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

Published OnlineFirst January 13, 2012; DOI: 10.1158/1940-6207.CAPR-11-0499

Cancer Prevention Research Article Research

Summer B. Dewdney1, Nora T. Kizer1, Abegail A. Andaya5, Sheri A. Babb1, Jingqin Luo4, David G. Mutch1, Amy P. Schmidt2, Louise A. Brinton5, Russell R. Broaddus6, Nilsa C. Ramirez7, Phyllis C. Huettner3, Donald Scott McMeekin9, Kathleen Darcy10, Shamshad Ali10, Patricia L. Judson12, Robert S. Mannel9, Shashikant B. Lele11, David M. O'Malley8, and Paul J. Goodfellow1,2

Abstract Serous uterine cancer is not a feature of any known hereditary cancer syndrome. This study evaluated familial risk of cancers for patients with serous uterine carcinoma, focusing on Lynch syndrome malignancies. 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 (MMR) abnormalities. Standardized incidence ratios for cancers in relatives were estimated. A second-stage analysis was undertaken using data from Gynecologic Oncology Group (GOG)-210. Incidence data for cancers reported in relatives of 348 patients with serous and mixed epithelial and 624 patients with endometrioid carcinoma were compared. Nineteen of 29 (65.5%) patients in the single-institution series reported a Lynch-related cancer in relatives. Endometrial and ovarian cancers were significantly overrepresented and a high number of probands (6 of 29, 20.7%) reported pancreatic cancers. None of the probands’ tumors had DNA MMR 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 patients with serous cancer [OR, 2.39; 95% confidence interval (CI), 1.06– 5.38]. We identified an excess of endometrial, ovarian, and pancreatic cancers in relatives of patients with serous cancer in a single-institution study. Follow-up studies suggest that only pancreatic cancers are overrepresented in relatives. DNA MMR 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. Cancer Prev Res; 5(3); 435–43. 2012 AACR.

Introduction increased risk for occult metastases in early-stage disease Uterine serous carcinoma is an uncommon form of compared with the more common histologic type, endo- endometrial cancer, comprising less than 10% of uterine metrioid endometrial carcinoma (2–4). UPSC is more epithelial cancers. Patients can present with pure uterine common among African-Americans than Caucasians, non- papillary serous carcinoma (UPSC) or with mixed UPSC/ obese rather than obese women, and affects primarily other histology tumors. Despite its rarity, UPSC accounts for postmenopausal women, whereas endometrial cancers a disproportionate number of endometrial cancer deaths have an increased incidence among perimenopausal (estimated at 40%; ref. 1). women (5–9). Unlike endometrioid endometrial cancer, The poor outcomes for patients diagnosed with UPSC are UPSC is not associated with an excess estrogen state and attributable, in part, to a later stage at diagnosis and an not surprisingly is associated with different molecular

Authors' Afﬁliations: Departments of 1Obstetrics and Gynecology, 2Sur- Note: Supplementary data for this article are available at Cancer Prevention gery,and 3Pathologyand Immunology, 4DivisionofBiostatistics,Washington Research Online (http://cancerprevres.aacrjournals.org/). University School of Medicine, St. Louis, Missouri; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute (NIH), Rockville, Mary- Current address for P.L. Judson: Mofﬁtt Cancer Center, Tampa, FL. land; 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 7Department of Pathology and Laboratory Medicine, The Research Institute at Nationwide Children's Hospital; 8Depart- Corresponding Author: Paul J. Goodfellow, Department of Surgery, ment of Obstetrics and Gynecology, Ohio State University and the James Washington University School of Medicine, 660 South Euclid, Box 8109, CancerCenter,Columbus,Ohio; 9DepartmentofObstetrics andGynecology, St. Louis, MO 63110. Phone: 1-314-362-2032; Fax: 314-362-8620; E-mail: University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; [email protected] 10Gynecologic Oncology Group Statistical and Data Center, 11Department of Gynecology, Roswell Park Cancer Institute, Buffalo, New York; and 12Depart- doi: 10.1158/1940-6207.CAPR-11-0499 ment of Obstetrics, Gynecology and Women's Health, University of Minne- sota School of Medicine, Minneapolis, Minnesota 2012 American Association for Cancer Research.

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abnormalities than the more common endometrioid ade- and history of cancer (including site, age at diagnosis, and nocarcinoma (10–15). city or hospital where treated). Medical record verification Serous-type uterine cancers are not a recognized feature of was sought. As standard practice, the genetic counselor any currently defined hereditary cancer syndromes. Several requested the proband contact the identified relative, or if studies have suggested an association between serous uter- deceased, the closest living family member, to obtain per- ine cancer and breast cancer. Most studies assessing the link mission to release their medical records. Medical records between breast cancer and UPSC, however, have been and/or death certificates were requested for confirmation of focused on the proband and there have been no large-scale, the cancer diagnosis. All records were reviewed indepen- in-depth family studies published to date. Although uterine dently by 2 gynecologic oncology fellows (N.T. Kizer cancer has been implicated in the hereditary breast and and S.B. Dewdney) and a cancer research investigator ovarian syndrome (16–22), an association between serous (P.J. Goodfellow). endometrial cancer and hereditary breast/ovarian syndrome has not been established. Microsatellite instability testing Endometrial carcinoma may be the most common cancer Using the National Cancer Institute recommended in women with Lynch syndrome attributable to germline microsatellite instability (MSI) markers (BAT25, BAT26, mutations in one of several DNA mismatch repair (MMR) D71S250, D2S125, and D5S346), both tumor and normal genes. Patients with Lynch syndrome have a dramatically DNA samples for each patient were analyzed for allelic shift increased risk for colon and endometrial and a significantly using a multiplex fluorescence-based PCR assay. Amplified increased risk for a number of other malignancies. The PCR products were then analyzed using capillary electro- majority of patients with Lynch syndrome with uterine phoresis on an ABI 3130 Genetic Analyzer (Applied Bio- cancers have endometrioid endometrial cancers, although systems), using the GeneMapper Analysis software provid- non-endometrioid histologies have been described for a ed by the manufacturer (Applied Biosystems). Tumors small number of patients with Lynch syndrome (23). showing allelic shift at 2 or more markers were considered The aim of this study was to evaluate familial risk for MSI-high; tumors showing allelic shift at only one marker Lynch-associated cancers in patients diagnosed with serous were classified as MSI-low; and tumors with no allelic shift uterine cancer and to assess DNA MMR status in the tumors were classified as microsatellite stable (MSS). of probands from family members affected with Lynch- associated malignancies. Immunohistochemical staining Immunohistochemistry (IHC) for the MMR gene products MLH1 (G168-15, 1:30; Pharmingen), MSH2 (FE11, Materials and Methods 1:100; Oncogene Science), and MSH6 [G70220 (GenBank), Description of participants 1:100; Transduction Laboratories) was conducted using We prospectively acquired tumor samples from hyster- formalin-fixed, paraffin-embedded sections as previously ectomy specimens of patients being treated for suspected described (25). Tumors were categorized as positive or uterine cancer by the Division of Gynecologic Oncology at negative for MHL1, MSH2, and MSH6 expression (R.R. Washington University Medical Center (St. Louis, MO). All Broaddus). participants consented to molecular analysis and follow-up as part of the Washington University Medical Center Gynecologic Oncology Group methods Human Research Protection Office–approved protocol We sought to validate the findings of our institutional (93-0828). Fifty cases of uterine serous or mixed serous cohort through the analysis of family history data for carcinomas were accrued to this protocol from January patients with serous cancer enrolled in the Gynecologic 2005 to December 2008. Participants consented to family Oncology Group-210 protocol (GOG-210). Briefly, this history and tumor studies as part of the approved protocol. protocol is an ongoing collection of tissue samples for This series was unselected for family history information, molecular and clinicopathologic analysis of endometrial age at diagnosis, or clinical features suggestive of an inher- cancer. The patients who participated in both the Washing- ited susceptibility to cancer. ton University study and GOG-210 were cross-referenced Probands were contacted and asked to participate in our and excluded from the GOG cohort, hence only to be study to obtain detailed family history data. Family history included in the Washington University cohort for the pur- data were obtained at 2 different times. First, as part of their poses of this study. routine clinical care, participants completed a medical The GOG-210 questionnaire contains a section inquir- history questionnaire that included a single question about ing about family history, which is completed by partici- the health of first-degree relatives. These data, as well as pants. The family history questionnaire section asked information documented in the initial medical encounter, only about first-degree relatives; number of relatives (liv- comprised the screening family history (24). A genetic ing and deceased), which relative(s) has a diagnosis of counselor (S.A. Babb) later obtained a detailed, 3-genera- cancer, age of diagnosis, and type of cancer. We obtained tional pedigree from each proband, either face-to-face or these data and identified patients with first-degree rela- over the telephone. The following data were obtained for all tives with cancer. Once a family was identified, a pedigree individuals in the pedigree: current age or age of death was created from the information provided on the

436 Cancer Prev Res; 5(3) March 2012 Cancer Prevention Research

Uterine Serous Cancer and Familial Risk for Other Malignancies

questionnaire. We analyzed both mixed (serous compo- Results nent) epithelial and pure serous histologic subtypes. The Cancer family histories for uterine serous cancer available data set included 245 pure serous histologies patients and 103 mixed (serous component) epithelial histolo- Washington University cohort. Fifty women with serous gies. After an initial analysis of the GOG serous histology endometrial cancers (N ¼ 21) or mixed serous histology cases, we attempted to confirm our findings by comparing tumors (N ¼ 29) consented to our ongoing molecular and the GOG serous group with a matched endometrioid family studies in the period from January 1, 2005, to histology group. We obtained data from women with December 31, 2008. Patient charts included cancer family endometrioid histology tumors matched with the serous histories for 44 (88%) of the women. Among those 44 N ¼ cases based on age, race, and stage ( 624). These data probands, 10 (23%) reported a Lynch-related tumor in one were collected from 2003 to 2008. or more first-degree relative(s). Detailed family histories were developed for 29 subjects Statistical analysis (58%). Among the 21 women for whom family histories Standardized incidence ratios (SIR) were estimated for were not obtained, 14 patients were deceased or in hospice the retrospective Washington University School of Medi- at the time of the contact, 5 women declined to participate, cine cohort study focusing on first- and second-degree and 2 failed to respond to written and phone requests to relatives. Probands were removed from the analyses for participate in the family history studies. conservative cancer risk estimation. Lynch-related cancers The demographic and clinicopathologic characteristics were defined as colon, pancreas, ovary, endometrial, gastric, of the 29 probands are presented in Table 1. Fourteen of brain, upper urologic tract, and hepatobiliary cancers. The 29 patients had pure serous tumors and 15 had mixed crude incidence rates of Lynch-related cancers overall and, epithelial histology tumors (serous plus other). Nineteen for each type separately, were calculated as the total number patients were Caucasian (67%) and 5 were African-Amer- of cases per unit of person-years at-risk per 100,000 people. ican (17%). Nearly half (14 of 29) presented with stage III or The person-year at-risk was defined as from birth to the IV disease at a median age of 67 years (range, 58–91 years). earliest cancer diagnosis or death or the date of ascertain- Similar data for the 21 probands for whom family histories ment during the lifetime exposure of individuals in the 29 were not obtained are presented in Supplementary Table S1. kindreds. Age was divided into nineteen 5-year intervals Cancer family history data included information for 769 following the Surveillance, Epidemiology, and End Results first- and second-degree relatives with a median family size of (SEER) database age categories, and the SEER’s age group– 24 (range, 10–52) and a gender ratio of 1:1.05 (male:female). specific incidence rates were obtained using the SEER 17 Thirteen of the 29 probands reported one or more Lynch- regions 2000–2006 limited-use database (26) with adjust- related cancer in a first-degree relative. Of note, only 8 of ment for impact of Katrina by the SEER Stat software (27). those women had indicated that a relative had a Lynch- The SIRs of each cancer were calculated as the ratio of the related cancer as part of the clinical family history screening total number of observed cases in our data to the expected intake. Of the 23 Lynch-related cancers in first-degree rela- number of cases on the basis of the age group–specific tives, 8 were confirmed by medical records (3 colon, 1 serous 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 Table 1. Clinical and demographic the exact confidence intervals (CI) on the basis of Poisson characteristics of 29 probands distribution (28, 29) and the 95% CI on the basis of Boice– Monson method (30) and bootstrap 95% percentile CIs N through 1,000 bootstrap sampling (31). The 2-sided P Characteristics (%) 2 values for the SIRs were calculated on the basis of c tests. Histologies To further identify any possible increased risk for cancers Mixed 15 (51.7) in the relatives of patients with serous uterine cancer, we Pure 14 (48.3) matched each serous family by approximately 2 endome- Stage trial families of endometrioid histology in terms of age, race, I 12 (41.5) and stage to conduct a case–control study. We compared II 3 (10.3) 348 serous families and 624 endometrioid families (Afri- III 11 (37.9) can-American matched 1:1 because of paucity of African- IV 3 (10.3) American endometrioid cases). Race Given that the data were clustered in the family level and Caucasian 19 (65.7) the matching case–control level, we analyzed the clustered African-American 5 (17.2) data using a generalized estimating equation method. Var- Hispanic 1 (3.4) ious correlation structures were assessed and compared, all Native American 1 (3.4) with similar results. ORs, accompanied with 95% CIs and P Unknown 3 (10.3) values on the Lynch-related cancer and each individual Age, y, median (range) 67 (58–91) cancer type of interest were estimated.

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Table 2. Characteristics and Lynch-related tion cohort. The data on cancers in relatives of the GOG-210 study population were reported by probands (no medical cancers reported in first- and second-degree record verification and uncertain involvement of family relatives members other than the proband in developing family histories) and were limited to first-degree relatives. Given Characteristics N that birth years and current ages of cancer-free children and Median family size (range) 24 (10–52) siblings were not collected, it was not possible to estimate Gender SIRs for Lynch-related cancers. Male 375 During the initial phase of GOG-210 accrual (September Female 392 22, 2003, to September 24, 2007), 3,738 patients were Unknown 2 enrolled in the study. Among those, 317 cases had serous First-degree relatives 222 endometrial cancers and 240 had mixed histology epithelial Second-degree relatives 547 cancers on the basis of the pathology reports provided by Lynch-related cancer 36 the individual GOG participating centers. Family cancer Colon 12 history data were available for 245 serous cancer cases and Uterine 7 for 103 of the mixed histology cases (limiting mixed his- Ovarian 4 tologies to those tumors that included a serous compo- Gastric 2 nent), for a total of 348 probands. These 348 serous/mixed Transitional cell/other 5 serous histology cases were age, race, and stage matched Pancreatic 6 with endometrioid cancer cases enrolled during the same Median age of diagnosis (range) 65 (43–92) time period (controls) and the numbers and types of Lynch- related cancers in the 2 groups were compared. Caucasian patients were matched 2:1 (14 of the 281 matched 1:1) and endometrial, 2 pancreatic, and 2 transitional cell cancers). African-Americans 1:1 (due to the relative paucity of Afri- Thirteen additional Lynch cancers were reported in second- can-American patients with endometrioid). Demographics, degree relatives of 8 probands (medical record verification clinicopathologic features and family information for the for only 3 tumors, 1 colon, 1 hepatobiliary cancer, and 1 GOG-210 cases and controls are presented in Supplemen- glioblastoma). The numbers and types of Lynch-related tary Table S2. The median family size was 7 for both cases cancers in relatives are presented in Table 2. Median age of and controls and there was no difference in the sex ratio of diagnosis of Lynch-related cancers was 65 years (ranging relatives of the cases and controls. from 43 to 92 years). Several probands had family histories A total of 317 Lynch-related cancers were reported in the suggestive of Lynch syndrome and, notably, 4 probands 313 relatives of the 2 groups. Among the serous cases, there reported pancreatic cancers in relatives (2 families each with were 47 reported colorectal cancers, 17 uterine, 15 pancre- 2 pancreatic cancers). Representative pedigrees suggestive of atic, 12 ovarian, 10 stomach, and 10 brain cancers. The inherited cancer susceptibility are shown in Fig. 1 (all remain- reported cancers in relatives of the controls included 90 ing pedigrees are shown in Supplementary Fig. S1). colorectal, 39 uterine, 11 pancreatic, 14 ovarian, 20 stom- We used cancer incidence and SIRs to determine whether ach, and 8 brain cancers (Table 4). When the number of Lynch-related cancers were over- or underrepresented in the reported Lynch-related cancers among at-risk family mem- relatives of the 29 serous endometrial cancer probands. bers was compared for the serous cancer probands (cases) These analyses suggested an excess of Lynch-related cancers and matched endometrioid probands (controls), there was overall, with overrepresentation of endometrial, ovarian, no difference in the number of Lynch-associated cancers in and pancreatic cancer and fewer than expected colon can- relatives (OR, 1.08; 95% CI, 0.85–1.38; P ¼ 0.50). There cers (Table 3). Seven endometrial cancers were reported (2.6 were fewer endometrial and colon cancers reported in expected) for an SIR of 2.69 (95% CI, 1.28–5.65; P ¼ 0.006) relatives of the serous cancer probands than endometrioid and 4 ovarian cancers were reported (1.5 expected) for an cancer probands (OR, 0.75; 95% CI, 0.40–1.43; and OR, SIR of 2.68 (95% CI, 1.01–7.14; P ¼ 0.04). The 1.40 SIR for 0.91; 95% CI, 0.64–1.31, respectively) but the differences pancreatic and 0.65 SIR for colon cancers were not statis- were not statistically significant. Ovarian and pancreatic tically significant (P ¼ 0.40 and 0.13, respectively). cancers on the other hand were more common in the relatives of the serous cancer probands than endometrioid Follow-up studies: a case–control study of 972 cancer probands. The excess of ovarian cancers was not endometrial cancer patients enrolled in the GOG-210 statistically significant (OR, 1.49; 95% CI, 0.67–3.33). protocol Pancreatic cancers were, however, significantly overrepre- We evaluated the cancer family histories for 972 patients sented in the relatives of the serous cancer probands with an with endometrial cancer enrolled in the GOG-210 study in OR of 2.39 (95% CI, 1.06–5.38; P ¼ 0.03; Table 4). an effort to determine whether the excess of Lynch-related cancers seen in the Washington University School of Med- MMR status of the probands’ endometrial cancers icine endometrial cancer cohort was also seen in patients Tumor and matched normal DNA was available for 26 of with serous cancer that are part of the large, multi-institu- the 29 probands from the Washington University cohort

438 Cancer Prev Res; 5(3) March 2012 Cancer Prevention Research

A 2401 2324 Caucasian Caucasian

Prostate Kidney Liver 70s 64 59 cancerpreventionresearch.aacrjournals.org Published OnlineFirstJanuary13,2012;DOI:10.1158/1940-6207.CAPR-11-0499 3 7 4 Uterine / colon / kidney Colon 43 / 50s / 70 50

MSS MSS 2 2 2 2 Breast / Endometrial IHC +++ Endometrial Colon IHC +++ endometrial 69 66 50s Type unknown 63 / 75 ~50

2 Jaw / tongue 66 2305 Caucasian Cancer Research.

Breast 76

MSS Key 2 Endometrial colon Squamous / colon IHC nd 67 62 5 other skin 45 on September 27, 2021. © 2012American Association for 72 Male, female Malignancies Other for Risk Familial and Cancer Serous Uterine Deceased 4 3 2 2 3 2 Unconfirmed cancer

Confirmed cancer B 2025 1972 African American Caucasian

Throat 64 acrPe e;53 ac 2012 March 5(3) Res; Prev Cancer

Pancreatic Pancreatic Type Pancreatic Breast Lung Lung Lung 74 70 unknown 77 61 81 86 72 60s

Myelo- MSS MSS Endometrial / Lymphoma 3 2 2 2 IHC +++ pituitary 61 dysplasia 3 5 2 3 2 2 IHC nd 72 Endometrial Lung Pancreatic adenoma Brain Ovarian Lung Pancreatic 66 71 late 50s 76 / 71 65 65 65 67

2 2 Breast Bladder Cervical 49 54 45

Figure 1. Representative 3-generation pedigrees for serous cancer probands suggestive of inherited cancer susceptibility. A, Lynch syndrome–like families. B. pancreatic cancer–prone families. þþþ, MLH1, MSH2, and MSH6 expressed; IHC, immunohistochemical assessment for MLH1, MSH2, and MSH6 expression; MSS, tumor microsatellite stable; nd, no data/not done. 439 Published OnlineFirst January 13, 2012; DOI: 10.1158/1940-6207.CAPR-11-0499

Dewdney et al.

Table 3. Incidence and SIRs of cancers

Crude incidence ratea No. of per 100,000 people Expected Tumor site cases (95% CI) cases SIR (95% CI)a,b Pc

Lynch-related cancer 36 83.84 (59.10–111.44) 30.10 1.20 (86–1.66) 0.28 Colon 12 27.88 (13.70–44.96) 18.48 0.65 (0.37–1.14) 0.13 Pancreatic 6 13.90 (4.57–25.72) 4.29 1.40 (0.63–3.11) 0.40 Endometrial 7 31.08 (9.28–54.81) 2.60 2.69 (1.28–5.65) <0.01 Ovarian 4 17.7 (4.29–38.09) 1.49 2.68 (1.01–7.14) 0.04

aCalculated for lifetime exposure. bSIR Boice–Monson 95% CI. cCompared with SEER population.

along with formalin-fixed tumor specimens for 18 (62%) Discussion probands. None of the tumors had DNA mismatch abnor- We identified a significant excess of ovarian and endo- malities based on MSI testing and/or IHC (MLH1, MSH2, metrial cancers in relatives of patients with endometrial and MSH6). All 26 tumors investigated were MSS and 18 of cancer with pure serous and mixed serous tumors based on 18 tumors evaluated expressed all 3 MMR proteins. Repre- detailed 3-generation family history data and medical sentative MSI and immunohistochemical analyses are pre- record confirmation of malignancies in a single-institution sented in Supplementary Fig. S2. cohort. Pancreatic cancers were also overrepresented in Tumor tissues from 9 serous cancer and 3 mixed relatives, but the observed excess was not statistically sig- serous/other histologic type tumors from probands in nificant. The excess of Lynch syndrome–related malignan- theGOG-210studywhoreportedpancreaticorboth cies in relatives was unexpected given that serous endome- colon and pancreatic cancers in first-degree relatives were trial cancers are uncommon in Lynch syndrome (carriers of also assessed for DMMR abnormalities by IHC. All 12 MSH2, MSH6, MLH1,orPMS2 mutations; ref. 32). Early- serous or mixed serous histology cancers expressed onset serous uterine cancers have, however, been reported MLH1, MSH2, and MSH6. IHC was also conducted for in MSH2 mutation carriers (23). The absences of tumor MSI 8 of the endometrioid endometrial cancer probands who and normal immunohistochemical findings make Lynch reported pancreatic (4) or pancreatic and colon (3) or syndrome very unlikely, as does the late age of onset of pancreatic and endometrial (1) cancers in first-degree uterine cancer in the probands studied. Only family 2401 relatives. All tumors expressed all 3 MMR proteins (5 had clinical testing for Lynch syndrome mutations (MSH2, tested for MSI and were negative). The pedigrees MSI and MLH1, and MSH6) and no abnormality was identified. immunohistochemical results for the GOG-210 probands Regardless, the SIRs for uterine and ovarian cancers esti- from the case–control study results are provided in Sup- mated for the 29 families from our institution suggest plementary Fig. S3. genetic risk for these cancers.

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

No. of cancers in relatives (men/women)

Tumor type Case (serous) Controls (endometrioid) OR (95% CI) P

All Lynch-related cancers 123 194 1.08 (0.85–1.38) 0.50 Colorectal 47 (20/27) 90 (41/49) 0.91 (0.63–1.31) 0.62 Endometrial 17 (0/17) 39 (0/39) 0.75 (0.40–1.43) 0.39 Pancreatic 15 (8/7) 11 (7/4) 2.39 (1.06–5.38) 0.03 Ovarian 12 (0/12) 14 (0/14) 1.49 (0.67–3.33) 0.33 Other 32 40 nd nd

NOTE: Numbers of Lynch-related cancers by category in serous and endometrioid are provided. ORs and an estimating equation (GEE) analysis. Abbreviation: nd, not determined.

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Uterine Serous Cancer and Familial Risk for Other Malignancies

The 2.69 SIR for endometrial cancer (95% CI, 1.28–5.65) that there would be shared risk factors for endometrioid and is considerably lower than the 4.1 SIR (95% CI, 2.9–5.6) serous/mixed serous endometrial cancers. The fact that both reported by Lindor and colleagues (33) for Amsterdam I histologic subtypes are present in a substantial fraction of all criteria, MMR gene mutation–positive Lynch families. The endometrial cancers speaks to the possibility of a common SIR for ovarian cancer in our study (2.68; 95% CI, 1.01– etiology. 7.14) is higher than for Lynch families (2.0; 95% CI, 1.3– Pancreatic cancers were reported more often in the rela- 3.2; ref. 33). The SIRs estimates for our study and Lindor and tives of the serous cancer cases from the GOG-210 popu- colleagues (33), however, have overlapping CIs and overall lation than for endometrioid controls’ families, consistent the SIRs are very similar. It is noteworthy that we did not with a shared risk for pancreatic and serous-type uterine observe an excess of colon cancer (SIR, 0.65; 95% CI, 0.37– cancer. A Swedish Family-Cancer Database study of 21,000 1.14) characteristic of Lynch syndrome. Lynch-related pancreatic cancers revealed a slight increase in the number malignancies in the families we investigated could reflect of pancreatic cancers among sons of women with endome- some as yet unidentified genetic susceptibility, shared envi- trial cancer (38). The study by Hemminki and Li (38) did ronmental risk factor, or simply chance occurrence. Site- not stratify uterine cancers by histologic subtype. In addi- specific endometrial cancer susceptibility, distinct from tion to Lynch syndrome, pancreatic cancer is associated Lynch syndrome, has been described (34–36), and it is with mutation in BRCA1 and BRAC2 (39–42), PALB2 (43), possible that some of the excess endometrial cancers and CDKN2 (44). There are conflicting reports on the role reported in these families are attributable to this sort of that inherited mutation in BRCA1 and BRCA2 play in risk genetic risk. BRCA1/2 mutation carriers may also have for serous endometrial cancers. Some studies have revealed increased risk for endometrial cancer. There is a recent frequent germ line mutations in patients with serous cancer report that endometrioid endometrial cancers may be more whereas others have not. The effects of population stratifi- common in relatives of BRCA1 carriers (37). Given the fact cation and tamoxifen therapy for breast cancer complicate that our probands had serous rather than endometrioid interpretation of findings for individual studies and for the histology cancer, it seems very unlikely that any excess of data as a whole (21, 45–47). The early-onset breast cancer in uterine cancers is due to BRCA1 mutation. the daughter of proband 1972, her father’s pancreatic The number of pancreatic cancers reported in relatives of cancer, along with the hematopoietic neoplasms in her serous endometrial cancer probands was greater than siblings (Fig. 1B) is highly suggested of a BRCA defect. expected (SIR, 1.4), but the excess was not statistically Clinical testing for BRCA1/2 mutation was not conducted significant (95% CI, 0.63–3.11; P ¼ 0.4). The SIR for in this family (only 1 family tested and was negative). pancreatic cancers in the 29 families is nonetheless similar Research testing for BRCA1/2 defects could shed light on to what was reported for Amsterdam I criteria, Lynch the role these genes play in familial risk for serous carcino- syndrome kindreds in a previous study (SIR, 1.7; 95% CI, ma of the uterus, particularly given the link between BRCA 0.7–2.8; ref. 33). Given the small number of families mutation and pancreatic cancer (39–42, 48). studied, it is not possible to exclude a small but clinically Our analysis of detailed 3-generation family histories for significant risk for pancreatic cancer in relatives of patients patients with uterine serous/mixed serous histology tumor is with serous uterine cancer. limited by the relatively small sample size. Uterine serous Our follow-up analysis of the cancer family histories for cancer is an uncommon malignancy with a poor prognosis. women enrolled in the GOG-210 study did not reveal an There is often a short interval from diagnosis to death, excess of endometrial and uterine cancers in the serous making collection of family history data even more difficult group compared with the endometrioid control group. in what is a comparatively older population. We recognize Because we did not calculate SIRs for the GOG-210 case the possibility that our study may be biased to include and control populations, it is not possible to comment on women and families who are aware of their familial risk for whether there was an excess of these cancers in first-degree cancers and motivated to enroll in a cancer research study; relatives compared with the general population. The GOG- however, eligibility for this study was simply a diagnosis of 210 family history data collected did not include the birth endometrial cancer, with serous or mixed serous histology. years or current ages of parents, siblings, and children. Finally, as in all family studies, recall bias is another limita- Estimating those would allow for a crude estimate of the tion. To confirm records, all family history was obtained incidence of Lynch-associated cancers. It is possible that directly from the proband, and subsequently validated by both the cases (serous and mixed serous histologies) and medical records when available. control group (endometrioid tumors) have increased num- The Washington University serous cancer cohort and the ber of ovarian and endometrial cancers in relatives com- GOG-210 serous cancer cases were similar overall with pared with the general population. We have previously respect to racial makeup, age, and stage at diagnosis. The reported that recall and accuracy of reporting for gyneco- Washington University cohort, however, had a higher pro- logic cancers among endometrial cancer probands is poor portion of serous mixed histologies (58%) than the cases (24). We do not believe that even a crude estimate of from the GOG-210 study (30%). This difference could incidence for ovarian and endometrial cancers in relatives reflect differences in how institutions report mixed histotype would be of value without extensive medical record verifi- uterine neoplasms, with the possibility that some serous cation. We note that in our case–control study, we believe cases with minor endometrioid or other histotype

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Dewdney et al.

components would not be described as such in the pathol- Acknowledgments ogy report (underreporting for non-serous components). The authors thank Patricia Werner for her help in preparing the manu- script, and all of the patients for their participation in this research. The Alternatively, tumors that are primarily endometrioid but following Gynecologic Oncology Group member institutions participated in with minor serous components could be described as endo- the primary treatment studies: Roswell Park Cancer Institute (Buffalo, NY), University of Alabama at Birmingham (Birmingham, AL), Duke University metrioid. Pathologic review for the GOG-210 population is Medical Center (Durham, NC), Abington Memorial Hospital (Abington, ongoing, with planned completion for all subjects enrolled PA), Walter Reed Army Medical Center (Washington, DC), Wayne State in the period from September 22, 2003, to September 24, University (Detroit, MI), University of Minnesota Medical School (Minnea- polis, MN), Northwestern Memorial Hospital (Chicago, IL), University of 2007, by January 2012. Our efforts to validate findings from Mississippi Medical Center (Jackson, MS), Colorado Gynecologic Oncology our single-institution series in the GOG-210 case–control Group P.C. (Aurora, CO), University of California at Los Angeles (Los study were complicated by the fact that we did not have a Angeles, CA), University of Washington (Seattle, WA), University of Penn- sylvania Cancer Center (Philadelphia, PA), Milton S. Hershey Medical Center cancer-free control population. As noted, without such a (Hershey, PA), University of Cincinnati (Cincinnati, OH), University of study group, it is impossible to say definitively whether North Carolina School of Medicine (Chapel Hill, NC), University of Iowa Hospitals and Clinics (Iowa City, IA), University of Texas Southwestern serous and endometrioid patients with endometrial cancer Medical Center at Dallas (Dallas, TX), Indiana University School of Medicine have increased familial risk for ovarian and endometrial (Indianapolis, IN), Wake Forest University School of Medicine (Winston cancers. The 2 groups did not differ with respect to these Salem, NC), University of California Medical Center at Irvine (Irvine, CA), Rush-Presbyterian-St. Luke’s Medical Center (Chicago, IL), Magee Women’s cancers in relatives. Pancreatic cancers were on the other Hospital (Pittsburgh, PA), University of New Mexico (Albuquerque, NM), hand more common in relatives of serous cancer cases. The Cleveland Clinic Foundation (Cleveland, OH), State University of New The excess of Lynch syndrome cancers (specifically uter- York at Stony Brook (Stony Brook, NY), Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center (New York, NY), Cooper ine, ovarian, and pancreatic) in relatives of patients with Hospital/University Medical Center (Camden, NJ), Columbus Cancer Coun- serous endometrial cancer may reflect an as yet unidentified cil (Columbus, OH), University of Massachusetts Medical School (Worces- ter, MA), Fox Chase Cancer Center (Philadelphia, PA), Women’s Cancer hereditary syndrome that includes uterine serous cancers. Center (Las Vegas, NV), University of Oklahoma (Oklahoma City, Okla- Exome or whole genome sequencing for probands could homa), University of Virginia Health Sciences Center (Charlottesville, VA), reveal mutations in candidate genes and/or pathways, some University of Chicago (Chicago, IL), Mayo Clinic (Rochester, MN), Case Western Reserve University (Cleveland, OH), Tampa Bay Cancer Consor- of which may be clinically relevant. Therapies that are tium (Tampa, FL), Yale University (New Haven, CT), University of Wisconsin tailored to key genetic abnormalities offer promise for better Hospital (Madison, WI), Women and Infants Hospital (Providence, RI), The treatments for this deadly form of uterine cancer. The recent Hospital of Central Connecticut (New Britain, CT), GYN Oncology of West Michigan (Grand Rapids, MI), PLLC (Bartow, FL), Aurora Women’s Pavilion discovery of clinical benefit for PARP inhibitors in patients of West Allis Memorial Hospital (Milwaukee, WI), University of California with germ line defects in double-strand break repair (San Diego, CA), San Francisco-Mt. Zion (San Francisco, CA), and Com- (49, 50) is but one example of gene-based advances in the munity Clinical Oncology Program (St. Louis Park, MN). treatment of malignancies. Large-scale genomic efforts to Grant Support better understand the genetic and epigenetic changes This study was supported by a National Cancer Institute P50 SPORE PJG important in uterine serous carcinoma such as the Endo- award (CA134254), grants to the Gynecologic Oncology Group (GOG) metrial Cancer TCGA project are not focused on germ line Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517), the GOG Cooperative Group factors. Family-based studies of serous cancers of the uterus (U10CA027469), and RO1 funding to P.J. Goodfellow (CA071754). are likely to yield important insights into the key genetic The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked factors involved in tumor initiation. advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Disclosure of Potential Conflicts of Interest S.B. Lele is a consultant/advisory board member for Genentech. No Received November 2, 2011; revised December 21, 2011; accepted January potential conflicts of interests were disclosed by other authors. 4, 2012; published OnlineFirst January 13, 2012.

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

Summer B. Dewdney, Nora T. Kizer, Abegail A. Andaya, et al.

Cancer Prev Res 2012;5:435-443. Published OnlineFirst January 13, 2012.

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