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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cancer Prev Res (Phila). Author manuscript; available in PMC 2013 March 1.
Published in final edited form as:
PMCID: PMC3294192
NIHMSID: NIHMS352291

Uterine Serous Carcinoma: Increased Familial Risk for Lynch-Associated Malignancies

Abstract

Purpose

Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for serous uterine carcinoma patients, focusing on Lynch syndrome malignancies.

Experimental design

Fifty serous or mixed serous endometrial carcinoma cases were prospectively enrolled. Pedigrees were developed for 29 probands and tumors were assessed for DNA mismatch repair abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second stage analysis was undertaken using data from GOG-210. Incidence data for cancers reported in relatives of 348 serous and mixed epithelial and 624 endometrioid carcinoma patients were compared.

Results

Nineteen of 29 (65.5%) patients in the single institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly over-represented and a high number of probands (6/29, 20.7%) reported pancreatic cancers. None of the probands’ tumors had DNA mismatch repair abnormalities. There was no difference in endometrial or ovarian cancer incidence in relatives of serous and endometrioid cancer probands in the case-control study. Pancreatic cancers were, however, significantly more common in relatives of serous cancer patients (OR 2.39, 95% CI 1.06–5.38).

Conclusions

We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of serous cancer patients in a single institution study. Follow-up studies suggest only pancreatic cancers are over-represented in relatives. DNA mismatch repair defects in familial clustering of pancreatic and other Lynch-associated malignancies are unlikely. The excess of pancreatic cancers in relatives may reflect an as yet unidentified hereditary syndrome that includes uterine serous cancers.

Keywords: Endometrial cancer, Uterine serous carcinoma, Lynch syndrome, Mismatch repair, Familial clustering of cancers

INTRODUCTION

Uterine serous carcinoma is an uncommon form of endometrial cancer, comprising less than 10% of uterine epithelial cancers. Patients can present with pure UPSC or with mixed UPSC/other histology tumors. Despite its rarity, UPSC accounts for a disproportionate number of endometrial cancer deaths (estimated at ~40%) (1).

The poor outcomes for patients diagnosed with UPSC are attributable, in part, to later stage at diagnosis and an increased risk for occult metastases in early stage disease compared to the more common histological type, endometrioid endometrial carcinoma (24). UPSC is more common among African-Americans than Caucasians, non obese rather than obese women, and affects primarily postmenopausal women whereas endometrioid cancers have an increased incidence among perimenopausal women (59). Unlike endometrioid endometrial cancer, UPSC is not associated with an excess estrogen state, and not surprisingly is associated with different molecular abnormalities than the more common endometrioid adenocarcinoma (1015).

Serous type uterine cancers are not a recognized feature of any currently defined hereditary cancer syndromes. Several studies have suggested an association between serous uterine cancer and breast cancer. Most studies assessing the link between breast cancer and UPSC, however, have been focused on the proband and there have been no large scale, in-depth family studies published to date. Although uterine cancer has been implicated in the hereditary-breast and ovarian syndrome (1622), an association between serous endometrial cancer and hereditary breast/ovarian syndrome has not been established.

Endometrial carcinoma may be the most common cancer in women with Lynch syndrome attributable to germline mutations in one of several DNA mismatch repair (MMR) genes. Lynch syndrome patients have a dramatically increased risk for colon and endometrial and a significantly increased risk for a number of other malignancies. The majority of Lynch syndrome patients with uterine cancers have endometrioid endometrial cancers, although non-endometrioid histologies have been described for a small number of Lynch patients (23).

The aim of this study was to evaluate familial risk for Lynch associated cancers in patients diagnosed with serous uterine cancer and to assess DNA mismatch repair status in the tumors of probands from family members affected with Lynch associated malignancies.

MATERIALS AND METHODS

Description of Participants

We prospectively acquired tumor samples from hysterectomy specimens of patients being treated for suspected uterine cancer by the Division of Gynecologic Oncology at Washington University Medical Center (St. Louis, MO). All participants consented to molecular analysis and follow-up as part of the Washington University Medical Center Human Research Protection Office-approved protocol (93-0828). Fifty cases of uterine serous or mixed serous carcinomas were accrued to this protocol from January 2005 to December 2008. Participants consented to family history and tumor studies as part of the approved protocol. This series was unselected for family history information, age at diagnosis, or clinical features suggestive of an inherited susceptibility to cancer.

Probands were contacted and asked to participate in our study to obtain detailed family history data. Family history data were obtained at 2 different times. First, as part of their routine clinical care, participants completed a medical history questionnaire that included a single question regarding the health of first-degree relatives. These data, as well as information documented in the initial medical encounter, comprised the screening family history (24). A genetic counselor (SB) later obtained a detailed, 3-generational pedigree from each proband, either face-to-face or over the telephone. The following data were obtained for all individuals in the pedigree: current age or age of death and history of cancer (including site, age at diagnosis, and city or hospital where treated). Medical record verification was sought. As standard practice, the genetic counselor requested the proband contact the identified relative, or if deceased, the closest living family member, to obtain permission to release their medical records. Medical records and/or death certificates were requested for confirmation of the cancer diagnosis. All records were reviewed independently by 2 gynecologic oncology fellows (NK and SD) and a cancer research investigator (PG).

Microsatellite Instability (MSI) Testing

Using the National Cancer Institute recommended MSI markers (BAT25, BAT26, D71S250, D2S125, and D5S346), both tumor and normal DNA samples for each patient were analyzed for allelic shift using a multiplex fluorescence-based polymerase chain reaction (PCR) assay. Amplified PCR products were then analyzed using capillary electrophoresis on an ABI 3130 Genetic Analyzer (Applied Biosystems, Foster City, CA), using the GeneMapper Analysis software provided by the manufacturer (Applied Biosystems, Foster City, CA). Tumors showing allelic shift at 2 or more markers were considered MSI-high; tumors showing allelic shift at only 1 marker were classified as MSI-low; and tumors with no allelic shift were classified as microsatellite stable (MSS).

Immunohistochemical staining

Immunohistochemistry (IHC) for the mismatch repair gene products MLH1 (G168-15, 1:30; Pharmingen, San Diego, CA), MSH2 (FE11, 1:100; Oncogene Science, Boston, MA), and MSH6 (G70220 [GenBank], 1:100; Transduction Laboratories, San Diego, CA) was performed using formalin-fixed, paraffin-embedded sections as previously described (25). Tumors were categorized as positive or negative for MHL1, MSH2 and MSH6 expression (R.R.B.).

GOG Methods

We sought to validate the findings of our institutional cohort through the analysis of family history data for serous cancer patients enrolled in the Gynecologic Oncology Group 210 protocol (GOG-210). Briefly, this protocol is an ongoing collection of tissue samples for molecular and clinicopathologic analysis of endometrial cancer.. The patients who participated in both the Washington University study and GOG-210 were cross referenced and excluded from the GOG cohort, hence only to be included in the Washington University cohort for the purposes of this study.

The GOG-210 questionnaire contains a section inquiring about family history, which is filled out by participants. The family history questionnaire section asked only about first-degree relatives; number of relatives (living and deceased), which relative(s) has a diagnosis of cancer, age of diagnosis, and type of cancer. We obtained these data and identified patients with first-degree relatives with cancer. Once a family was identified, a pedigree was created from the information provided on the questionnaire. We analyzed both mixed (serous component) epithelial and pure serous histologic subtypes. The available dataset included 245 pure serous histologies and 103 mixed (serous component) epithelial histologies. After an initial analysis of the GOG serous histology cases, we attempted to confirm our findings by comparing the GOG serous group with a matched endometrioid histology group. We obtained data from women with endometrioid histology tumors matched with the serous cases based on age, race and stage, N=624. These data was collected from 2003 to 2008.

Statistical Analysis

Standardized incidence ratios were estimated for the retrospective Washington University School of Medicine cohort study focusing on first and second-degree relatives. Probands were removed from the analyses for conservative cancer risk estimation. Lynch-related cancers were defined as colon, pancreas, ovary, endometrial, gastric, brain, upper urologic tract, and hepatobiliary cancers. The crude incidence rate of Lynch-related cancers overall and, for each type separately, were calculated as the total number of cases per unit of person-years at risk per 100,000 people. The person-year at risk was defined as from birth to the earliest cancer diagnosis or death, or the date of ascertainment during the lifetime exposure of individuals in the 29 kindreds. Age was divided into 19 5-year intervals following the Surveillance, Epidemiology, and End Results (SEER) database age categories, and the SEER’s age group specific incidence rates were obtained using the SEER 17 regions 2000–2006 limited-use database (26) with adjustment for impact of Katrina by the software SEER*Stat (27). The standardized incidence ratios (SIRs) of each cancer were calculated as the ratio of the total number of observed cases in our data to the expected number of cases on the basis of the age group specific incidence rates from SEER (i.e., the sum of the product of the age group specific person years at risk and the SEER age group specific incidence rates). For the SIRs, we calculated the exact confidence intervals based on Poisson distribution (28, 29) and the 95% CI based on the Boice-Monson method (30) and bootstrap 95% percentile confidence intervals through 1000 bootstrap sampling (31). The 2-sided p-values for the SIRs were calculated on the basis of Chi-square tests.

To further identify any possible increased risk for cancers in the relative of serous uterine cancer patients, we matched each serous family by approximately two endometrial families of endometrioid histology in terms of age, race and stage to conduct a case-control study. We compared 348 serous families and 624 endometrioid families (African-American matched 1:1 due to paucity of African-American endometrioid cases).

Given that the data were clustered in the family level and the matching case-control level, we analyzed the clustered data using a generalized estimating equation method. Various correlation structures were assessed and compared, all with similar results. Odds ratio, accompanied with 95% confidence interval and P-value on the Lynch-related cancer and each individual cancer type of interest were estimated.

RESULTS

Cancer family histories for uterine serous cancer patients

Washington University Cohort

Fifty women with serous endometrial cancers (N=21) or mixed serous histology tumors (N=29) consented to our ongoing molecular and family studies in the period 1/1/2005-12/31/2008. Patient charts included cancer family histories for 44 (88%) of the women. Among those 44 probands, 10 (23%) reported a Lynch-related tumor in 1 or more first-degree relative(s).

Detailed family histories were developed for 29 subjects (58%). Among the 21 women for whom family histories were not obtained, 14 patients were deceased or in hospice at the time of the contact, 5 women declined to participate and 2 failed to respond to written and phone requests to participate in the family history studies.

The demographic and clinicopathologic characteristics of the 29 probands are presented in Table 1. Fourteen of 29 patients had pure serous tumors and 15 had mixed epithelial histology tumors (serous plus other). Nineteen patients were Caucasian (67%) and 5 were African-American (17%). Nearly half (14 of 29) presented with stage III or IV disease at a median age of 67 (range from 58 to 91). Similar data for the 21 probands for whom family histories were not obtained are presented in Supplementary Table 1.

Table 1
Clinical and demographic characteristics of 29 probands.

Cancer family history data included information for 769 first- and second-degree relatives with a median family size of 24 (range 10–52), and a gender ratio was 1:1.05 (male: female). Thirteen of the 29 probands reported one or more Lynch-related cancer in a first-degree relative. Of note, only 8 of those women had indicated a relative had a Lynch-related cancer as part of the clinical family history screening intake. Of the 23 Lynch-related cancers in first-degree relatives, 8 were confirmed by medical records (3 colon, 1 serous endometrial, 2 pancreatic and 2 transitional cell cancers). Thirteen additional Lynch cancers were reported in second-degree relatives of 8 probands (medical record verification for only 3 tumors, 1 colon, 1 hepatobiliary cancer and 1 glioblastoma). The numbers and types of Lynch-related cancers in relatives are presented in Table 2. Median age of diagnosis of Lynch-related cancers was 65 (ranging from 43 to 92). Several probands had family histories suggestive of Lynch syndrome and, notably, 4 probands reported pancreatic cancers in relatives (2 families each with 2 pancreatic cancers). Representative pedigrees suggestive of inherited cancer susceptibility are shown in Figure 1 (all remaining pedigrees are shown in Supplemental Figure 1).

Figure 1
Representative three-generation pedigrees for serous cancer probands suggestive of inherited cancer susceptibility. A. Lynch syndrome like families. B. Pancreatic cancer-prone families.
Table 2
Characteristics and Lynch-related cancers reported in first- and second-degree relatives.

We used cancer incidence and standardized incidence ratios (SIR) to determine whether Lynch-related cancers were over- or under-represented in the relatives of the 29 serous endometrial cancer probands. These analyses suggested an excess of Lynch-related cancers overall, with over-representation of endometrial, ovarian and pancreatic cancer and fewer than expected colon cancers (Table 3). Seven endometrial cancers were reported (2.6 expected) for a SIR of 2.69 (95% CI1.28–5.65, p=0.006) and 4 ovarian cancers were reported (1.5 expected) for a SIR of 2.68 (95% CI 1.01–7.14, p=0.04). The 1.40 SIR for pancreatic and 0.65 SIR for colon cancers were not statistically significant (p=0.40 and p=0.13, respectively).

Table 3
Incidence and standardized incidence ratios (SIR) of cancers.

Follow-up studies: A case-control study of 972 endometrial cancer patients enrolled in the Gynecologic Oncology Group (GOG) 210 protocol

We evaluated the cancer family histories for 972 endometrial cancer patients enrolled in the GOG-210 study in an effort to determine whether the excess of Lynch-related cancers seen in the Washington University School of Medicine endometrial cancer cohort was also seen in serous cancer patients that are part of the large, multi-institution cohort. The data on cancers in relatives of the GOG-210 study population were reported by probands (no medical record verification and uncertain involvement of family members other than the proband in developing family histories) and are limited to first-degree relatives. Given that birth years and current ages of cancer-free children and siblings were not collected, it was not possible to estimate standardized incidence ratios for Lynch-related cancers.

During the initial phase of GOG-210 accrual (9/22/2003-9/24/2007) 3,738 patients were enrolled in the study. Among those, 317 cases had serous endometrial cancers and 240 had mixed histology epithelial cancers based on the pathology reports provided by the individual GOG participating centers. Family cancer history data were available for 245 serous cancer cases and for 103 of the mixed histology cases (limiting mixed histologies to those tumors that included a serous component), for a total of 348 probands. These 348 serous/mixed serous histology cases were age, race and stage matched with endometrioid cancer cases enrolled during the same time period (controls) and the numbers and types of Lynch-related cancers in the two groups were compared. Caucasian patients were matched 2:1 (14 of the 281 matched 1:1) and African-Americans 1:1 (due to the relative paucity of African-American endometrioid patients). Demographics, clinicopathologic features and family information for the GOG-210 cases and controls are presented in Supplemental Table 2. The median family size was 7 for both cases and controls and there was no difference in the sex ratio of relatives of the cases and controls.

A total of 317 Lynch-related cancers were reported in the 313 relatives of the 2 groups. Among the serous cases, there were 47 reported colorectal cancers, 17 uterine, 15 pancreatic, 12 ovarian, 10 stomach, and 10 brain cancers. The reported cancers in relatives of the controls included 90 colorectal, 39 uterine, 11 pancreatic, 14 ovarian, and 20 stomach, and 8 brain cancers (Table 4). When the number of reported Lynch-related cancers among at-risk family members were compared for the serous cancer probands (cases) and matched endometrioid probands (controls) there was no difference in the number of Lynch associated cancers in relatives (OR 1.08, 95% CI= 0.85 – 1.38; P=0.50). There were fewer endometrial and colon cancers reported in relatives of the serous cancer probands than endometrioid cancer probands (OR 0.75, 95% CI 0.40–1.43 and 0.91, 95% CI 0.64–1.31, respectively) but the differences were not statistically significant. Ovarian and pancreatic cancers on the other hand were more common in the relatives of the serous cancer probands than endometrioid cancer probands. The excess of ovarian cancers was not statistically significant (OR 1.49, 95% CI 0.67 – 3.33). Pancreatic cancers were, however, significantly over-represented in the relatives of the serous cancer probands with an odds ratio of 2.39 (95% CI 1.06 – 5.38, P=0.03) (Table 4).

Table 4
Lynch-associated cancers reported in first-degree relatives of the GOG-210 study population.

Mismatch repair status of the probands’ endometrial cancers

Tumor and matched normal DNA was available for 26 of the 29 probands from the Washington University cohort along with formalin-fixed tumor specimens for 18 (62%). None of the tumors had DNA mismatch abnormalities based on MSI testing and/or IHC (MLH1, MSH2 and MSH6). All 26 tumors investigated were MSI stable and 18 of 18 tumor evaluated expressed all three MMR proteins. Representative MSI and IHC analyses are presented in Supplemental Figure 2.

Tumor tissues from 9 serous cancer and 3 mixed serous/other histologic type tumors from probands in the GOG-210 study who reported pancreatic or both colon and pancreatic cancers in first-degree relatives were also assessed for DMMR abnormalities by IHC. All 12 serous or serous mixed histology cancers expressed MLH1, MSH2 and MSH6. IHC was also performed for 8 of the endometrioid endometrial cancer probands who reported either pancreatic (4) or pancreatic and colon (3) or pancreatic and endometrial (1) cancers in first-degree relatives. All tumors expressed all 3 MMR proteins (five tested for MSI and were negative). The pedigrees MSI and IHC results for the GOG-210 probands from the case-control study results are provided in Supplemental Figure 3.

DISCUSSION

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 (3436), 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 (3942), 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, 4547). The early onset breast cancer in the daughter of proband 1972, her father’s pancreatic cancer, along with the hematopoietic neoplasms in her siblings (Fig 1B) 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 (3942, 48).

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, 50) 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.

Supplementary Material

3

Supplemental Figure 1:

Three-generation pedigrees for 24 additional serous cancer patients treated at Washington University School of Medicine in the period 2005–2008.

MSS: tumor microsatellite stable.

IHC: immunohistochemical assessment for MLH1, MSH2 and MSH6 expression.

+++: MLH1, MSH2 and MSH6 expressed

nd: no data/not done.

4

Supplemental Figure 2:

Representative IHC for serous and mixed serous tumors from probands. Three cancers showing IHC-positivity for MLH1, MSH2 and MSH6.

5

Supplemental Figure 3:

GOG-210 endometrial cancer families reporting pancreatic and other Lynch-associated malignancies. Microsatellite instability testing and IHC results reported for probands tumors.

MSS: tumor microsatellite stable.

IHC: immunohistochemical assessment for MLH1, MSH2 and MSH6 expression.

+++: MLH1, MSH2 and MSH6 expressed

nd: no data/not done.

Acknowledgments

We want to thank Patricia Werner for her help in preparing this manuscript. We also want to thank all of the patients for their participation in this research. The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: Roswell Park Cancer Institute, University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, Northwestern Memorial Hospital, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group P.C., University of California at Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Rush-Presbyterian-St. Luke’s Medical Center, Magee Women’s Hospital, University of New Mexico, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Women’s Cancer Center, University of Oklahoma, University of Virginia Health Sciences Center, University of Chicago, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Yale University, University of Wisconsin Hospital, Women and Infants Hospital, The Hospital of Central Connecticut, GYN Oncology of West Michigan, PLLC, Aurora Women’s Pavilion of West Allis Memorial Hospital, University of California, San Francisco-Mt. Zion and Community Clinical Oncology Program.

GRANT SUPPORT

This study was supported by a National Cancer Institute P50 SPORE award (CA134254), grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517), the GOG Cooperative Group (U10CA027469) and RO1 funding to PJG (CA071754).

Footnotes

Potential Conflict of Interest: None

References

1. Moore KN, Fader AN. Uterine papillary serous carcinoma. Clin Obstet Gynecol. 2011;54:278–91. [PubMed]
2. Ueda SM, Kapp DS, Cheung MK, Shin JY, Osann K, Husain A, et al. Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths. Am J Obstet Gynecol. 2008;198:218, e1–6. [PubMed]
3. Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer. 2006;94:642–6. [PMC free article] [PubMed]
4. Fader AN, Boruta D, Olawaiye AB, Gehrig PA. Uterine papillary serous carcinoma: epidemiology, pathogenesis and management. Curr Opin Obstet Gynecol. 2010;22:21–9. [PubMed]
5. Maxwell GL, Tian C, Risinger J, Brown CL, Rose GS, Thigpen JT, et al. Racial disparity in survival among patients with advanced/recurrent endometrial adenocarcinoma: a Gynecologic Oncology Group study. Cancer. 2006;107:2197–205. [PubMed]
6. McCullough ML, Patel AV, Patel R, Rodriguez C, Feigelson HS, Bandera EV, et al. Body mass and endometrial cancer risk by hormone replacement therapy and cancer subtype. Cancer Epidemiol Biomarkers Prev. 2008;17:73–9. [PubMed]
7. Matthews RP, Hutchinson-Colas J, Maiman M, Fruchter RG, Gates EJ, Gibbon D, et al. Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women. Gynecol Oncol. 1997;65:206–12. [PubMed]
8. Mendivil A, Schuler KM, Gehrig PA. Non-endometrioid adenocarcinoma of the uterine corpus: a review of selected histological subtypes. Cancer Control. 2009;16:46–52. [PubMed]
9. Bjorge T, Engeland A, Tretli S, Weiderpass E. Body size in relation to cancer of the uterine corpus in 1 million Norwegian women. Int J Cancer. 2007;120:378–83. [PubMed]
10. Fader AN, Starks D, Gehrig PA, Secord AA, Frasure HE, O’Malley DM, et al. An updated clinicopathologic study of early-stage uterine papillary serous carcinoma (UPSC) Gynecol Oncol. 2009;115:244–8. [PubMed]
11. Villella JA, Cohen S, Smith DH, Hibshoosh H, Hershman D. HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer. 2006;16:1897–902. [PubMed]
12. Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ, et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005;11:6422–30. [PubMed]
13. Zheng W, Cao P, Zheng M, Kramer EE, Godwin TA. p53 overexpression and bcl-2 persistence in endometrial carcinoma: comparison of papillary serous and endometrioid subtypes. Gynecol Oncol. 1996;61:167–74. [PubMed]
14. Odicino FE, Bignotti E, Rossi E, Pasinetti B, Tassi RA, Donzelli C, et al. HER-2/neu overexpression and amplification in uterine serous papillary carcinoma: comparative analysis of immunohistochemistry, real-time reverse transcription-polymerase chain reaction, and fluorescence in situ hybridization. Int J Gynecol Cancer. 2008;18:14–21. [PubMed]
15. Dedes KJ, Wetterskog D, Ashworth A, Kaye SB, Reis-Filho JS. Emerging therapeutic targets in endometrial cancer. Nat Rev Clin Oncol. 2011;8:261–71. [PubMed]
16. Biron-Shental T, Drucker L, Altaras M, Bernheim J, Fishman A. High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol. 2006;32:1097–100. [PubMed]
17. Slomovitz BM, Burke TW, Eifel PJ, Ramondetta LM, Silva EG, Jhingran A, et al. Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases. Gynecol Oncol. 2003;91:463–9. [PubMed]
18. Geisler JP, Sorosky JI, Duong HL, Buekers TE, Geisler MJ, Sood AK, et al. Papillary serous carcinoma of the uterus: increased risk of subsequent or concurrent development of breast carcinoma. Gynecol Oncol. 2001;83:501–3. [PubMed]
19. Gehrig PA, Bae-Jump VL, Boggess JF, Groben PA, Fowler WC, Jr, Van Le L. Association between uterine serous carcinoma and breast cancer. Gynecol Oncol. 2004;94:208–11. [PubMed]
20. Chan JK, Manuel MR, Cheung MK, Osann K, Husain A, Teng NN, et al. Breast cancer followed by corpus cancer: is there a higher risk for aggressive histologic subtypes? Gynecol Oncol. 2006;102:508–12. [PubMed]
21. Goshen R, Chu W, Elit L, Pal T, Hakimi J, Ackerman I, et al. Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol. 2000;79:477–81. [PubMed]
22. Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P, et al. The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol. 2007;104:7–10. [PubMed]
23. Meyer LA, Broaddus RR, Lu KH. Endometrial cancer and Lynch syndrome: clinical and pathologic considerations. Cancer Control. 2009;16:14–22. [PMC free article] [PubMed]
24. Ivanovich JL, Babb SA, Goodfellow PJ, Mutch DG, Herzog TJ, JSR Evaluation of the family history collection process and the accuracy of cancer reporting among a cohort of women with endometrial cancer. Clin Cancer Res. 2002;8:1849–56. [PubMed]
25. Lu KH. Hereditary gynecologic cancers: differential diagnosis, surveillance, management and surgical prophylaxis. Fam Cancer. 2008;7:53–8. [PubMed]
26. SEER 17 Database. Surveillance epidemiology and End Results (SEER) Program Limited-Use Data (1973–2004) Released April 2009, based on the November 2008 submission.
27. SEER Surveillance Research Program. National Cancer Institute SEER*Stat software V.6.5.2. Released April 2007, based on the November 2006 submission.
28. Sahai H, Khurshid A. Confidence intervals for the mean of a poisson distribution: a review. Biometrical Journal. 1993;35:857–67.
29. Sahai H, Khurshid A. Statistics in epidemiology: methods, techniques and applications. Boca Raton, FL: CRC Press, Inc; 1996. pp. 172–3.
30. Rothman Greenland. Modern Epidemiology. 2. 1998. p. 242.
31. Efron B, Tibshirani R. In: An introduction to bootstrap. Hall Ca., editor. London: Chapman and Hall; 1993. pp. 153–4.
32. Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2006;66:7810–7. [PubMed]
33. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85. [PMC free article] [PubMed]
34. Sandles LG, Shulman LP, Elias S, Photopulos GJ, Smiley LM, Posten WM, et al. Endometrial adenocarcinoma: genetic analysis suggesting heritable site-specific uterine cancer. Gynecologic Oncology. 1992;47:167–71. [PubMed]
35. Lorenzo Bermejo J, Buchner FL, Hemminki K. Familial risk of endometrial cancer after exclusion of families that fulfilled Amsterdam, Japanese or Bethesda criteria for HNPCC. Ann Oncol. 2004;15:598–604. [PubMed]
36. Ollikainen M, Abdel-Rahman WM, Moisio AL, Lindroos A, Kariola R, Jarvela I, et al. Molecular analysis of familial endometrial carcinoma: a manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome? J Clin Oncol. 2005;23:4609–16. [PubMed]
37. Duffy DL, Antill YC, Stewart CJ, Young JP, Spurdle AB. Report of endometrial cancer in Australian BRCA1 and BRCA2 mutation-positive families. Twin Res Hum Genet. 2011;14:111–8. [PubMed]
38. Hemminki K, Li X. Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. Int J Cancer. 2003;103:525–30. [PubMed]
39. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999;91:1310–6. [PubMed]
40. Stadler ZK, Salo-Mullen E, Patil SM, Pietanza MC, Vijai J, Saloustros E, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer. 2011 [Epub ahead of print] [PubMed]
41. Kim DH, Crawford B, Ziegler J, Beattie MS. Prevalence and characteristics of pancreatic cancer in families with BRCA1 and BRCA2 mutations. Fam Cancer. 2009;8:153–8. [PMC free article] [PubMed]
42. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–15. [PubMed]
43. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324(5924):217. [PMC free article] [PubMed]
44. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;333:975–7. [PubMed]
45. Bruchim I, Amichay K, Kidron D, Attias Z, Biron-Shental T, Drucker L, et al. BRCA1/2 germline mutations in Jewish patients with uterine serous carcinoma. Int J Gynecol Cancer. 2010;20:1148–53. [PubMed]
46. Barak F, Milgrom R, Laitman Y, Gemer O, Rabinovich A, Piura B, et al. The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients. Gynecol Oncol. 2010;119:511–5. [PubMed]
47. Lavie O, Hornreich G, Ben Arie A, Renbaum P, Levy-Lahad E, Beller U. BRCA1 germline mutations in women with uterine serous papillary carcinoma. Obstet Gynecol. 2000;96:28–32. [PubMed]
48. Ghiorzo P, Pensotti V, Fornarini G, Sciallero S, Battistuzzi L, Belli F, et al. Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy. Fam Cancer. 2011 [Epub ahead of print] [PubMed]
49. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34. [PubMed]
50. Ellisen LW. PARP inhibitors in cancer therapy: promise, progress, and puzzles. Cancer Cell. 2011;19:165–7. [PMC free article] [PubMed]