The National Comprehensive Cancer Network (NCCN) is a nonprofit alliance of 27 U.S.-based cancer centers, the majority of which have been designated as comprehensive cancer centers by the NCI. Among the NCCN's important functions is to provide guidelines for the prevention, diagnosis, and treatment of cancer and support of cancer patients to ensure the best outcomes for them.
The NCCN has recommended that women carrying pathogenic variants (PV) of BRCA1 and BRCA2 or the mismatch repair genes associated with Lynch syndrome (PMS2, MSH2, MSH6, and MLH1) consider risk-reducing salpingo-oophorectomy (RRSO), as mutations in those genes have a strong association with ovarian cancer. Recently, the NCCN added RAD51C, RAD51D, and BRIP1 to their guidelines, as mutations in these genes have been associated with an increased risk of developing ovarian cancer. However, the typical age of ovarian cancer diagnosis in these women has not been thoroughly investigated, and thus, optimal age for suggested RRSO was not fully established.
A team led by Lydia Usha, MD, initiated a study that assessed the clinical presentation of women who were confirmed to have PV of BRIP1, RAD51C, or RAD51D to better gauge the ovarian cancer risks associated with these mutations and determine the most appropriate age for RRSO.
Genetic Mutations Linked to Ovarian Cancer
Both BRCA1 and BRCA2 serve as tumor suppression genes, encoding the proteins BRCA1 and BRCA2, respectively. These proteins perform a vital function by participating in the repair of double-strand DNA breaks via the error-free homologous recombination (HR) pathway.
RAD51C and RAD51D are two of the five paralogs for the RAD51. The others are RAD51B, XRCC2, and XRCC3. As with the BRCA proteins, all five RAD51 paralogs participate in the homologous recombination DNA repair pathway. The presence of all five paralogs is required for proficient HR, as the lack of any one greatly reduces the frequency of DNA repair via this mechanism.
The BRCA1-interacting protein 1 (BRIP1, also referred to as Fanconi anemia group J protein) is encoded by the BRIP1 gene. This protein, as the name implies, participates with BRCA1 in the error-free process of HR. Mutations of this gene have been associated with Fanconi anemia, as well as both breast and ovarian cancers.
DNA mismatch repair (MMR) is required when improper insertion, deletion, or misincorporation of bases occurs. Such events may transpire during the processes of DNA replication and recombination. Humans have seven DNA MMR proteins, PMS1, PMS2, MSH2, MSH3, MSH6, MLH1, and MLH3, which act in a concerted and stepwise manner to effect DNA repairs. Of these seven proteins, the genes that encode four were included in these studies. These four genes, MSH2, MSH6, PMS2, and MLH1 are implicated in the autosomal dominant genetic condition called Lynch syndrome (formerly referred to as hereditary nonpolyposis colorectal cancer). In addition to colorectal cancer, this condition is also associated with increased incidences of endometrial cancer, digestive adenoma, and ovarian cancer.
“Early diagnosis is especially important for people having this condition, as there is a higher rate of early cancer diagnoses,” Usha noted. For example, the average age for colorectal cancer diagnosis for someone with this condition is approximately 45 years, as compared to 72 years for the general population. For women with Lynch syndrome, nearly 30 percent who develop ovarian cancer will receive this diagnosis before they are 40.
When asked to describe the methods of this study, Usha explained, “Women were tested with a 25-gene hereditary cancer panel between September 2013 and July 2016. Those who were determined to have a PV in RAD51C, RAD51D, or BRIP1 were clinically assessed via a provider-completed request form.”
Patients having a family or personal history of ovarian cancer were noted. A patient was defined to have a family history of ovarian cancer if one or more first- or second-degree relative had a diagnosis for the disease. If a patient developed ovarian cancer, the age at which they received the diagnosis was recorded. As comparisons, women having PV in BRCA1, BRCA2, or the four genes associated with Lynch syndrome were assessed in a similar manner. “These genes are included in the NCCN guidelines for ovarian cancer,” Usha explained.
Of the women tested, 375 had a PV for RAD51C and, of these, 81 were diagnosed with ovarian cancer (21.6%) and 131 had a family history of the disease (34.9%). The mean age of diagnosis for this group that had a personal history of the disease was 60.7 years (standard deviation (SD)–10.57 years). There were 166 patients who had a PV for RAD51D. For this group, 31 (18.7%) had a personal history of ovarian cancer with a mean diagnosis age of 56.6 years (SD–9.19 years) and 67 (40.4%) had a family history of the condition. For the BRIP1 gene, 771 women had a PV and, of these, 126 (16.3%) had a personal diagnosis of ovarian cancer with a mean age at diagnosis of 63.7 years (SD–11.65 years) and 287 (37.2%) had a familial history.
In comparison, 3,458 women had a PV for BRCA1, with 567 (16.4%) receiving an ovarian cancer diagnosis at a mean age of 53.5 years (SD–9.73 years). Additionally, 1,206 (34.9%) had a family history of the disease. For BRCA2, there were 3,731 patients who had a PV for that gene and, of that group, 425 (11.4%) had a personal history of ovarian cancer with a mean age of 59.33 years (SD–10.11 years) at diagnosis; 1,103 also had a family history of the disease.
Interestingly, the lowest mean ages at diagnosis for ovarian cancer among these patients were those having PV of the MMR genes associated with Lynch syndrome. There were 73 ovarian cancer patients who had a PV for MSH6 with a mean age at diagnosis of 51.3 years (SD–10.77 years). The mean age of diagnosis for the 51 patients with a PV for PMS2 was 50.8 years (SD–14.45 years). For the 16 ovarian cancer patients having a PV for MLH1, the mean diagnosis age was 47.3 years (SD–10.20 years). The lowest mean age of diagnosis (45.2 years; SD–9.89 years) was obtained for the 45 ovarian cancer patients with a PV of MSH2.
Those ovarian cancer patients surveyed (13,683) in this study not having a PV included in the gene panel had a mean age of diagnosis of 57.1 years (SD–14.87 years). In this study, ovarian cancer family histories were not reported for patients having a PV of the MMR genes or those not having a PV included in the gene panel.
“Based on the mean ages of ovarian cancer diagnosis in carriers of mutations in these three genes (BRIP1, RAD51C, and RAD51D), we confirmed that it is reasonable for these women to consider RRSO between ages of 45-50,” Usha noted. “Currently, the recommended age for RRSO for PV BRCA1 carriers is 35-40 years old, assuming the patient no longer wishes to become pregnant. For those having mutated BRCA2, the recommended age is a bit older, 40-45 years, based on the generally later onset of the disease within that patient group.
“The patients in our study who clearly had the lowest mean ages of diagnosis were those having PV of the MMR genes; for two of these genes, MLH1 and MSH2, the mean ages of diagnosis were fewer than 50 years.”
Richard Simoneaux is a contributing writer.