Incorporating genetics into practice was once straightforward for our specialty. Prenatal genetic diagnosis was mostly relevant to women over age 35 at delivery, plus those in a particular ethnic group. Single genes seemed unlikely to be causative for more than exceptional cases. For example, searches for individual genes causing polycystic ovary syndrome (PCOS) and endometriosis floundered and proved hard to find for common cancers. We knew increased risks existed in first-degree relatives for some women with these conditions, but the etiologies were unclear and risks in these relatives were generally less than 5%. We invoked polygenic inheritance: many genes of small affect when present individually could cumulatively influence the presence or absence of the condition. In gynecological cancers, the applicable conditions involved breast, ovary and endometrium. However, management was, after all, the same whether the cause was familial or not. So, why bother delving into the arcane science of genetics?
Well, the genomic era and facile ability to sequence an individual’s cell- or tissue-derived DNA has upended our comfort zone. No longer can we remain aloof.
The contribution in this issue by Leslie M. Randall MD, MAS, and Katherine Coakley, MD, illustrates well the new reality. New conceptual approaches are here today for gynecological cancer and soon will be applicable for other conditions. With the cost of gene sequencing decreasing (perhaps one-third or less than an in vitro fertilization cycle) and the ease of bioinformatic interpretation increasing correspondingly, we can expect precision medicine to be inculcated in practices. We cannot hide any longer.
To appreciate our new responsibility, let’s take a step back and consider gynecological cancer and its heritability. We have long known that familial cases existed, but classic autosomal-dominant pedigrees were rare and the genetic mechanism was unknown. The relatively low recurrence risk in first-degree relatives dissuaded some of a single-gene etiology, consistent with reasoning that individuals with the same histology must have the same condition. Of course, we now know that all common, adult-onset disorders are heterogenous in their genetic etiology. Different genes and non-genetic etiologies contribute to the aggregate sum of cases. In gynecological cancer, the role of single mutant genes is now well-illustrated by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome, an important cause of endometrial and colon cancer.
Clinically, some cases of gynecological cancer appear to be inherited, whereas others are sporadic. This was traditionally explained based on the assumption that cancer arises—whether inherited or not—by sequential mutations. The once touted “two-hit” hypothesis is less sacrosanct than before, but multiple hits are unequivocally involved. All this differs from genetic disorders like sickle cell anemia or cystic fibrosis, which require only a single “hit” in the requisite gene.
In heritable cancers in any organ, it is assumed that a parent has transmitted a mutant gene to offspring, even if he/she is asymptomatic. But there still must occur a second (or more) mutagenic “hit” for cancer to originate. One does not have to have a transmissible mutation to develop cancer, but if a person has one of the two or more required mutations, she has an unfortunate head start. In such cases, age at cancer onset is earlier than if two somatic mutations are required. Given that the transmitted mutation would have been in the embryo, the mutant gene would be present throughout the body (germline). Thus, it can be conveniently detected in the patient’s blood.
In contrast, the second hit must be specific to the organ (breast, ovary, endometrium) that will manifest cancer. Thus, one can detect this somatic mutation (not transmitted) only in the organ affected. This type of testing becomes applicable if genetic characteristics of the tumor dictate specific therapy.
How did we learn this?
In the genomic era, it became possible to sequence individuals and tissues, providing novel information concerning genes altered in a specific condition. Among the cohort of women with HBOC and Lynch syndrome it was possible to identify causative genes and determine the number of individuals having those genes. For example, 70% of patients with HBOC have BRCA1 or BRCA2 mutations. Faulty DNA repair genes—mismatch repair (MMR) genes MLH1, NLH2, MSH6; PHS2, EPCAM—are causative in Lynch syndrome. Other mutations play roles, but less frequently.