons get germ cell tumors — perhaps there is some sort of gene involved.”

Dick challenged me on the underlying concepts that I was trying to postulate, debated their relevance to tumor biology and then offered to edit the paper; he kept it for a weekend and returned an opus entitled, “Father-son testicular malignancy: Does genetic anticipation occur?” We proposed the concept of linear evolution of germ cell malignancy, through familial generations, with the parental setting being a harbinger of the aggressiveness of the disease process in the next generation — namely, genetic anticipation.

The important tenet of mentorship was Dick’s ability to look at my tyro efforts, see the essence of an interesting idea, and evolve it to an entity that taught me an important concept.

In addition, the idea was one that could be published in a substantial cancer journal of the day and provoke others to consider its implications for clinical practice and an understanding of a basic mechanism in tumor biology.

From that process, I gained a broader insight into thinking scientifically out of the box (always predicated on a fundamental hypothesis), and Dick’s editing sharpened my ability to write (when I saw where the red lines had been inserted). How much easier would it have been for the mentor simply to state that this was not a particularly important study and unlikely to be published?

PAGE BREAK

With the changing relationship between mentors and mentees in medical education, predicated on the exigencies of the Taylor Laws and other work- and lifestyle-based constraints, we must be careful not to lose the Socratic principle within our professional education process, which requires time commitment and purpose from both parties. Those who focus only on work-life balance and monitoring the time clock risk losing that precious element of medical learning.

‘Close interplay of science and medicine’

But, I digress. This topic came to mind because of a fascinating study by Coorens and colleagues published last month in Science that identified potential mechanisms that could explain genetic anticipation.

In the intervening decades since our paper, a great deal has been learned about the genetic basis of testicular cancer, often through genome-wide association studies, including the demonstration of the more common linkages with the short arm of chromosome 12, expression of c-KIT (a homolog of the steel gene that is associated with teratoma formation in 129 strain mice) and occasional association with p53 mutations and aberrations of NRAS/KRAS, among others. However, most testicular cancers appear to occur in the absence of these changes, so alternative mechanisms to explain testicular oncogenesis and its association with cryptorchidism, family history and infertility still have been required.

Coorens and colleagues studied a different model — pediatric Wilms tumor — focusing on premalignant clonal expansion of renal tissue and gene expression in Wilms tumor tissue, normal kidney and parental specimens. To identify potential precursors, these investigators used somatic mutations to infer the phylogenetic relationship between cancers and corresponding normal tissues (kidney and blood). This was predicated on variant allele frequencies and distribution of mutations in the tissues studied.

The reason this is potentially relevant to the biology of germ cell tumors is that Wilms tumor is a prototypical embryonal malignancy of children, arises from abnormal fetal nephrogenesis (which it resembles morphologically and transcriptionally), and occurs sporadically or occasionally bilaterally, and sometimes in association with urogenital developmental disorders. In other words, there are substantial biological similarities between Wilms tumor and germ cell tumors.

Coorens and colleagues analyzed 229 whole-genome sequences of 54 individuals, including 23 children with Wilms tumor and 16 parents of affected children, and various other renal tumors or control tissues. In 14 of the 23 cases, the researchers identified premalignant clonal expansion in normal renal tissue that antedated the formation of Wilms tumor. In a confirmatory set of samples — including an additional 15 unilateral Wilms tumors with available normal tissues — clonal nephrogenesis was again discerned as a harbinger of malignancy. Researchers identified clonal nephrogenesis in all of four cases of bilateral Wilms tumor.

PAGE BREAK

The investigators searched for driver events, as the clonal nephrogenesis mutations were predominantly noncoding or did not generate likely oncogenic events. They found hypermethylation of the H19 locus in seven of 12 normal kidney tissues with clonal nephrogenesis, but in none of the normal kidney tissues (or in blood samples) in which clonal nephrogenesis was absent. Further, these associations did not occur in renal cell carcinoma.

This work may well have relevance to the genesis of germ cell tumors and other malignancies that arise in pediatric and young adult populations, perhaps linking the genesis of familial and nonfamilial variants. Moreover, aberrations of DNA methylation during embryonic development are associated with defective spermatogenesis and infertility, which also are linked to the genesis of testicular cancer.

As noted by Coorens and colleagues, these malignancies may represent insurrections on the background of a premalignant tissue bed, driven by an epigenetic mechanism. Eventually the ability to interfere with aspects of clonal nephrogenesis (or germ cell genesis, if this is a relevant analogy) may allow the prevention of a range of pediatric malignancies.

These extraordinary studies and concepts require close interplay of science and medicine. It will be so sad if our focus on pragmatism and time-clock watching in medical education leads to a process in which young physicians think only inside the box and stop trying to link biology with clinical outcomes in their various domains of medical endeavor.

References:

Coorens THH, et al. Science. 2019;doi:10.1126/science.aax1323.

Raghavan D, et al. Cancer. 1980;45:1005-1009.

Raghavan D, et al. N Engl J Med. 1980;302:811.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.

Disclosure: Raghavan reports no relevant financial disclosures.