We identified a significant excess of ovarian and endometrial cancers in relatives of endometrial cancer patients with pure serous and mixed serous tumors based on detailed 3 generation family history data and medical record confirmation of malignancies in a single institution cohort. Pancreatic cancers were also over represented in relatives, but the observed excess was not statistically significant. The excess of Lynch syndrome related malignancies in relatives was unexpected given that serous endometrial cancers are uncommon in Lynch syndrome (carriers of MSH2, MSH6, MLH1 or PMS2 mutations) (32
). Early-onset serous uterine cancers have, however, been reported in MSH2 mutation carriers (23
). The absences of tumor MSI and normal IHC findings make Lynch syndrome very unlikely, as does the late age of onset of uterine cancer in the probands studied. Only family 2401 had clinical testing for Lynch syndrome mutations (MSH2, MLH1 and MSH6) and no abnormality was identified. Regardless, the SIRs for uterine and ovarian cancers estimated for the 29 families from our institution suggest genetic risk for these cancers.
The 2.69 SIR for endometrial cancer (95% CI 1.28–5.65) is considerably lower than the 4.1 (95% CI 2.9–5.6) reported by Lindor and colleagues (33
) for Amsterdam 1 criteria, mismatch repair gene mutation positive Lynch families. The SIR for ovarian cancer in our study (2.68, CI 1.01–7.14) is higher than for Lynch families (2.0, CI 1.3–3.2) (33
). The SIRs estimates for our study and Lindor et al.(33
), however, have overlapping confidence intervals and overall the SIRs are very similar. It is noteworthy that we did not observe an excess of colon cancer (SIR 0.65, 95% CI 0.37–1.14) characteristic of Lynch syndrome. Lynch-related malignancies in the families we investigated could reflect some as yet unidentified genetic susceptibility, shared environmental risk factor or simply chance occurrence. Site-specific endometrial cancer susceptibility, distinct from Lynch syndrome has been described (34
), and it is possible some of the excess endometrial cancers reported in these families are attributable to this sort of genetic risk. BRCA1/2 mutation carriers may also have increased risk for endometrial cancer. There is a recent report that endometrioid endometrial cancers may be more common in relatives of BRCA1 carriers (37
). Given the fact that our probands had serous rather than endometrioid histology cancer, it seems very unlikely any excess of uterine cancers is due to BRCA1 mutation.
The number of pancreatic cancers reported in relatives of serous endometrial cancer probands was greater than expected (SIR 1.4), but the excess was not statistically significant (95%CI 0.63–3.11, p=0.4). The SIR for pancreatic cancers in the 29 families is nonetheless similar to what was reported for Amsterdam I criteria, Lynch syndrome kindreds in a previous study (SIR 1.7, 95%CI 0.7–2.8) (33
). Given the small number of families studied, it is not possible to exclude a small, but clinically significant risk for pancreatic cancer in relatives of patients with serous uterine cancer.
Our follow-up analysis of the cancer family histories for women enrolled in the GOG-210 study did not reveal an excess of endometrial and uterine cancers in the serous group compared to the endometrioid control group. Because we did not calculate standardized incidence ratios for the GOG-210 case and control populations, it is not possible to comment on whether there was an excess of these cancers in first-degree relatives compared to the general population. The GOG-210 family history data collected did not include the birth years or current ages of parents, siblings and children. Estimating those would allow for a crude estimate of the incidence of Lynch associated cancers. It is possible that both the cases (serous and mixed serous histologies) and control group (endometrioid tumors) have increased number of ovarian and endometrial cancers in relatives compared to the general population. We have previously reported that recall and accuracy of reporting for gynecologic cancers among endometrial cancer probands is poor (24
). We do not believe even a crude estimate of incidence for ovarian and endometrial cancers in relatives would be of value without extensive medical record verification. We note that in our case-control study we believe there would be shared risk factors for endometrioid and serous/mixed serous endometrial cancers. The fact that both histologic subtypes are present in a substantial fraction of all endometrial cancers speaks to the possibility of a common etiology.
Pancreatic cancers were reported more often in the relatives of the serous cancer cases from the GOG-210 population than for endometrioid controls’ families, consistent with a shared risk for pancreatic and serous type uterine cancer. A Swedish Family-Cancer Database study of 21,000 pancreatic cancers revealed a slight increase in the number of pancreatic cancers among sons of women with endometrial cancer (38
). The study by Hemminki and Li (38
) did not stratify uterine cancers by histologic subtype. In addition to Lynch syndrome, pancreatic cancer is associated with mutation in BRCA1 and BRAC2 (39
), PALB2 (43
) and CDKN2 (44
). There are conflicting reports on the role that inherited mutation in BRCA1 and BRCA2 play in risk for serous endometrial cancers. Some studies have revealed frequent germline mutation in serous cancer patients while others have not. The effects of population stratification and tamoxifen therapy for breast cancer complicate interpretation of findings for individual studies and for the data as a whole (21
). The early onset breast cancer in the daughter of proband 1972, her father’s pancreatic cancer, along with the hematopoietic neoplasms in her siblings () is highly suggested of a BRCA defect. Clinical testing for BRCA1/2 mutation was not performed in this family (only 1 family tested and was negative). Research testing for BRCA1 or -2 defects could shed light on the role these genes play in familial risk for serous carcinoma of the uterus, particularly given the link between BRCA mutation and pancreatic cancer (39
Our analysis of detailed 3 generation family histories for patients with uterine serous/mixed serous histology tumor is limited by the relatively small sample size. Uterine serous cancer is an uncommon malignancy with a poor prognosis. There is often a short interval from diagnosis to death, making collection of family history data even more difficult in what is a comparatively older population. We recognize the possibility that our study may be biased to include women and families that are aware of their familial risk for cancers and motivated to enroll in a cancer research study, however, eligibility for this study was simply a diagnosis of endometrial cancer, with serous or mixed serous histology. Finally, as in all family studies, recall bias is another limitation. In order to confirm records, all family history was obtained directly from the proband, and subsequently validated by medical records when available.
The Washington University serous cancer cohort and the GOG-210 serous cancer cases were similar overall with respect to racial makeup, age and stage at diagnosis. The Washington University cohort, however, had a higher proportion of serous mixed histologies (58%) than the cases from the GOG-210 study (30%). This difference could reflect differences in how institutions report mixed histotype uterine neoplasms, with the possibility that some serous cases with minor endometrioid or other histotype components would not be described as such in the pathology report (under-reporting for non-serous components). Alternatively, tumors that are primarily endometrioid but with minor serous components could be described as endometrioid. Pathologic review for the GOG-210 population is ongoing, with planned completion for all subjects enrolled in the 9/22/2003 to 9/24/2007 period by January 2012. Our efforts to validate findings from our single institution series in the GOG-210 case-control study were complicated by the fact that we did not have a cancer-free control population. As noted, without such a study group it is impossible to say definitively whether serous and endometrioid endometrial cancer patients have increased familial risk for ovarian and endometrial cancers. The 2 groups did not differ with respect to these cancers in relatives. Pancreatic cancers were on the other hand, more common in relatives of serous cancer cases.
The excess of Lynch syndrome cancers (specifically uterine, ovarian, and pancreatic) in relatives of serous endometrial cancer patients may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers. Exome or whole genome sequencing for probands could reveal mutations in candidate genes and/or pathways, some of which may be clinically relevant. Therapies that are tailored to key genetic abnormalities offer promise for better treatments for this deadly form of uterine cancer. The recent discovery of clinical benefit for PARP inhibitors in patients with germline defects in double strand break repair (49
) is but one example of gene-based advances in the treatment of malignancies. Large scale genomic efforts to better understand the genetic and epigenetic changes important in uterine serous carcinoma such as the Endometrial Cancer TCGA project are not focused on germline factors. Family based studies of serous cancers of the uterus are likely to yield important insights into the key genetic factors involved in tumor initiation.